Endocrine Reviews 18 (2): 157-179
Copyright © 1997 by The Endocrine Society
The Somatogenic Hormones and Insulin-Like Growth Factor-1: Stimulators of Lymphopoiesis and Immune Function
Ross Clark
Endocrinology Group, Genentech, Inc., South San Francisco,
California 94080
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Abstract
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- I. Introduction
- II. Local GH Axis in Lymphoid Tissue
- A. Background: extrapituitary production?
- B. GH expression
- C. GH regulation
- D. GHRs
- E. GHR signaling
- III. GH Administration
- A. Effects on the thymus
- B. Pattern of GH exposure
- C. GH and immune function in humans
- IV. PRL
- A. PRL expression in lymphoid tissues
- B. PRL receptors
- C. Administration of PRL, anti-PRL antibodies, or bromocriptine
- V. Insulin-like Growth Factors
- A. Background
- B. IGF peptides
- C. Regulation of lymphocyte IGF-I
- D. IGF receptors on lymphocytes
- E. IGFBPs
- VI. Actions of IGF-I
- A. Bone marrow
- B. Effects on lymphoid organ size
- C. Effect of in vivo treatment on lymphocyte number and
in vitro function
- D. Functional effects of IGF-I in vivo: antibody responses
- E. Immune reconstitution
- F. Mechanism of action: apoptosis
- VII. IGF-I in Different Physiological States
- A. IGF-I in pregnancy
- B. IGF-I in diabetes
- C. IGF-I in gastrointestinal disorders
- D. IGF-I action in polycythemia vera
- VIII. GH/IGF-I as Antistress Hormones
- IX. Therapeutic Potential
- X. Conclusions
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I. Introduction
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THE chief messenger systems between organs and tissues are
the nervous, endocrine, and immune systems, which must be integrated on
all levels to maintain homeostasis. The central hypothesis of this
review is that the anabolic hormones (Fig. 1
) GH, PRL,
and the insulin-like growth factors (IGFs) that regulate whole body
growth, metabolism, tissue repair, and cell survival also play an
integrating role (Fig. 2
) in the growth, maintenance,
repair, and function of the immune system.

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Figure 1. The GH/IGF-I axis. This figure depicts the sites
of production of GH and IGF-I, the feedback loops regulating their
secretion, binding proteins, and main metabolic actions. The
hypothalamic hormones GHRH and somatostatin control GH secretion from
the pituitary. GH circulates in the blood, in part bound to a
GH-binding protein (GHBP), to inhibit its own secretion and to
stimulate the production of insulin-like growth factor 1 (IGF-1) in the
liver. IGF-I circulates in the blood bound primarily to IGF-binding
protein-3 (IGFBP-3), which is in turn complexed to a third protein, the
acid-labile subunit (ALS), but a total of six IGFBPs are known.
IGFBP-IGF complexes are subject to protease attack, which assists the
dissociation of IGF-I. The actions of GH are exerted either directly or
indirectly, via the generation of IGF-I.
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Figure 2. Endocrine GH secreted by the pituitary stimulates
the production of endocrine IGF-I by the liver and local IGF-I in many
other tissues, including the stromal cells of hematopoietic tissues. GH
and PRL also act directly on lymphocytes or their precursors in
hematopoietic tissues such as bone marrow, spleen, and thymus.
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In the 1930s the mastery of hypophysectomy in the rat by Smith (1) was
crucial to the discovery of the pituitary hormones. Smith (1) also
found that "after the total ablation of the anterior hypophysis the
thymus began to regress almost immediately." This discovery of a
pituitary influence on the thymus caused a search for the causative
factors (2, 3). Although there were reports that injections of
pituitary extracts with somatotrophic activity stimulated thymic growth
in rodents (4), this was not a consistent finding (3), possibly because
the somatotrophic preparations used were impure and were sometimes
contaminated with other pituitary hormones. More evidence for
immunological activity of the somatogenic hormones came from the study
of hypophysectomized rats (5), which showed a dramatic and continual
age-related fall in both blood hemoglobin and white cell count,
compared with the stable blood cell counts in normal animals, and a
reduced antibody response to antigen that could be improved by GH and
PRL treatment (6). The immunological activity of the pituitary was also
revealed in studies of genetically hypopituitary rodents. The
homozygous Snell-Bagg dwarf mouse was found to be deficient in GH, PRL,
and thyroid hormones and to have an associated poorly developed immune
system including a marked hypertrophy of the spleen and thymus, a
progressive loss of small lymphocytes in the thymic cortex, and a
decreased number of peripheral blood lymphocytes (7, 8). It is now
established that the inhibition or stimulation of many hormone systems
can affect immune responses (9). Such hormones fall into two classes.
In vivo, GH, PRL, and thyroid hormones increase immune
responses whereas ACTH, glucocorticoids, estrogen, progesterone, and
androgens depress immune responses (10, 11, 12, 13, 14, 15, 16, 17). This review marshals the
evidence that, in addition, the insulin-like growth factors (IGF-1 and
IGF-II) have an important role in stimulating lymphocyte production and
function.
To dissect the effects of GH, PRL, and IGF-I on the immune system, it
is important to understand the relative importance of the mediating
role of IGF-I generation to the effects of GH (Fig. 1
). This is not a
simple exercise. The history of the mechanism of action of GH is a long
one, strewn with many theories. For example, fragments of GH were once
proposed to mediate all the effects of GH (18). In 1953, Salter and
Best (19) described body growth in hypophysectomized rats treated with
insulin, a result that was not confirmed by others (20). Such data led
to the hypothesis that insulin mediates many of the growth-promoting
effects of GH (21). This hypothesis was proposed almost
contemporaneously with the discovery, in the serum of hypophysectomized
rats treated with GH, of a sulfation factor activity (22) that was
different from insulin (23). The hormones with this activity were later
renamed the somatomedins (24). Purification (25, 26) led to the finding
that somatomedins and nonsuppressible insulin-like activities (27) were
identical and they were then renamed (25, 26) IGF-I and IGF-II.
The finding that human IGF-I purified from serum caused significant
whole body growth in the rat (28) seemingly confirmed that many, if not
all, of the growth-promoting effects of GH were mediated via the
systemic generation of IGF-I in the liver: the somatomedin theory of
growth regulation (29). It was then discovered, using recombinant human
IGF-I (rhIGF-1) and recombinant human GH (rhGH), that rhIGF-1 and rhGH
have very distinct differential effects on the size of different body
organs in the rat (30, 31). If the effects of GH were all mediated by
IGF-I generation, then this would not be the case. Earlier it had been
proposed (32) that some of the endocrine effects of GH were a result of
its direct action on tissues (Fig. 1
) rather than being indirect via
the generation of IGF-I in the liver. The much greater effect of
rhIGF-1 than of rhGH on the weight of the spleen and thymus in the rat
(30, 31) was one of the first indications that IGF-I and GH had
different growth- promoting activities in vivo. That IGF-I,
GH, and PRL can have different activities on the lymphoid tissue will
be discussed throughout this review. The review will also focus on the
evidence for an autocrine or paracrine GH/PRL/IGF system in lymphoid
tissues that produce PRL and GH, contain PRL and GH receptors (GHRs),
express IGF-I, contain IGF-I receptors, and secrete IGF-binding
proteins.
This review is timely in that rhIGF-1 is being tested in large clinical
trials in several human diseases (33), and it is possible that the
immunological activities of GH/IGF-I may be found useful in the
treatment of immune-deficient states in humans (34). For related
information not included in this review, particularly the effects of
GH/IGF-I on other hematopoietic cells, several related recent reviews
(9, 35, 36, 37, 38, 39, 40) and a monograph (41) are available.
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II. Local GH Axis in Lymphoid Tissue
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A. Background: extrapituitary production?
Human GH is a protein of 191 amino acids produced and released by
the anterior pituitary gland to circulate as an endocrine hormone (42).
Until the placental GHs were discovered, GH was considered to be an
exclusively pituitary hormone (42). It is now apparent that cells and
tissues other than the pituitary and its somatotrophs also produce GH.
Very recently, normal mammary tissue and mammary tumors, particularly
under steroid stimulation, have been shown to produce surprisingly
large amounts of GH (43, 44) that can be so large as to be detectable
in blood.
This recent demonstration of GH production at an extrapituitary site
may shed new light on the following discussion of the production of GH
by lymphoid tissue. The total production of GH by extrapituitary
tissues must be low compared with the production by the pituitary
because hypophysectomy has such profound effects on body growth in a
young animal. These findings, i.e. in some tissues GH is
produced locally and probably acts locally, reinforce the idea (32)
that GH has many actions on tissues that are not mediated by endocrine
IGF-I.
B. GH expression
The first evidence of GH production by lymphoid cells came from
direct staining using fluorescent-labeled anti-GH antibodies (45) and
showed that about 10% of unstimulated human peripheral blood
mononuclear cells (PBMCs) were positive for GH, whereas after mitogen
stimulation 20% were positive. This surprising result was then
independently confirmed (46) and extended to show that GH mRNA is
expressed in lymphocytes (47) and that anti-GH antisense
oligonucleotides inhibit lymphocyte proliferation (48). A plaque assay
confirmed that the GH produced by human PBMCs is biologically active GH
(49). Two human cell lines, the B cell lymphoma line IM-9 (50) and the
Burkitt lymphoma cell line sfRamos (51), have been shown to synthesize
and release human GH (hGH). These results suggest that GH is
synthesized de novo and perhaps continually secreted from
lymphocytes. By in situ hybridization and
immunocytochemistry, GH was shown to be expressed in human and rat bone
marrow, spleen, thymus, lymph nodes, and in human tonsil (41). A recent
study (52) of human tissues, using in situ hybridization and
RT-PCR, has also shown GH mRNA in spleen, lymph node, tonsil, and
thymus. The GH mRNA was present not only in lymphocytes but also in the
supporting structures, e.g. in the thymus GH was expressed
by epithelial cells and reticular cells (52). There are reports that
granulocytes, rather than lymphocytes, are the main cell type producing
GH in peripheral blood (41). In marked contrast, another study in the
rat showed that although GH was expressed in developing lymphoid
tissues, it was not expressed in adult tissues (53). The consensus of
all the literature data, however, is that GH is expressed locally in
lymphoid tissues (41).
