Abstract
Bone marrow was recently proposed as an alternative and potentially immune-privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow) and 10 days (kidney capsule). Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation.
Highlights
The incidence of type 1 diabetes is constantly rising in children and adolescents since the mid-1950’s [1,2]
The liver, the currently used site for islet transplantation, has several disadvantages including: (i) immediate blood-mediated inflammatory reaction (IBMIR) characterized by the activation of complement, platelets and coagulation as well as neutrophil recruitment, induces the loss of as many as 50–75% of islets during engraftment [25]; (ii) risk for hemorrhages associated with the infusion through the liver parenchyma into the portal vein; and (iii) increase of portal pressure during the procedure which limits both the number and mass of administered islets, and precludes the transplantation of encapsulated islets with a diameter up to 500 mm [26]
Transplantation into the bone marrow (BM) of 1000 rat islets equivalent (IEQ) and 3000 human IEQ per mice was required in order to reverse diabetes, which is 2–3 times higher than what is required for a xenogeneic islets transplant under the kidney capsule (KC) [19]
Summary
The incidence of type 1 diabetes is constantly rising in children and adolescents since the mid-1950’s [1,2]. Allotransplantation of pancreatic islets is currently an option for the treatment of diabetic type-I patients suffering from repetitive and severe hypoglycemic episodes. The possibility of receiving an islet transplant is limited mainly due the shortage of organ and the need for life-long immunosuppression. The utilization of islets from other species (xenograft) and administration in encapsulated form represent attractive strategies to overcome both problems. Clinical trials of allogeneic human or xenogeneic pig encapsulated islets have been reported in only a few cases [3,4]. After intra-peritoneal transplantation all patients showed a modest reduction in insulin requirement and a significant diminution of hypoglycemic episodes without any detectable immune response against the islets. Sustained insulin-independence was not achieved after encapsulated allogeneic islet transplantation. Islets are highly vascularized structures depending on an arterial oxygen supply of
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