Resolving the Conundrum of Islet Transplantation by Linking Metabolic Dysregulation, Inflammation, and Immune Regulation
Xiaolun Huang1,
Daniel J. Moore1,
Robert J. Ketchum,
Craig S. Nunemaker,
Boris Kovatchev,
Anthony L. McCall and
Kenneth L. Brayman
Department of Surgery (X.H., R.T.K., K.L.B.), Division of Transplantation; Department of Medicine (C.S.N., A.L.M.), Division of Endocrinology; and Department of Psychiatry and Neurobehavioral Sciences (B.K.), University of Virginia, Charlottesville, Virginia 22908; Department of Pediatrics (D.J.M.), Division of Pediatric Endocrinology, Vanderbilt Children’s Hospital, Nashville, Tennessee 37232-9170
Although type 1 diabetes cannot be prevented or reversed, replacementof insulin production by transplantation of the pancreas orpancreatic islets represents a definitive solution. At present,transplantation can restore euglycemia, but this restorationis short-lived, requires islets from multiple donors, and necessitateslifelong immunosuppression. An emerging paradigm in transplantationand autoimmunity indicates that systemic inflammation contributesto tissue injury while disrupting immune tolerance. We identifymultiple barriers to successful islet transplantation, eachof which either contributes to the inflammatory state or isaugmented by it. To optimize islet transplantation for diabetesreversal, we suggest that targeting these interacting barriersand the accompanying inflammation may represent an improvedapproach to achieve successful clinical islet transplantationby enhancing islet survival, regeneration or neogenesis potential,and tolerance induction. Overall, we consider the proinflammatoryeffects of important technical, immunological, and metabolicbarriers including: 1) islet isolation and transplantation,including selection of implantation site; 2) recurrent autoimmunity,alloimmune rejection, and unique features of the autoimmune-proneimmune system; and 3) the deranged metabolism of the islet transplantrecipient. Consideration of these themes reveals that each isinterrelated to and exacerbated by the other and that this connectionis mediated by a systemic inflammatory state. This inflammatorystate may form the central barrier to successful islet transplantation.Overall, there remains substantial promise in islet transplantationwith several avenues of ongoing promising research. This reviewfocuses on interactions between the technical, immunological,and metabolic barriers that must be overcome to optimize thesuccess of this important therapeutic approach.
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