C. GH regulation
The transcription of the GH, PRL, and TSH genes in the pituitary
depends on the activity of the transcription factor Pit-1 (54). The
presence of this transcription factor in lymphoid tissues, and its
colocalization with GH and PRL, strongly supports the idea of regulated
extrapituitary GH production in spleen, bone marrow, and thymus (41, 55).
GH production in the pituitary gland is directly regulated by the
hypothalamus, which produces the inhibitory factor somatostatin and the
stimulatory factor GHRH (56). GHRH peptide and mRNA have been detected
in human lymphocytes (57). Somatostatin has been identified in lymphoid
tissue (58) as has the somatostatin receptor (59). However, whether
somatostatin and GHRH are involved in the local production of GH is
less clear (60). Physiological concentrations of GHRH and somatostatin
have been reported to have no effect on the secretion of GH from human
lymphocytes (60). The effects of GHRH and somatostatin on the activity
of cultured lymphocytes have produced conflicting data: various assays
have reported stimulation (61), inhibition (61, 62), or no effect (62).
It is possible that somatostatin has a direct effect on IGF-I
production because in the liver somatostatin exerts a direct inhibitory
effect on IGF-I generation (63). A recent review suggests that,
compared with GHRH, there is more evidence for somatostatin having an
immune- modulatory role (64). However, there seems to be no published
data testing for a direct effect in vitro of somatostatin on
IGF-I mRNA or peptide in lymphocytes. The regulation of local GH may be
different from that in the pituitary because the addition of IGF-I to
lymphocyte cultures has been reported not to affect their secretion of
GH (65). The most convincing evidence of PRL/GH release from both T and
B lymphocytes has been that seen after direct mitogen stimulation
in vitro (66). Small amounts of GH (0.20.6 pg/well,
measured by RIA) are released by nonstimulated human PBMCs, but after
phytohemagglutinin (PHA, a T cell mitogen) or pokeweed mitogen (a B
cell mitogen), a dose-related increase in GH to several picograms per
well has been shown (60). It appears likely that the regulation of GH
in the immune system differs from that in the endocrine system.
D. GHRs
The finding that GH is produced locally by lymphoid tissues has
been given more of a functional significance by evidence that
lymphocytes also express GHRs. GH binding was first detected on a human
B cell lymphoma (IM-9) lymphocyte cell line (67) and subsequently
identified (68) on human PBMCs. The development of specific monoclonal
antibodies against the GHR allowed flow cytometry to confirm that GHRs
are present on human IM-9 cells (69) and in human PBMC with the highest
expression on B cells (70). The GHR on lymphocytes has been sequenced
(71, 72) and found to be identical to the GHR cloned from liver (73). A
more recent study confirmed that the hGH receptor is present on more
than 90% of B lymphocytes and monocytes, but only variably present on
T lymphocytes. B lymphocytes and monocytes had approximately 6000 GHRs
per cell, and this number was not affected by a donor being
GH-deficient (74).
E. GHR signaling
The purification and cloning of the GHR (73), the discovery of the
dimerizing stochiometry of the GH-(GHR)2 complex (75), and the
crystallization of this complex (76) have revolutionized understanding
not only of GH but of the new family of the helix bundle peptide (HBP)
cytokine receptors (40). The placing of the GH and PRL receptors in the
family of hematopoietic cytokines (77), which includes erythropoietin,
granulocyte-colony-stimulating factor, granulocyte/macrophage
colony-stimulating factor, and the interleukins, has provided a
theoretical basis to the experimental results showing that GH and PRL
have significant activity as hematopoietic cytokines (40).
Like other members of the HBP receptor superfamily, GH signals through
the JAK kinase/STAT cascades. However, because many of these
intracellular signaling mechanisms appear to share several
receptor/ligand systems, it has been difficult to see how specificity
is maintained (78). If signaling pathways do overlap, then the
responses of lymphocytes to GH/PRL could be viewed as minor
epiphenomena, with other ligands or receptors mediating the same
responses with more potency and specificity. However, mice with a
disrupted STAT1 gene show defects in interferon signaling but normal
responses to other cytokines, including GH (79). Such specificity was
not predicted from in vitro studies and suggests that GH and
PRL do have unique effects in lymphocytes.
GH action involves the sequential binding of an initial site on hGH
(site 1) to a GHR molecule to form a GH/GHR monomer complex, followed
by the binding of another GHR molecule to the second site on hGH (site
2), to form a receptor dimer complex (75). It is this complex that
activates the JAK2/STAT cascades. GH analogs with mutations in the
second binding site, but with an intact site 1, prevent dimer formation
and can act as antagonists (80). Because the affinity of these mutant
GH molecules for GHR remains high, and can be engineered to increase
the affinity for site 1 selectively, highly potent hGH antagonists have
been produced. A GH antagonist (80) is potentially a useful tool for
elucidating the importance of GH to lymphoid tissues. Unfortunately the
mutant hGH molecules that act as antagonists at the hGH receptor show
no evidence of antagonist activity when administered to rats (81). The
reason for the species specificity of hGH antagonists is unclear
because native hGH binds the rat GHR with high affinity and stimulates
body growth. A GH antagonist fully active in the rat is eagerly awaited
because it would help explain the importance of endogenous GH, the
importance of local GH production, and especially the importance of GH
to lymphoid tissues.
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III. GH Administration
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A. Effects on the thymus
The thymus grows rapidly postnatally in mammals, peaks in size at
around sexual maturity, and then slowly involutes with age (82). In
humans, maximal thymic size is attained at puberty and then by 4550
yr of age involutes so that only 510% of the cellular mass remains.
In mice, maximal size (70 mg) is attained at puberty (6 weeks) while by
9 months of age the thymus has declined in weight to only 20 mg.
Involution of the thymus with age was recognized (83) well before its
immunological role (84). These changes in thymic structure and function
follow the rising activity of the GH system, with serum IGF-I levels
peaking at puberty and declining gradually with advancing age (85, 86, 87)
suggestive of a causative relationship. The age-related decline in
immune function is poorly explained. A portion of this decline could be
related to the lack of activity, or resistance to the actions, of the
anabolic hormones.
The first studies suggesting that treatment with GH could affect the
thymus in nonrodents was a study in hypopituitary dwarf Weimaraner dogs
(88). In follow-up studies, young, middle-aged, and aged dogs were
treated with GH. Thymic growth was observed in middle-aged, but not in
aged, dogs and the blood level of thymic hormone increased (89). The
thymus glands of the treated dogs were described (90) as "resembling
thymic tissue of young dogs." In the aged rat, the implantation of
GH3 pituitary cells reversed age-related thymic atrophy and increased
the number and function of T cells in the thymus (91). The next section
discusses in more detail the effects in rodents of continuous infusions
of hGH, which are very effective at stimulating thymic growth (92). It
should be noted that GH3 cells may produce GH, but little PRL, in
vivo (93), and their release of GH would be continuous, perhaps
accounting for the clear effects reported above (91) on the thymus.
B. Pattern of GH exposure
In several tissues the pattern of GH administration or exposure
can have major quantitative and qualitative tissue-specific effects
(94, 95). For example, different patterns of endogenous GH exposure,
best illustrated by differences in GH-secretory profiles in male and
female rats, cause a number of sexually dimorphic responses (96). The
administration of GH to rats either by daily injection (male pattern)
or by continuous infusion (female pattern) can replicate these
dimorphic responses, which include influencing hepatic enzymes (97),
hepatic growth (98), and lipid metabolism (99). In mice that
overexpress bovine GH, there is an enlargement of the internal organs,
particularly of the spleen, which may be due to both the high levels of
GH and the continuous pattern of GH exposure (100).
As described above, it is likely that GH is produced locally in
lymphoid tissues. The production of this GH is probably by constitutive
expression and release, giving a continuous pattern of local GH
exposure. To explore this idea, GH was given by injection or infusion,
and the effects on different body tissues were compared (98). It was
found that in rats (Fig. 3A
), injections of GH are much
less potent than GH infusions at stimulating lymphoid tissue growth
(98). Figure 3A
shows that in hypophysectomized rats the spleen more
than doubles in size after GH infusions, whereas the same doses of GH
given by injection elicit no splenic growth. It has been stated that in
mice, 20- to 40-fold higher doses of GH and PRL are needed by
injection, compared with minipump infusion, to reverse
corticosterone-induced suppression of splenic lymphocyte responses to
mitogens (101). Recent data in young castrate and intact genetically
obese pigs also suggest that treatment with porcine GH can affect
thymic size and thymosin concentration in serum (102). When porcine GH
was given by injection or by a slow release depot formulation, there
was a greater effect on the thymic parameters of the slow release
formulation (102). A different form of long-acting GH, i.e.
that made by coupling polyethylene glycol (PEG) to hGH, has now been
described (103). The administration by infrequent injection of PEG-rhGH
to hypophysectomized rats also induced lymphoid organ overgrowth
compared with daily injections of nonmodified rhGH. This difference was
probably due to the more continuous pattern of GH exposure caused by
the long plasma half-life of the PEG-rhGH (103).

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Figure 3. Spleen weight (A) and serum IGF-I concentrations
(B) in hypophysectomized rats treated with excipient, or three doses of
hGH given by injection or infusion. At these doses, infusions, but not
injections of hGH, increased serum IGF-I concentrations, perhaps
explaining the selective effect of hGH infusions on spleen weight.
Means and SDs are shown. [Derived from Ref. 98.]
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Some of these differences between injected and infused GH could be due
to continuous GH exposure, via hepatic stimulation, inducing higher
serum IGF-I levels (Fig. 3B
) than injections of GH (94, 99). These
findings have been confirmed in monkeys where a depot form of hGH that
chronically elevated blood GH levels gave higher serum IGF-I levels
than did a comparable dose of GH given by daily injections (104). The
higher concentrations of endocrine IGF-I (Fig. 3B
) may be the cause of
lymphoid tissue growth. There seems to be no comparative data on the
local production of IGF-I in lymphoid tissues in response to injections
or infusions of GH. Alternatively, it is possible that these
pattern-dependent direct effects of GH on lymphoid tissues may not be
mediated by IGF-I.
C. GH and immune function in humans
The strong evidence from studies in animals that the pituitary
(3), GH (35), PRL (16), and IGF-I (36) affect hematopoietic and
lymphoid tissues is generally accepted. However, the evidence in humans
is perceived by recent reviewers as being unconvincing (39, 105). The
most cited evidence (39, 105) is that GH-deficient children are not
clinically immunodeficient and therefore replacement therapy with hGH
would not be expected to have significant effects on immune function.
