Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation?

Abstract

The remarkable difference in success rates between clinical pancreas transplantation and islet transplantation is poorly understood. Despite the same histocompatibility barrier and similar immunosuppressive treatments in both transplantation procedures, human intraportal islet transplantation has a much inferior success rate than does vascularized pancreas transplantation. Thus far, little attention has been directed to the possibility that islets transplanted into the blood stream may elicit an injurious incompatibility reaction. We have tested this hypothesis in vitro with human islets and in vivo with porcine islets. Human islets were exposed to nonanticoagulated human ABO-compatible blood in surface-heparinized polyvinyl chloride tubing loops. Heparin and/or the soluble complement receptor 1 (sCR1) TP10 were tested as additives. Adult porcine islets were transplanted intraportally into pigs, and the liver was recovered after 60 min for immunohistochemical staining. Human islets induced a rapid consumption and activation of platelets. Neutrophils and monocytes were also consumed, and the coagulation and complement systems were activated. Upon histological examination, islets were found to be embedded in clots and infiltrated with CD11+ leukocytes. Furthermore, the cellular morphology was disrupted. When heparin and sCR1 were added to the blood, these events were avoided. Porcine islets retrieved in liver biopsies after intraportal islet allotransplantation showed a morphology similar to that of human islets perifused in vitro. Thus, exposure of isolated islets of Langerhans to allogenic blood resulted in significant damage to the islets, a finding that could explain the unsatisfactory clinical results obtained with intraportal islet transplantation. Because administration of heparin in combination with a soluble complement receptor abrogated these events, such treatment would presumably improve the outcome of clinical islet transplantation by reducing both initial islet loss and subsequent specific immune responses.

Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor

“…Intrahepatic infusion of isolated islets is the preferred site for clinical islet transplantation. However, instant coagulation/inflammation reaction (IBMIR), which is characterised by activation of the coagulation and complement systems, rapid binding and activation of platelets, leucocyte infiltration into the islets [13,14], and activation of endothelial cells, occurs regularly during this procedure, even without clinical signs of intraportal thrombosis [15][16][17]. Finally, these effects contribute to the disruption of islet morphology, islet dysfunction and death.…”

Exendin-4 treatment improves metabolic control after rat islet transplantation to athymic mice with streptozotocin-induced diabetes

“…If diabetes reversal could be achieved with a single donor, it would reduce costs and increase the availability of the islet transplantation procedure [2]. In the immediate posttransplantation period, a significant part of the graft is destroyed by the so-called instant blood-mediated inflammatory reaction [3]. The islet mass may diminish further as a result of hypoxia and hyperglycaemia.…”

“…Consequently, nonalloantigen-specific inflammatory events seem to be important in early graft destruction [4]. To confer protection on islets, various agents have been proposed for the pretreatment of donors [5], the culturing of islets [6] or the treatment of recipients [3,7,8] after transplantation, but the number of clinical studies to date is limited.…”

Clinical Islet Cell Transplantation – Recent Advances

“…In IBMIR, the discharged cytokines and chemokines, in relationship with antigen-presenting cells (APCs) assume a key role in the dynamics and pathogenies of this inflammation process. Furthermore, the primary damage to the islets is due to the invasion of leukocytes and macrophages before engraftment 19,20 . IBMIR is likewise characterized by coagulation, discharge of chemokine and complement activation.…”