This perception of a general lack of effect of GH deficiency or GH
replacement treatment on immune function has been taken as evidence
that the GH/IGF axis has a lesser effect on lymphoid tissues in humans
(39). A lesson can be taken here from animal studies with other HBP
cytokines, such as interleukin-6 (IL-6), which has a range of
pleiotropic actions on T cell and B cell proliferation that it shares
with IL-1, IL-2, IL-4, and IL-5 (106). The overexpression of IL-6 in
mice has only a mild effect on B cells (107). Another example of the
pleiotropic actions of cytokines is that disruption of the IL-2 gene
allowed almost normal hematopoiesis (108). These cytokines do have
important actions on the immune system, but the presence of multiple
cytokines ensures that homeostasis is maintained. Therefore, the
apparent lack of effect of an endocrine GH deficiency in humans should
not be taken as evidence that GH has no effects on immune function in
humans.
Human studies have concentrated on discovering the immunological
phenotype of patients who lack pituitary GH. There has been almost no
effort toward discovering whether these patients are deficient in local
GH, local IGF peptides, or receptors or have a changed local
IGF-binding protein (IGFBP) status. Even if pituitary GH is disturbed,
it is likely that in many patients the local paracrine/autocrine axis
in lymphoid tissue is intact. In GH-deficient humans it is possible
that the GH produced locally in the immune system compensates for the
lack of endocrine GH. The much higher endogenous levels of GH (96) in
the rat, about 10-fold higher than in the human (85), would be expected
to cause locally produced GH to be less important in the rat that in
humans. In addition, rats, particularly female rats, have relatively
high GH-binding protein levels that may act to enhance the activity of
GH (109). This may help explain why in humans a deficiency in pituitary
GH or endocrine IGF-I appears to have minor effects on immune function
compared with the effect of such deficiencies in the rat. One group of
patients who may be immunologically impaired are patients with
defective GHR function who were once termed Laron dwarfs but are now
described as having GH insensitivity syndrome (110). The largest cohort
yet described, that localized in Ecuador, may have a significantly
higher pediatric mortality (110), perhaps indicating an impaired immune
system. A recent monograph includes a lengthy discussion of the
relative importance of hormones to immunological status in rodents and
humans (41). A proposal by these authors that should be considered, but
for which there is little or no evidence, is that IGF-I expression is
less dependent on GH in humans than in rodents (41) and that this may
account for the apparent lack of effect on immune function of GH
deficiency in humans. Another reason could be that IGF-II
concentrations in adult rodents are very low compared with the
concentrations in humans. Therefore, a deficiency of GH in rodents,
leading to a fall in IGF-I concentrations, has a greater impact than in
GH-deficient humans in whom the maintained IGF-II concentrations may
preserve blood IGF concentrations and activity.
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IV. PRL
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A. PRL expression in lymphoid tissues
The first cytokines in the HBP family to be identified were GH and
PRL. Because hGH, unlike rat GH, also binds with high affinity to PRL
receptors, it was unclear, until human PRL was purified by Friesen and
colleagues (111), whether humans had a separate PRL. PRL has always
been viewed as having a very broad range of activities (40); therefore
the subsequent demonstration that it had effects on lymphoid tissue was
not surprising. The discovery of PRL expression in lymphocytes was a
surprise. A sensitive bioassay, based on immunostaining of Nb2 cells,
showed PRL-like activity to be present in the culture fluid from
concanavalin A (ConA)-activated murine splenocytes (112).
ConA-stimulated thymidine incorporation was reduced by adding an
antibody against PRL, suggesting that a PRL-like molecule was produced
by the splenocytes and was essential for lymphocyte proliferation
(112). Using an enzyme-linked immunoplaque assay, human PRL secretion
was found after ConA or PHA stimulation of PBMCs, but not in
unstimulated PBMCs (113). Murine and human T- and B cell mitogen
proliferation has been shown to be inhibited by antibodies to PRL, due
to a block in the G1 to GS transition in the cell cycle (114). In
situ hybridization showed the presence of an mRNA in murine
splenocytes that hybridized with a rat PRL cDNA probe (115). The PRL
protein in human lymphocytes appears to be similar to pituitary PRL,
i.e. the multiple forms present in the pituitary are also
present in lymphocytes (116). The PRL gene is also expressed in rat
thymus (117). As described above for GH, the extrapituitary production
of PRL in lymphoid tissue is not unique; the PRL gene, like the GH gene
(43, 44), also appears to be transcribed in the mammary gland (118).
B. PRL receptors
Lymphocytes not only produce PRL but also possess PRL receptors.
The use of the rat Nb2 T cell line for bioassaying PRL clearly
suggested the presence of PRL receptors on lymphoid cells (119). PRL
binding on normal lymphocytes was first demonstrated on human T and B
lymphocytes (120). Since then, biotinylated monoclonal antibodies
against the human PRL receptor (121) have been used to show PRL
receptors in the mouse (122), particularly on B cells, and the presence
of receptors throughout human hematopoietic tissues including bone
marrow and thymus. B cells were the most strongly labeled, while T
cells showed an increased labeling upon activation (121). In the mouse
and rat, PRL receptors are present in bone marrow, thymus, spleen,
lymph nodes, and on peripheral blood lymphocytes (122), with receptor
number increasing in a draining lymph node after foot pad immunization
(123) and on T cells after ConA administration (124). In the thymus,
PRL receptor number is greatest in the cortex and in thymic epithelial
cells (125). Two forms of the PRL receptor, which differ in the length
of their cytoplasmic domains, are present in lymphoid tissues in the
mouse and rat (117). The PRL receptor can be detected by PRL binding,
by antibodies, and by PCR in many lymphoid cell lines (both T and B
cell) and hemopoietic cell lines (41). The signaling of PRL, especially
in Nb2 cells, has been studied intensively and reviewed recently (40).
C. Administration of PRL, anti-PRL antibodies, or bromocriptine
Hypophysectomized rats are almost devoid of a primary antibody
response after the injection of sheep red blood cells (126).
Replacement with lactogenic hormones (40 µg/day) at the time of
immunization restored antibody titers to those of a normal rat (126).
After complete hypophysectomy an animal should be completely
PRL-deficient if the pituitary were the only source of PRL. However,
Nagy and Berczi (127) used the Nb2 cell bioassay to show that
immediately after hypophysectomy rats have unexpectedly high blood PRL
concentrations, 1020% of normal, which then rise to 50% of normal 8
weeks after hypophysectomy. In normal rats, PRL had been described as
having an effect on hematopoiesis; however, in the hypophysectomized
rat, red cell count, although low, was compatible with life. It was
therefore reasonable to conclude that PRL is of marginal importance to
red cell biology. In an important set of experiments Nagy and Berczi
(127) gave anti-PRL antibodies to hypophysectomized rats to neutralize
this residual PRL. After the anti-PRL sera was given, severe anemia
developed and all the animals were dead within 6 weeks (127). This is
very compelling evidence that significant amounts of PRL are made by
extrapituitary sources and that this local PRL has vital functions,
especially for hematopoietic tissues. Comparable studies using anti-GH
antibodies would be of great interest. The sensitivity of
hypophysectomized rats to the lethal effects of estrogens also needs
reevaluating (128).
In humans, the administration of hGH, as it binds to hGH and human PRL
receptors, will activate both GH and PRL receptors and their signaling
pathways. The apparent lack of effect of hGH administration in humans
on immunological function may be due to a lack of selectivity. The
administration in humans of hPRL, a specific hPRL receptor ligand, or
V-gene hGH (42), a more specific hGH receptor ligand, may show
different effects than hGH administration. The prospective availability
of a GH antagonist (80, 81) provides the opportunity to antagonize both
local and systemic hGH. Treatment with a GH antagonist may therefore
cause a different immunological phenotype than a deficiency of
pituitary GH.
Published data (66) describe the immunological effects of
bromocriptine, a dopamine ergot alkaloid that inhibits the release of
PRL from the pituitary. A bromocriptine-treated rat has been reported
to show a reduced mixed lymphocyte reaction in vitro and a
reduced graft-vs.-host reaction in vivo (66),
presumably due to a suppression of pituitary PRL. This may not be the
case. Bromocriptine appears to have direct effects in vitro
on lymphocyte proliferation in the absence of added PRL (129, 130).
Animal studies in transplantation (131) and a clinical trial using
bromocriptine, in combination with cyclosporine, as an
immunosuppressive regimen, have met with some success (132). The
production of genetically engineered PRL-deficient mice or PRL
receptor-deficient mice may help answer the question of the importance
of PRL to lymphocytes and to immune function.
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V. Insulin-Like Growth Factors
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A. Background
The chief regulators of the IGF-I levels in blood are GH status
(133) and nutrition (134, 135). GH and IGF-I, acting together, ensure
ordered body growth and therefore are involved in complex interactions
with most organ systems, tissues, cell types, and also with many growth
factors (133, 136). Due to these multiple effects, GH, PRL, and IGF-I
can affect diverse physiological processes, including immune function,
in many ways, both directly and indirectly (133, 136). The GH system
regulates and coordinates whole body growth to ensure that different
tissues grow in unison and are then maintained in an optimal proportion
to the rest of the body. The immune system may be one such tissue. For
example, GH and IGF-I stimulate cartilage growth and lengthen bones
causing statural growth (136). By controlling the size of the bones in
the growing animal, GH and IGF-I therefore indirectly control the
volume of bone marrow and thus the production of hematopoietic cells
(137). Recent evidence shows that IGF-I differs from insulin in that,
at physiological concentrations, it also plays a direct and significant
role in regulating hematopoiesis, especially lymphopoiesis and immune
function (36).
B. IGF peptides
IGF-I and IGF-II, peptides of 70 and 67 amino acids, respectively,
were named because of the similarity of their actions to that of
insulin (138) and their chemistry to that of proinsulin (25, 26). A
major difference between these hormones and insulin is that the IGF
peptides are expressed almost ubiquitously (139, 140, 141). In adult humans,
IGF-I and IGF-II are both present in large amounts in blood, as they
are in fetal rodents, but in adult rodents IGF-II concentrations in
blood are very low (142). It is unclear whether these differences
between IGF-I and IGF-II status result in species-specific effects on
immune function. IGF-I concentrations in blood are controlled by GH
status; IGF-II levels are much more GH-independent (142). Exons 1 and 2
of the IGF-I gene contain two distinct promoters that give rise to
IGF-I mRNAs containing either exon 1 or exon 2 (143). Exon 1 mRNA is
the form in fetal tissue, whereas the exon 2 form appears postnatally
when GH responsiveness is acquired (143). These different forms of
IGF-I mRNA perhaps supply either GH-dependent endocrine IGF-I (exon 2)
or local GH-independent paracrine or autocrine IGF-I (exon 1) (143). In
myeloid cells, IGF-I transcripts have been found to be exclusively
initiated within exon 1, characteristic of extrahepatic IGF-I mRNA
(144). IGF mRNA and peptides are produced by myeloid cells,
particularly by macrophages, in relatively large amounts (36, 144) and
by human peripheral lymphocytes in small amounts (36, 144, 145). Bone
marrow stromal cells also release IGF-I (146, 147) as do thymic
epithelial cells (93), which can be stimulated by GH in culture (148).
Therefore, there are ample data showing the local production of IGF-I
in lymphoid tissues. However, there is scant evidence describing the
regulation of this locally produced IGF-I or the relative importance to
lymphoid tissues of local or endocrine IGF-I.
C. Regulation of lymphocyte IGF-I
Considerable amounts of IGF-I are regulated by GH-independent
pathways, as seen by the presence of significant serum IGF-I levels in
GHR-deficient humans (110) and sex-linked dwarf chickens (149).
Treatment with GH increases IGF-I mRNA in many tissues (140), whereas
in other tissues IGF-I generation is controlled by factors or hormones
other than GH. For example, in the rat uterus IGF-I may be regulated
chiefly by estrogen, rather than by GH (150). Cytokines other than GH
affect IGF-I synthesis in lymphoid tissues, e.g. in
macrophages tumor necrosis factor-
has been shown to regulate IGF-I
production (151). Tumor necrosis factor-
and prostaglandin
E2 (PGE2) stimulate IGF-I synthesis in
macrophages by two separate pathways, with PGE2 stimulating
IGF-I synthesis through a cAMP/protein kinase A pathway (152). The
colony-stimulating factors also induce the expression of IGF-I mRNA in
macrophages (153), whereas the T cell-derived cytokine IFN-
reduces
macrophage IGF-I mRNA in a time- and dose-dependent manner (154).
It is therefore likely that lymphocytes are exposed to endocrine IGF-I
from the circulation, their own autocrine IGF-I, and perhaps most
importantly, in lymphoid organs and bone marrow, a third source of
IGF-I from epithelial cells (148) and stromal cells (35). The
proliferation of thymic epithelial cells can be stimulated in
vitro by both hGH and IGF-I (155) and the effect of hGH blocked by
either an anti-IGF-I or an anti-IGF-I receptor antibody (93). This
effect of hGH may be via the PRL receptor, rather than the GHR, as rat
and bovine GH (which do not bind to the PRL receptor) appear to be
inactive in this model (156). However, in vivo in the mouse,
although hGH and ovine GH exerted positive effects on thymic
development, ovine PRL was described as having "the opposite effect
of GH on the thymus" (157). Careful comparisons of GH and PRL
activity using homologous systems are needed to discover their relative
activities on lymphoid tissues. The effects of GH on the thymus may be
due to local IGF-I generation (148), which would fit with the in
vivo data of IGF-I administration having larger effects than GH on
thymic growth (31). However, it should be remembered that GH and PRL
may have effects, including on lymphoid tissues (158), that are not
mediated via IGF-I generation.
Normal human PBMCs express very low amounts of the IGF peptides, which
can be increased after mitogen stimulation (36, 144, 145). In contrast,
macrophages are reported to produce much more IGF-I especially when
they are differentiating to the mature phenotype (36). Human IM-9
lymphocytes (B lineage cells) also express IGF-I mRNA, but this message
is not sensitive to treatment with hGH, despite evidence of GH-induced
tyrosine phosphorylation (159). In contrast, transformed B cells (160)
release IGF-I in response to GH. In human T lymphoblast cell lines, the
stimulation of colony formation produced by GH may be mediated by IGF-I
(161). The growth of T-acute lymphoblastic leukemic (ALL) cell lines
can be slowed by antibodies against either IGF-I or the Type 1 IGF-I
receptor, suggesting autocrine or paracrine activity of IGF-I in T-ALL
cell lines (162).
D. IGF receptors on lymphocytes
The insulin receptor and the Type 1 IGF receptor are both tyrosine
kinase receptors, have similar structures, and both bind insulin and
the IGFs, albeit at lower affinities for the heterologous ligands
(163). The receptors are so similar that their subunits are believed to
be interchangeable so that they can naturally form so-called hybrid
receptors (163, 164). Both the IGFs and insulin therefore have similar
powerful metabolic effects, but the Type 1 IGF receptor also possesses
many of the differentiating and mitotic effects found for the
ligand/receptor complexes of other tyrosine kinase receptors such as
c-kit/KL and c-fms/colony-stimulating factor-1.
Such receptors are important regulators of the differentiation of
hematopoietic cells (165). As described above, the GH and PRL receptors
are members of another family, the HBP family of cytokine receptors,
which also regulate many processes in hematopoietic cells (40). As
would be predicted from this discussion, the IGFs and the Type 1 IGF
receptor have differentiating and mitogenic activities, including in
hematopoietic cells (35, 133).
A third IGF receptor, termed the IGF-II receptor, is also the
mannose-6-phosphate receptor, whose role in IGF biology is unclear
(166) although it does not appear to transmit a direct intracellular
signal (167). This receptor binds IGF-II with high affinity but binds
IGF-I with about 100-fold less affinity (168). The IGF-II receptor may
act mainly as a functional IGF-II "antagonist" to regulate local
IGF-II cell exposure and may have tumor suppressor-like properties
(167).
Twenty years ago the binding of insulin to resting (169) and activated
(170) lymphocytes was an active area of research. This was followed by
the discovery of IGF-I binding to human leukemic lymphoblasts (171),
PBMC, resting and activated T cells (172, 173), and the cross-linking
of IGF-I to activated T cells (172, 173). This strongly suggested the
presence of IGF-I receptors on lymphocytes. The functional importance
of these receptors to lymphocyte activation by mitogens was shown by
the peak receptor number occurring at the same time as maximal
thymidine incorporation (172). The use of two-color flow cytometry,
staining with antibodies against the human Type 1 IGF-I receptor, the
insulin receptor, and lymphocyte markers, showed that both IGF-I and
insulin receptors are present on most monocytes and B lymphocytes, but
on only 2% of T lymphocytes (174). Using similar techniques, IGF-I
receptors were found in high numbers on monocytes, natural killer
cells, and CD4+ cells, an intermediate number on CD8+ cells, and a
relatively low number of receptors on B cells (175). Using flow
cytometry and biotinylated des(1, 2, 3)IGF-1, IGF-I receptors were
detected on rat T cells, B cells, and monocytes with the expression on
resting CD4+ cells being greater than on CD8+ cells and increasing
severalfold after ConA stimulation (176). Why there are discrepancies
between these studies is unclear. In another study, T lymphocyte
activation, by PHA or the OKT-3 monoclonal antibody (which binds to the
CD-3 antigen of the T-cell receptor), led to peaks in IGF-I receptor
mRNA after 2060 h and IGF-I receptor content after 4872 h (177). If
the increased IGF receptor number caused by mitogens is physiologically
relevant, the addition of IGF-I should increase proliferation caused by
the mitogens. This has been shown for human peripheral lymphocytes
(178) and thymocytes (179). Freshly isolated human peripheral
lymphocytes have been shown to express IGF-I receptors by RT-PCR (145),
and human T lymphoblast cell lines possess IGF-I receptors (180). Some
of the differences between the data sets for IGF receptors on
peripheral lymphocytes could be methodological, either due to
differences between rodents and humans or to lymphocyte receptors being
atypical IGF receptors. For example, it has been claimed that the
majority of the IGF-I receptors on human IM-9 lymphocytes (B lineage
cells) are atypical IGF-I receptors (150).
IGF-I receptors have also been identified on rodent (181) and human
thymocytes (179, 182). The signal transduction in normal human
thymocytes and T cells appears to be similar to that in other tissues,
e.g. it involves the phosphorylation of insulin-receptor
substrate-1 (IRS-1) (182). In human thymocytes, DNA synthesis can be
stimulated directly by IGF-I in vitro, and DNA synthesis
initiated by the mitogen PHA can be potentiated by adding physiological
concentrations of IGF-I (179).
E. IGFBPs
The IGFs also differ from insulin in that in vivo they
are bound (Fig. 1
) to a family of at least six specific, soluble,
high-affinity IGFBPs, termed IGFBPs 16, which are unrelated
structurally to the IGF receptors or the insulin receptor (133). It is
possible that novel IGFBPs remain to be discovered. In fact, mac25
(183) and PSF (184) or ESM-1 (185) show marked structural similarity to
the IGFBPs. The binding proteins differ in their modes of regulation
and perform a variety of functions. For example, the majority of the
IGF in blood is bound to IGFBP-3 (Fig. 1
), and this complex is bound by
a third protein, the acid-labile subunit, to form a large stable
150-kDa complex (186). IGFBP-3 and acid-labile subunit are regulated
primarily by GH, have a slow clearance from blood, and provide an
accessible pool and reservoir of IGF in the blood (133). In contrast,
IGFBP-1 concentrations in blood can change rapidly, are regulated by
insulin, and may serve an acute metabolic role to bind and inactivate
unbound IGF (187).
Many tissues and cell types secrete IGFBPs, including hematopoietic
cells. By RT-PCR, normal human peripheral lymphocytes express mRNAs for
the IGF-I receptor, the IGF-II receptor, IGFBP-2 and -3, but not the
IGF peptides (145). After stimulation with PHA they express IGF-I,
IGF-II, and IGFBP-4 and -5, in addition to IGFBP-2 and -3 (145). Ligand
blotting of lymphocyte-conditioned media with labeled IGF-I revealed
34-, 43-, and 49-kDa IGFBPs. The addition of estrogen, progesterone,
IGF-I, or GH did not affect secretion of IGFBPs by lymphocytes (145).
IM-9 cell-conditioned medium has also been shown to contain a 30-kDa
IGFBP (141). Murine stromal bone marrow cells, which support developing
hematopoietic cells, not only produce IGF-I but also secrete IGFBPs
(147). By ligand blotting (188), the most prominent IGFBPs were IGFBP-4
and IGFBP-5 whereas, by RNase protection assay, murine stromal cells
expressed IGFBP-2 to IGFBP-6 mRNAs, with IGFBP-4, IGFBP-5, and IGFBP-6
mRNAs being predominant. These authors (188) suggest that IGFBPs 46
are released by stromal cells to modulate the hemopoietic response to
IGFs. Sheep thymus cells also produce IGFBPs in culture, secretion is
increased by mitogen stimulation, and medium from these cells also
degrades recombinant human [125I]IGFBP-3, suggesting
IGFBP-3 protease production (189).
IGFBP-2 is the predominant IGFBP during fetal life (as IGFBP-3 is in
the adult) and is expressed in a range of tumor cell lines (190).
Significantly increased serum levels of IGFBP-2 have been detected in
the sera from ALL and non-Hodgkin-lymphoma patients (191). At the time
of diagnosis with leukemia, non-Hodgkins lymphoma, or solid tumors
the serum concentrations of IGF-I, IGF-II, and IGFBP-3 are very low in
children (192). Such low concentrations of these proteins are normally
seen only in patients with GH deficiency or during starvation (192).
Somewhat surprisingly, IGFBP-2 levels were elevated (192), and it seems
that the IGFBP-2 is produced by the tumor cells (193). Leukemic T cell
lines, but not B cell lines, produce large amounts of IGFBP-2 and
express mRNA for IGFBP-2, confirming data from the patients with tumors
(193). The biological significance of this discovery is unclear.
Some evidence indicates that the IGFBPs regulate IGF action in lymphoid
tissues. Preliminary data suggest that mice that are null for the
IGFBP-2 gene show no gross phenotype except for a reduced spleen size,
to 50% of normal (194). The above evidence, of IGFBP-2 production by T
cells but not B cells, suggests that the distribution of lymphocyte
subsets in these null mice may be altered. Overexpression of IGFBP-1 in
transgenic mice has led to inconsistent effects on spleen size (195, 196), whereas overexpression of IGFBP-3 causes increased spleen size
(197). An intriguing recent paper (198) shows that activation of the
tumor suppressor gene p53, which induces apoptosis, stimulates IGFBP-3
expression. It is possible that the IGF system plays a role in the
regulation of apoptosis (Fig. 4
) via p53 stimulating
IGFBP-3, leading to a local inhibition of IGF-I action with the
induction of apoptosis. This provides a mechanism by which, in lymphoid
tissue, locally produced IGFBPs, by regulating the availability of
IGF-I, may help control cell division and survival.

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Figure 4. Possible mechanism for the antiapoptotic effects
of IGF-I and the apoptotic effects of IGFBP-3. Injury can induce the
expression of the tumor suppression gene p53, which in turn may
increase the expression of IGFBP-3. Because IGF-I is bound by IGFBP-3,
this might prevent the activation of the IGF-I receptor and allow
apoptosis to proceed. In contrast, exogenous IGF-I can allow cell
survival.
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 |
VI. Actions of IGF-I
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A. Bone marrow
This section will focus on the effects of IGF-I on B cell
development, which is comparatively well characterized compared with
its effects on other hematopoietic lineages. Hematopoiesis takes place
in bone marrow in the intersinusoidal spaces of the medullary cavity
with multiple cell types being in close association with the developing
lymphocytes. For example, in long-term culture, the differentiation and
growth of B cells require the presence of fibroblastic bone marrow
stromal cells, which produce many growth factors (199). These stromal
cells, which include macrophages, produce factors that act in a
paracrine manner to regulate B cell lymphopoiesis (146). Factors
affecting B cell development have been categorized by Dorshkind (199)
as belonging to four categories. First, proliferation factors regulate
developing B lineage cell growth, including IL-3 and IL-7. Second,
proliferation cofactors synergize with cytokines that stimulate growth
but have little intrinsic activity, including c-kit ligand
and IGF-I. Third, differentiation factors potentiate B cell maturation
and include IGF-I, c-kit ligand (Kl), IL-7, and ftl3 ligand.
Fourth, negative regulators inhibit B cell development and include
IL-1, IL-3, IL-4, interferons, and estrogens.
IGF-I has two of these major effects on B cell development (Fig. 5
); it acts as a differentiation factor to potentiate
pro-B to pre-B cell maturation (200), and it also acts as a B cell
proliferation cofactor to synergize with IL-7 (201). The first
indication that B cell differentiation factors exist came from clinical
studies in infants with cyclic neutropenia in which the production of
erythroid and myeloid cells oscillates. In the marrow of these
children, pre-B cells also oscillate as does the presence in their
urine of a factor that in vitro stimulates normal human
marrow cells to generate pre-B cells (202, 203). The factor
specifically affects differentiation as this occurs in the absence of
proliferation. A bone marrow stromal cell line was found to release a
similar activity. This activity was identified as IGF-I based on the
use of anti-IGF-I antibodies, antisense to IGF-I, and that recombinant
IGF-I could substitute for the activity (200). In the presence of
IGF-I, pro-B cells mature to pre-B cells, as judged by their ability to
proliferate in response to IL-7 (204). As described above, there is
evidence that macrophages are a rich source of IGF-I and that bone
marrow stromal cells also produce IGFBPs (147). The treatment of mice
with rhIGF-1 confirmed these observations (Fig. 6
) as it
increased the number of pre-B and mature B cells in bone marrow (205).
The mature B cell remains sensitive to IGF-I as immunoglobulin
production is also stimulated by IGF-I in vitro and in
vivo (206).

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Figure 5. The differentiative and proliferative actions of
IGF-I during the stages of B cell development. IGF-I is unique in that
by itself it stimulates the differentiation of Pro-B cells. IGF-I also
acts as a proliferative cofactor throughout B cell development.
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Figure 6. Treatment with rhIGF-1 (4 mg/kg/day, sc infusion
for 2 weeks) more than doubles the number of Pre-B cells (B220+,
sIgM-) in the bone marrow of normal adult mice. Means and
SDs are shown. [Derived from Ref. 205.]
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The activity of IGF-I as a cofactor (201) affecting IL-7-induced B cell
proliferation is not unique. IGF-I acts as a cofactor in many
situations. For example, traditional GH-like responses, such as the
growth of the whole body, require optimal IGF-I levels for GH to
produce maximal effects, and vice versa (99, 207). This has
been amply shown in humans, in whom high dose IGF-I administration
suppresses GH, leading to a loss of IGF-I efficacy unless GH is
coadministered (33). In the periphery, IGF-I enhances the proliferative
response of lymphocytes to mitogens (208). During or after immune
system damage, which is commonly associated with a catabolic state,
systemic and local IGF-I levels are likely to be low. Therefore, for
optimal recovery, supplementing this co-factor seems logical to
stimulate anabolism and immune reconstitution. There have, as yet, been
few animal studies using IGF-I in combination with other growth
factors, except for studies with IGF-I and GH (207). In the Snell dwarf
mouse, treatment with bovine GH restores many measures of lymphocyte
function, but pre-B cell numbers in bone marrow are not restored by
bovine GH or ovine PRL (209). Further studies are needed in Snell mice
to explain which hormones cause this B cell deficiency and thereby
discover the factors that are important to normal B cell development.
The effects of IGF-I on T cell development are not as well
characterized, although thymic T cell progenitors proliferate in
response to IGF-I before they respond to any other known cytokine
(210). It is also clear that thymic epithelial cells produce IGF-I,
functional IGF-I receptors are present on thymocytes (181), and the
administration of IGF-I to animals affects the number of T cells in the
thymus (92). There is as yet no information on the thymic role of IGF-I
in processes of positive or negative selection of thymocytes. It has
been claimed that rhGH can induce significant migration of resting and
activated human T cells (211). These authors speculate that, by
directly altering their adhesive and migratory capacities, GH may play
a role in normal lymphocyte recirculation. This finding is as yet
unconfirmed and raises the question of the activity of IGF-I in these
assays.
B. Effects on lymphoid organ size
An involvement of the somatomedins (IGFs) in the regulation of
lymphoid organ growth was suggested when IGF-I was administered to
hypophysectomized rats because it caused preferential thymic and
splenic growth to a greater degree than did GH (31). Such studies were
then extended to the mutant dw/dw rat, which showed a similar
disproportionate growth of lymphoid tissue (30) whereas in normal aged
18-month-old rats, IGF-I stimulated thymic growth (Fig. 7
) and increased lymphocyte numbers (212). Figure 8
shows the effect of 28 days treatment with rhIGF-1,
rhGH, or rhIGF-1 plus rhGH on thymic architecture. It is clear (Fig. 7
)
that rhIGF-1, and to a lesser extent rhGH, stimulates thymic growth.
Because the rat is not the preferred species for immunological studies,
the mouse was selected as an experimental animal. At the time, there
was very little information on effective doses or dosing regimens of
IGF-I in the mouse apart from some early anabolic studies using
somatomedin preparations in mutant dwarf mice (213) and isolated more
recent studies with rhIGF-1, also in mutant mice (214). Instead of
using GH-deficient animals, the effects of IGF-I were studied in
normal, 9-month-old, retired breeder "middle-aged" male mice (92).

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Figure 7. Thymic histology in 18-month-old male rats
treated for 4 weeks with either excipient (panel A), rhIGF-1 (panel B,
1.1 mg/rat/day, sc minipump infusion), rhGH (panel C, 1 mg/rat/day,
daily sc injection), or rhIGF-1 plus rhGH (panel D). Formalin-fixed
hematoxylin-eosin-stained sections. The hormone treatments,
particularly rhIGF-1, caused a dramatic expansion and rejuvenation of
the involuted thymus of aged rats [R. Clark, unpublished data].
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Figure 8. Antibody production in mice immunized with 0.1
µg DNP2OA at week 0, then boosted at week 5. In addition,
the mice were treated with either excipient or rhIGF-1 (4 mg/kg/day)
for 2 weeks after each immunization. Treatment with rhIGF-1 enhanced
antibody production, especially after the secondary immunization. Means
and SDs are shown. [Derived from Ref. 206.]
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Older animals were chosen with the hope that their relatively impaired
immune status could be improved by treatment with rhIGF-1, as had been
seen in aged rats where GH3 cell implantation reversed age-related
thymic atrophy (91). A range of doses of rhIGF-1 (0.25, 1, 4 mg/kg/day)
were given by subcutaneous minipump infusion to avoid the need for the
very frequent injections that were shown in growth studies to be most
effective in mice. These doses doubled total serum IGF-I
concentrations, induced a dose-related weight gain, and had minor
effects on blood glucose, yet doubled the weight of both the thymus and
spleen (92). Therefore, the effects of rhIGF-1 seen in GH-deficient
rats could be duplicated in normal mice.
The administration of IGF-I has been shown to increase the size of
lymphoid organs in several species. In rats and mice numerous studies
report increases in lymphoid tissue mass with IGF-I administration
(36). In 1-yr-old sheep, an 8-week regimen of three daily injections of
rhIGF-1 (50 µg/kg) increased spleen weight by 40% (215). In the
rabbit, cat, and dog similar effects of IGF-I have been observed (R.
Clark, unpublished observations). In the rhesus monkey, IGF-I also
expands lymphocyte numbers (216). This finding is discussed in more
detail in Section IX. Lymphoid organ expansion has been
reported in children with GH insensitivity who have been treated
long-term with rhIGF-1 (110). This is the first direct confirmation
that the immunological effects of administering IGF-I to animals are
also present in humans.
Mice transgenic for GH or IGF-I have enlarged lymphoid organs (217). An
effect of endogenous IGF-I on lymphoid tissue growth was presumed in a
large study (218) where lines of mice were selected over many
generations on the basis of high or low serum IGF-I levels. The high
IGF-I line had spleens 30% heavier than the low IGF-I line. Thymus
weights were also greater in high-line than in the low-line mice, and
developmental patterns of thymus weight closely paralleled those of
circulating IGF-I (218).
Compared with the ample data on the effects of IGF-I, the effects of
IGF-II on lymphopoiesis are not as well studied (219, 220). IGF-II
binds less well to the Type I IGF-receptor; therefore, higher
concentrations are probably needed (although much less than insulin) to
mimic the effects of IGF-I. However, there are reports, based on IGF-II
transgenic mice, that IGF-II also has immune modulator properties (219, 220). In some situations, in some species, IGF-II may play a role in
lymphoid tissue function. Adult humans, unlike rodents, have blood
concentrations of IGF-II equal to or greater than those of IGF-I. The
regulation of IGF-II production is an active area of research and has
produced surprising findings. For example, IGF-II production may be
controlled by a rapamycin-sensitive pathway (221).
C. Effect of in vivo treatment on lymphocyte number and in vitro
function
In mice treated with rhIGF-1 for 7 or 14 days, analysis of the
lymphocyte subsets showed that a large part of the increased spleen
weight was due to a doubling in the number of both T- and B lymphocytes
(92). The increased thymic mass was also due to a doubling in Thy
1-positive cells (T lymphocytes) and an increase in peanut agglutinin
receptor binding (a marker for immature thymocytes), but there were no
changes in Thy-1, CD4, or CD8 expression on single or double positive
thymocytes. In the spleen, there was a preferential increase in the
number or sIg+ cells (B-lymphocytes) compared with T lymphocytes (92).
For the splenic T lymphocytes, the numbers of both CD4- and
CD8-positive cells were increased. Peripheral lymph nodes were also
increased in size and lymphocyte number but in peripheral blood
lymphocyte number decreased by 20%, whereas neutrophil number
increased. There were no changes in other blood cell numbers (92).
To test lymphocyte function, cells from spleen and lymph nodes were
incubated in vitro with mitogens (92). After 14 days of
treatment with rhIGF-1, the responses to ConA (T cells),
lipopolysaccharide (LPS, B cells), and pokeweed mitogen (both T- and B
cells) were increased 4-fold in spleen and doubled in lymph nodes.
Cells from rhIGF-1-treated and control mice showed identical responses
in a mixed lymphocyte response to allogenic splenocytes, suggesting
unchanged antigen-specific T cell responses. To test B cell function,
mice were immunized with dinitrophenyl-ovalbumin (DNP2OA)
and given a boost 35 days later and treated with rhIGF-1. When tested
in vitro, splenocytes from IGF-treated mice had a doubling
of their basal and antigen-stimulated immunoglobulin production.
Therefore, there was clear evidence that treatment with rhIGF-1
increased both the number of lymphocytes and their function (92). In
comparison, injections of hGH were much less potent and effective
(143).
D. Functional effects of IGF-I in vivo: antibody responses
It was clear from the literature (222) and our own studies that B
cells are preferentially responsive to rhIGF-1 and show an enhanced
immunoglobulin production in vitro (92). To discover whether
IGF-I enhanced immune function in vivo, immunization
experiments (Fig. 8
) were perfomed in retired breeder mice using
DNP2OA as the antigen (206). In the first experiments, mice
were treated with rhIGF-1 for 14 days, commencing at the time of an
antigen challenge, and showed a dramatically enhanced primary antibody
response, as measured by the serum anti-DNP IgG concentration assayed
by ELISA. This protocol was then repeated, but a secondary immunization
was given after 21 days to test the effect of rhIGF-1 on the memory
response to DNP2OA (206). The anti-DNP IgG concentration at
the peak of the secondary response was 4-fold higher in mice treated
with rhIGF-1. A second 14-day course of rhIGF-1 treatment (begun 8
weeks after the first course), initiated when lymphoid organ cell
numbers had returned to baseline, also increased lymphoid organ cell
number. Lastly (Fig. 8
), the ability of rhIGF-1 to enhance the antibody
response to a suboptimal dose of antigen was tested (206). In this
study the mice were treated with rhIGF-1 twice, at the primary
immunization and then after 5 weeks at the secondary immunization.
Primary and secondary responses to a suboptimal dose of antigen were
greatly enhanced, reaching levels similar to those induced by an
optimal antigen dose in excipient treated animals (206). In diabetic
rats, IGF-I treatment did not improve the primary antibody response to
an antigen challenge (223). It is unclear why this study in rats failed
to show the effects on antibody generation seen in mice. However, the
older literature (126) shows that in hypophysectomized rats, which have
very suppressed antibody responses, there is a dramatic enhancement of
antibody generation after treatment with GH.
E. Immune reconstitution
IGF-I treatment increases T and B cell number and improves
antibody responses, suggesting that it might have a normal role in B
and T cell function. To address the site(s) of action of IGF-I, mice
were lethally irradiated and then reconstituted with a transplant of 10
million bone marrow cells from syngeneic donors (205). The catabolic
effects of the radiation were attenuated by IGF-I with body weight loss
reduced, spleen and thymus weight improved, and splenic T cell number
and function improved 23 days after transplantation. Treatment with
rhIGF-1 also doubled thymus weight, and thymic cell count tripled. In
this model IGF-I increased the rate of peripheral lymphocyte
repopulation by acting directly on bone marrow progenitors and by
stimulating the entry of mature peripheral splenic lymphocytes into S
phase of the cell cycle (205). After chemically destroying lymphoid
tissues, similar restorative effects of rhIGF-1 have been shown in rats
(224). In mice with severe combined immune deficiency (SCID), GH has
also been shown to improve T cell engraftment after the transfer of
human or murine cells (225). It is unclear whether IGF-I is involved in
these effects of GH, although in our hands GH is much less effective
than IGF-I at promoting immune reconstitution after bone marrow
transplantation.
F. Mechanism of action: apoptosis
Programmed cell death (apoptosis) is fundamental to many levels of
the immune system from the development of precursor cells in bone
marrow, selection in the thymus, to deletion of mature cells in the
periphery (226). How IGF-I expands B and T cell number is unclear
(199); it could act positively to potentiate differentiation or it
could act passively to enhance survival, e.g. by reducing
apoptosis (Fig. 9
). IGF-I has marked anti-apoptotic
effects (227) in many tissues and cell types, which may be important in
normal growth and differentiation, in tumor growth (228), and for the
protection of tissues from damage. IGF-I has been especially impressive
at protecting the kidney (229), heart (230), and brain (231) from
damage after ischemic injury. This protection may, in part, involve
anti-apoptotic mechanisms. The bulk of evidence for the identification
of IGF-I and the Type I IGF receptor, as powerful inhibitors of
apoptosis and survival factors for cells, comes from the field of tumor
biology (228). Apoptosis is regulated by a rapidly growing array of
families of signaling molecules; as a consequence, the pathway(s)
affected by IGF-I will be described in the future. For example, in
several interleukin 3 (IL-3)-dependent cell lines, IGF-I can prevent
apoptosis after IL-3 withdrawal (232). In some cell types, even where
it is a poor mitogen, IGF-I is the key antiapoptotic growth factor
(227); therefore, it is reasonable to assume that IGF-I does signal
through apoptotic pathways in lymphoid cells. There is, as yet, no
direct published evidence that IGF-I increases lymphoid cell number in
animals by inhibiting apoptosis, but a theoretical framework for such
activity can be postulated, as illustrated in Fig. 9
.

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Figure 9. A proposed scheme of how the GH/IGF-I axis might
modulate apoptosis. An insult or injury induces GH resistance and IGF
resistance, which adrenal steroids exacerbate. The inhibition of the
effects of GH and IGF-I probably enhances the likelihood of damaged
cells dying from apoptosis.
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 |
VII. IGF-I in Different Physiological States
|
|---|
A. IGF-I in pregnancy
It is well established (233) that the thymus atrophies when blood
concentrations of estrogen rise. Conversely, thymic involution is
delayed by castration. The involution of the thymus in pregnancy is
dramatic. Gross thymic weight falls from about 40 mg to 10 mg by day 17
of pregnancy in the mouse, due to both cell death and the specific loss
of cortical CD4+ CD8+ lymphocytes (234); while
the cortex shrinks the medulla is rearranged. These changes probably
contribute to the immune suppression of the mother to paternal and
fetal antigens. Prevention of lactation causes thymic repopulation,
which takes about 3 weeks (234). Clearly, pregnancy and lactation are
physiological states in which the GH and IGF-I systems are very active,
and these effects of steroids on the thymus may involve interactions
with the GH and IGF systems. An interesting issue is the apparent
immune reconstitution of the weanling Snell-Bagg mice if weaning is
delayed from 21 to 30 days of age (235). Whether this effect is due to
dwarf mice being particularly sensitive to stress at this age or is due
to factors in milk is unknown. The administration of T4 to
Snell-Bagg mice has significant effects on lymphopoiesis (236), and
recent discoveries in animals (237) and humans (238) show that
hormones, e.g. T4, can be absorbed from milk,
suggesting that maternal influences on immune function persist beyond
pregnancy and may also be hormonal in nature.
In pregnant mice the number of immature B-lymphocytes
(sIgM+, sIgD-, heat-stable antigen, HSA
hi) in bone marrow and spleen are reduced, but the number
of mature B cells in peripheral sites is not affected. The number of
immature B lymphocytes is also reduced in normal mice by estrogen
treatment (239) while in hypogonadal mice the number of these cells is
greatly elevated (240). Kincade et al. (233) state that for
estrogens to affect B cell precursors stromal cells must be present,
inferring that stromal factors mediate their effects. IGF-I has been
shown to be produced by marrow stromal cells and to stimulate B cell
development (200, 201, 205). In some systems, including bone, estrogens
are known to inhibit the activity of GH (241), while in the uterus
estrogens synergize with the ability of GH to stimulate IGF-I mRNA
(242). In lymphoid tissues steroids may also modify the activity of the
GH system. The reverse is also true, as GH can affect estrogen receptor
(ER) levels (243). In adult female rats, hypophysectomy reduced hepatic
ER levels 10-fold and treatment with PRL had no effect, but continuous
infusion of GH to hypophysectomized animals tripled ER and doubled ER
mRNA levels. These authors (243) state that GH is the most important
hormone affecting ER protein levels. The interactions between the GH
system and sex steroids in bone marrow stromal cells and their
influence on B cell development may lead to a more general
understanding of the molecular and signaling interactions between
steroids and the GH system.
Therefore, at the level of the marrow, thymus, and spleen, reproduction
and reproductive hormones have profound effects. It is likely that the
GH and IGF-I systems are involved in these processes, which may help
explain the remarkable inhibition of maternal immunity to fetal
antigens and thus how the embryo escapes damage from the maternal
immune system (233). Knowledge of these natural phenomena may aid in
devising strategies for allogenic transplantation and also help to
explain gender differences in autoimmune disease.
B. IGF-I in diabetes
The marked thymic atrophy in streptozotocin-diabetic rats can be
reversed by treatment with insulin or IGF-I (223). In this situation,
insulin probably corrects the thymic atrophy indirectly, by normalizing
the metabolic derangements, including causing glucose uptake into
tissues. However, treatment with IGF-I can restore thymic size without
normalizing blood glucose (223). There is a growing interest in IGF-I
as a glucose-regulatory hormone with a view to its use as a therapeutic
agent in diabetes (138, 244). The use in Type I diabetes of IGF-I, a
potentially immunologically active molecule that has even been
implicated in the development of this disease (245), should proceed
with caution. However, a recent study (246) shows that the treatment of
nonobese diabetic mice (NOD) with IGF-I has protective, rather than
deleterious, effects. Nondiabetic mice received 7 million activated T
cells from diabetic NOD mice, and 12 of 21 became diabetic; only six of
24 mice treated with IGF-I became diabetic and the IGF-I-treated mice
retained 49% of their islets intact while in the control mice only
1.6% of the islets were intact. These authors state (246) that IGF-I
has protective effects in autoimmune diabetes and that this opens new
preventive strategies in human Type I diabetes. Careful repetition of
these important experiments is needed as are experiments in animal
models of other autoimmune diseases to discover whether this is a
disease-specific effect of IGF-I or whether IGF-I has therapeutic
potential in a range of autoimmune diseases.
C. IGF-I in gastrointestinal disorders
GH and IGF-I affect the growth and function of the
gastrointestinal tract in animals (247, 248) and in humans (249). For
example, after 80% gut resection in rats, treatment with IGF-I can
cause the remaining gut to hypertrophy and to show an increased
function (247). After a 50% burn in rats, gut mucosal atrophy and
increased permeability were associated with a 89% incidence of
bacterial translocation to mesenteric lymph nodes (250). However, if
the rats were treated with IGF-I (3 mg/kg/day, sc, minipump), gut
mucosal weight increased, and the incidence of bacterial translocation
was reduced to 30% (250). These beneficial effects of IGF-I treatment
on gut structure in burned rats have been confirmed (251). IGF-I may
inhibit bacterial translocation by affecting both gut integrity and the
guts immune response. In a rat model of cecal ligation and sepsis,
combined with total parenteral nutrition, IGF-I (4 mg/kg/day for 3
days) increased gut metabolism, reduced mucosal atrophy, and reduced
the hepatic portal blood endotoxin concentrations (252). The authors
conclude that IGF-I may play a role in maintaining gut barrier function
in sepsis (252). A recent report (253) tested the efficacy of GH and
IGF-I in a murine model of sepsis. Normal female mice were pretreated
(three times a day, sc) with rhIGF-1 (2.4 or 24 mg/kg/day), rhGH (0.48
and 4.8 mg/kg/day), or excipient for 6 days, then challenged with
Escherichia coli (1 x 108 units, ip).
IGF-I and GH significantly prolonged survival, reduced bacterial counts
in the peritoneum, and suppressed cytokine production. The authors
conclude that GH and IGF-I improve host defenses via immunomodulation
in murine sepsis (253). However, in another model of septic shock, the
opposite result has been reported (254). Normal rats were pretreated
for 3 days with an infusion of rhGH (192 µg/day, sc, minipump) or
excipient and then given endotoxin LPS (5 mg/kg). The infusion of rhGH
in this study (254) potentiated endotoxinemia, as measured by liver and
kidney enzymes and metabolites in blood 14 h later. Why this study
produced such discordant results is unclear. The evidence therefore
suggests that IGF-I may play a role in maintaining gut structure and
function and that treatment with IGF-I may be useful therapeutically to
improve gut function when it is compromised.
A reason why IGF-I status may be important in sepsis is that bacterial
endotoxins reduce blood IGF-I levels (255, 256). The intravenous
administration of LPS to rats dramatically decreases serum IGF-I to
50% of normal in only 4 h due to a direct effect of LPS on the
liver (256). If IGF-I is important to gut barrier function, such an
immediate effect of endotoxin on blood IGF-I concentrations would
further exacerbate gut failure and allow even more bacterial
translocation. There is much to understand in this promising new area
of research, including the effects of IGF-I on the largest lymphoid
system in the body, that of the gut.
D. IGF-I action in polycythemia vera
It is interesting and instructive to consider recent developments
regarding the effects of IGF-I on erythropoiesis. Erythroid cell number
is primarily regulated by erythropoietin but is impacted by many other
growth factors. For example, hypophysectomized rats show low blood cell
counts (3) for erythroid, myeloid, and lymphoid cells, and there is a
deep literature showing effects of both GH, PRL, and IGF-I on all
hematopoietic lineages (15, 35, 137, 257, 258, 259). However, mice with
disrupted IGF peptides or IGF-receptors have normal erythropoiesis
(260, 261). The significance of IGF-I in hematopoiesis has also been
questioned (262), chiefly on the basis of IGF receptor-positive bone
marrow cells lacking clonable hematopoietic progenitor cells (262).
These authors (262) also refer to the lack of effect of GH deficiency
on blood morphology. Recent findings (263, 264) in polycythemia vera
(PV) will renew interest in the role of IGF-I in hematopoiesis. PV is a
chronic myeloproliferative disease of a deregulated clonal expansion of
a pluripotent stem cell giving rise to granulocytosis, thrombocytosis,
and erythrocytosis (265), which is not erythropoietin dependent. Correa
et al. (263) developed a serum-free system culture system
for circulating erythroid progenitors and discovered that PV cells are
100-fold more sensitive to IGF-I. An antibody against the IGF-I
receptor blocked IGF-I stimulation (263). Why the IGF-I receptor in PV
is supersensitive to ligand is unknown. These unexpected findings
should be seen as instructive in terms of the role of IGF-I in
lymphopoiesis and disease. It is likely that diseases or deficiencies
of the immune system will be found that are caused by aberrations in
the local GH, PRL, and IGF axes in hematopoietic cells. What is
recognized by the endocrinologist as systemic GH, PRL, or IGF
deficiency or excess may be of little importance to the hematologist to
whom the paracrine or autocrine mechanisms regulating the same
molecules or their receptors may be more relevant.
 |
VIII. GH/IGF-I as Antistress Hormones
|
|---|
For efficient homeostatic regulation, most physiological systems
are regulated by inhibitors and stimulators. This section will explore
the hypothesis that, physiologically, the adrenal steroids are the
major immunosuppressive hormones while the somatogenic hormones are a
major counterbalancing immunostimulatory system (266). It is also
proposed (Fig. 9
) that, in situations of extreme stress or where the
immune system is damaged, the somatogenic hormones also have a repair
function.
As described above, IGF-I is "insulin-like" in that it is sensitive
to nutritional status. During the lifespan in most species, and
certainly in most of mankind, periods of starvation are common, and so
hormonal systems have evolved to manage this state. Some of the effects
of undernutrition may be mediated by IGF-I (135). In nutritional stress
or injury (Fig. 9
) the hypothalamic-pituitary-adrenal axis is activated
so that glucocorticoid production rises leading to many changes in the
GH/IGF axis. A GH resistant state is induced so that local and systemic
concentrations of IGF-I fall, which is exacerbated by a fall in
systemic IGFBP-3 because of reduced production and increased protease
activity (Fig. 1
). The amount of IGFBP-1 and IGFBP-2 in the circulation
rises (133), and the induction of p53 may increase local BP-3
concentrations so that local IGF resistance also occurs. This
combination of GH and IGF resistance is associated with anabolism being
suppressed and subsequently bone marrow depletion and perhaps immune
function being compromised. It is unknown whether IGF-I can be used to
assist in the protection of the immune system during undernutrition.
Replacement of IGF-I during undernutrition can, at best, only partly
protect against these deleterious effects. However, the anabolic
hormones have a clear role in recovery from stress and undernutrition
and in reconstituting the immune system, as shown by studies in
radiated mice (205). It is unclear whether pretreatment with IGF-I
would protect lymphoid tissues from the damage caused by radiation or
other stresses, as it does in other damaged tissues such as kidney
(229), heart (230), and brain (231).
There are animal studies suggesting that anabolic hormones can
counteract some of the anticatabolic and immunosuppressive effects of
administered glucocorticoids. There is evidence that GH, either given
by injection or endogenously elevated by stress, can in the rat partly
reverse the leukopenia (267) and the reduced antibody levels (268)
caused by steroids. More recent studies (101) in mice have shown that
rhGH, ovine PRL, or bovine GH (24 µg/day, sc osmotic pump) all
reversed corticosterone (50 µg/day)-induced suppression of spleen
lymphocyte responses to T cell mitogens. In contrast, the thymic
atrophy caused by corticosterone was not reversed by rhGH. These
authors (101) also show a suppression of liver PRL receptor levels by
corticosterone, their recovery by the lactogenic hormones, and a
relationship with the immune responses observed. They propose a similar
effect of corticosterone on lymphocyte PRL receptors. In a more recent
study in C57/Bl/6J mice, the coadministration of rhGH (0.8, 4, 8
IU/kg/day) with prednisolone (10 mg/kg/day, ip, for 10 days) was found
to prevent the reduction in thymic and splenic weight and cell number
caused by the steroid (269). Whether this is a practical treatment must
be balanced against the diabetogenic effects of high-dose GH
exacerbating the metabolic risks (insulin resistance, hyperglycemia,
hypertriglyceridemia) of glucocorticoid treatment (270). On the other
hand, IGF-I treatment in humans, because it suppresses GH production
(271) and has insulin-like rather than diabetogenic effects when given
in combination with prednisone (272), should have fewer adverse
metabolic effects.
In the rat, the whole body weight loss caused by dexamethasone (20
µg/rat/day, by sc minipump) was partly inhibited by cotreatment with
IGF-I for 7 days (247). In these studies, IGF-I could restore spleen
weight almost back to normal, but the thymus did not regrow on a gross
weight basis (247). These reports of differences between GH and IGF-I
in their ability to reduce thymic involution in rodents are worthy of
further investigation.
Lymphopoiesis may be regulated normally by local IGF-I, whereas for the
task of repopulating marrow after damage it may be necessary to access
the larger pool of IGF-I present in blood. Systemic IGF-I may be
required in a damaged marrow or thymus as the supporting stromal cells,
which produce IGF-I locally, will be damaged reducing the supply of
locally produced IGF-I. Therefore, in different situations either
endocrine or local IGF-I production may have differing contributions to
lymphopoiesis. Studies using transgenic and IGF-I and IGF receptor null
mice (260, 261, 273) will help shed light on the relative contribution
of locally produced IGF-I and endocrine IGF-I in the regulation of
immune function. Mice with tissue-specific expression of IGF-I crossed
on to an IGF-I null background may help establish the relative
importance of IGF-I of local and endocrine origins not only for
lymphopoiesis but for its effects in general.
 |
IX. Therapeutic Potential
|
|---|
A recent study (216) suggests that the immunological effects of GH
or IGF-I treatment in rodents may also be present in primates. In aged
(16- to 20-yr-old) rhesus macaque monkeys, infusions of rhGH and
rhIGF-1 for 7 weeks affected the phenotype of lymphocytes in blood,
spleen, and lymph nodes as measured by flow cytometry (Fig. 10
). Quite different effects of treatment were seen in
the blood compared with the peripheral lymphoid organs. In blood, the
percent CD4 cell count and the CD4/CD8 ratio fell with rhIGF-1
treatment but were normalized by rhGH plus rhIGF-1. In the spleen (Fig. 10
) combination treatment almost tripled the percent CD4 cells and more
than doubled the CD4/CD8 ratio (216). This paradox of differential
effects on lymphocyte populations in different body compartments may be
due to the anabolic hormones affecting lymphocyte trafficking as rhGH
and rhIGF-1 appear to cause lymphocytes to accumulate in lymphoid
organs at the expense of lymphocyte numbers in the circulation (92, 205). One implication of this effect is that in humans, where it is
only practical to sample blood lymphocytes, the activities of rhGH and
rhIGF-1 may be difficult to detect. These observations in primates make
it more likely that rhIGF-1 will prove useful in humans to improve
immune function, especially after damage to the immune system or in
immune senescence in the elderly. Growth factors are used in humans to
restore hematopoietic cells after radiation, chemotherapy, or bone
marrow transplantation. At present, no growth factor therapy is
available that would speed the slow and incomplete recovery of
lymphopoiesis. As a consequence, infections remain a major long-term
problem even after the most successful bone marrow transplantation
regimens have been used (274).

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Figure 10. CD4+ T lymphocytes in the spleen of adult rhesus
macaques treated by sc minipump infusion with excipient, rhIGF-1 (120
µg/kg/day), hGH (100 µg/kg/day), or rhIGF-1 plus hGH for 7 weeks.
The combination of rhIGF-1 and hGH almost tripled the percentage of
splenic cells that were CD4 positive. Means and SEs are
shown. [Derived from Ref. 216.]
|
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The importance of the effects of IGF-I on the thymus has assumed a more
interesting dimension with the recent publications by Gress et
al. (275, 276). There is an increased incidence of opportunistic
infections after intensive cancer chemotherapy; therefore, immune
incompetence may be a dose-limiting toxicity for high dose chemotherapy
(275). In children, the recovery of CD4+ T cells, after treatment with
chemotherapeutic agents, occurs primarily by a thymus-dependent pathway
(276). With advancing age, the contribution of this pathway declines
rapidly. The degree of immune reconstitution after damage is directly
related to the age of the patient and, more importantly, the amount of
residual thymic function (276). Therefore it is possible that if thymic
growth and function could be stimulated by growth factors, such as
rhIGF-1 or rhGH, then lymphocyte function might be more rapidly
restored after chemotherapy, especially in adults. In the setting of
combined chemotherapy and bone marrow transplantation, treatment with
growth factors may be doubly valuable. The effect of such growth
factors on tumor growth needs to be addressed, although initial
short-term studies with IGF-I suggest that tumor growth is not enhanced
(277).
GH is being tested as an anabolic treatment for patients with
AIDS-associated wasting (278). In other experiments, testing IGF-I and
the combination of IGF-I and GH as a therapy for AIDS wasting, there
was some evidence of a beneficial effect on body composition (279).
These studies have been relatively short-term; appropriate dosing
regimens or dose levels in humans are not established; and measures of
lymphocyte number and function, if made at all, have been based on
blood cell counts. As stated above, the idea that peripheral blood
lymphocyte numbers and ratios provide useful information about immune
status has been questioned (280) as only a few percent of the
lymphocytes in the body are circulating in blood, with the majority of
the cells being in the lymphoid organs. This problem is inherent to the
use of anabolic hormones that can double lymphoid organ size while
having minor effects on blood cell counts. Measuring the immunological
effects of IGF-I in human studies will be difficult. In rodent or
monkey studies, lymphocyte number and function can be measured directly
in lymphoid organs removed when the animals are killed; measuring
potential benefits solely by studying effects on the number or function
of the lymphocytes in the peripheral blood is more difficult.
Much is to be learned in this fascinating area of IGF research. For
example, data from animal studies suggest that GH and IGF-I can protect
against bacterial infections (252, 253). Although GH has been reported
to augment human immunodeficiency virus growth (281), an intriguing
recent paper indicates that IGF-I may directly inhibit human
immunodeficiency virus replication in vitro (282). Mice
given the antiviral drug azidothymidine (AZT) showed significant
myelotoxic effects, which treatment with rhIGF-1 reversed as measured
by splenic and bone marrow progenitor cell content and blood cell
counts (283). The thymic atrophy caused by AZT in mice can also be
reversed by treatment with rhIGF-1 (284). Similar effects of GH have
been reported when it is given with AZT (285). The use of IGF-I in some
human diseases with an immunological component is also bought into
question by its immunological activities. For example, the
hypomyelination in the IGF-I null mouse (286) and the re-myelination in
damaged tissue in animal models of multiple sclerosis (287) suggest
that IGF-I might be useful for the treatment for multiple sclerosis.
However, the possible benefits of IGF-I on oligodendrocytes must be
balanced against the possible adverse effects of IGF-I enhancing immune
function and so stimulating the underlying immunological disease.
 |
X. Conclusions
|
|---|
Aging, stress, and nutrition affect blood concentrations of the
anabolic hormones GH, PRL, and IGF-I, which in turn modulate immune
function. Recent studies show that IGF-I plays an important role in the
maturation of lymphocytes in bone marrow and assists their function in
the periphery. In rodents, treatment with IGF-I can restore age-related
thymic involution, increase lymphocyte number and activity and improve
the reduced antibody response to an antigen challenge, and accelerate
lymphoid reconstitution after radiation and bone marrow
transplantation. IGF-I may act on lymphoid tissues via its potent
anti-apoptotic effects. Perhaps the anabolic hormones have a dual role
in regulating lymphopoiesis. First, in the well-fed, nonstressed state,
normal bone marrow may utilize the IGFs as cofactors for ongoing
lymphopoiesis. Second, during stress, IGF may be protective from tissue
damage, but if damage occurs it may also help restore a damaged immune
system. For these latter effects there may be a requirement for
endocrine IGF-I. These results imply that IGF-I may be useful as a
therapeutic in immunodeficient states.
 |
Acknowledgments
|
|---|
Dr. Paula Jardieu is thanked for her help and advice on matters
immunological and for the long and fruitful research collaboration that
led to much of the data and many of the ideas in this review.
Longstanding collaborations with Dr. Kenneth Dorshkind (University of
California, Riverside) and Dr. I. C. A. F. Robinson (Medical Research
Council, London) have also helped develop ideas, stimulated
experiments, and aided data interpretation. The excellent research
support at Genentech is acknowledged, especially that of Deborah
Mortensen, Joseph Strasser, Wesley Won, Yan Hui Ma, Winnie Werther, Kim
Robbins, Susan McCabe, and Dan Tumas.
 |
Footnotes
|
|---|
Address reprint requests to: Ross Clark, Ph.D., Endocrinology Group, MS 37, Genentech Inc., 390 Pt San Bruno Boulevard, South San Francisco, California 94080.
 |
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