Pancreas And Islet Transplant For Autoimmune Type 1 Diabetes Mellitus

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In contrast to HSCT for rheumatic autoimmune diseases, HSCT for patients with type 1 diabetes cannot provide relief from clinical symptoms of chronic disease. Frequently, clinical presentation of type 1 diabetes is subsequent to autoimmune-mediated damage to islet p cells; therefore, damaged or destroyed endocrine tissue must be regenerated or replaced in order to alleviate clinical manifestations of disease. Conversely, islet or pancreas transplant may lead to recurrent autoimmune-mediated destruction of donor tissue, and thus HSCT may be necessary to cure autoimmunity before endocrine tissue replacement.

Pancreatic transplantation has been used to correct insulin deficiency in patients with type 1 diabetes, and is performed most often in conjunction with renal transplantation in patients with diabetic nephropathy (55). Solid-organ transplantation for type 1 diabetes is limited to patients with life-threatening disease; however, because of the risks associated with invasive surgical procedures and toxicity of immunosuppressive therapies, it is necessary to induce and maintain allograft tolerance (55). Nevertheless, in a review of more than 2000 pancreas transplants performed in the United States, functional survival of transplanted pancreas was observed in greater than 70% of patients 1 year after transplant, although this rate declined to 66% at 2 years, and 59% at 3 years (55).

Transplantation of pancreatic islets alone may be as effective as pancreas transplant in reversing insulin dependence, and pancreatic islets can be implanted into the portal vein without resort to invasive surgery. Until recently, islet transplantation for type 1 diabetes was largely unsuccessful in the clinical setting; only 8% of patients receiving allogeneic islet transplants remained insulin independent for more than 1 year (56). Recently, a small number of patients received islet allografts from cadaveric donors with immunosuppressive therapy modi fied to omit corticosteroids, and with procedural modifications in islet preparation (known as the Edmonton protocol) (57). Successful engraftment of cadaveric pancreatic islets was achieved in 15 of 21 patients (71%) with the Edmonton protocol (58), and 1 year after transplant, 12 of these 15 patients were insulin-independent (59). In a more recent report, 82% of 40 patients accepting cadaver islet transplants with the Edmonton protocol at the University of Alberta remained insulin-independent at 1 year posttransplant (60).

The improved success of islet transplantation with the Edmonton protocol may be explained, in part, by procedural modifications in donor islet preparation, the large number of viable islets transplanted (>9,000 islet equivalents/kilogram body weight of the patient), and the modifications made to the immunosuppressive therapy. The Edmonton protocol uses a corticosteroid-free immunosuppressive regimen consisting of daclizumab (Zenapax), low-dose tacrolimus (Prograf), and sirolimus (Rapamune). The omission of corticosteroids, particularly in light of the possible synergy in diabetogenic effect between tacrolimus and corticosteroids (61), may allow for improved outcome of allogeneic islet transplants by controlling immune response toward allogeneic cells while suppressing autoimmune response.

Although the markedly improved success of islet transplantation with the Edmonton protocol is promising, both the high number of donor islets (requiring two to three donor pancreases per transplant recipient) and the necessity for chronic immunosuppressive therapy remain barriers to widespread clinical application. Also, although indications for islet transplant include severe hy-poglycemia unawareness or severe metabolic instability, intrahepatic islet transplant does not restore hypoglycemic hormonal counterregulation (62). Finally, risk of recurrent autoimmune disease after pancreas or islet transplantation has yet to be adequately addressed.

Consistent with the finding that autoimmune T-cell reactivity toward islet antigens may persist up to 26 years after disease onset (63), autoimmune destruction of donor islets (as opposed to allogeneic graft rejection) has been observed in a subset of patients after cadaveric pancreas transplants (64). Likewise, antibodies specific to islet p-cell antigens have been observed after pancreas transplant, despite continued graft function and immunosuppressive therapies (65). Furthermore, of the three patients transplanted with the Edmonton protocol who had initially successful islet grafts but that subsequently failed, two patients had antibodies specific to glutamic acid decarboxylase and islet cell antigen after islet transplant, suggesting that graft failure resulted from recurrent autoimmunity.

The incidence of recurrent autoimmunity after islet or pancreas transplant may be dependent on the extent of immunosuppression. In one clinical study, autoimmune reactivity toward islet p cells of donor pancreas was associated with decreased immunosuppressive therapies in recipients of HLA-matched sibling and identical twin donor organs (66). Whereas patients receiving reduced immunosuppressive therapy following HLA-matched sibling and identical twin organs showed recurrent autoimmunity toward transplanted islet p cells, patients receiving sibling-matched donor pancreas transplant with aggressive immuno-suppressive therapy did not manifest recurrent autoimmune destruction of islet p cells. If pseudo-autologous (identical twin) or HLA-matched sibling organs are protected from autoimmune-mediated destruction after aggressive immunosup-pressive therapy, then dose escalation of immunosuppressive therapy with subsequent autologous HSCT to recapitulate hematopoieses is a promising approach to inducing tolerance to islet p cells. Nevertheless, alternative explanations for the observed autoimmune recurrence are possible. For instance, cumulative effects of chronic immunosuppressive agents such as tacrolimus may contribute to the loss of insulin independence. Another explanation is that patients with autoimmune recurrence following allogeneic islet or pancreas transplantation may represent a specific subset of patients with unique disease severity or manifestation (perhaps resulting from impaired renal function or specific genetic susceptibility loci). Finally, studies in the NOD mouse model suggest that MHC class II matching favors recurrent destruction of transplanted islet cells (67).

Ultimately, the possibility of recurrent autoimmune destruction of transplanted islets or allograft rejection after islet or pancreas transplant necessitates use of chronic immunosuppressive therapy. Chronic immunosuppressive therapies are associated with organ toxicity, opportunistic infections, and an increased incidence of cancer (reviewed in ref. 43). Clearly, therapies designed to induce immunologic tolerance to transplanted islet p-cell antigens (both autoimmune stimulating and allograft associated antigens) would improve the quality of life of transplant recipients, and likewise may improve rates of both engraftment and function of transplanted pancreatic islets.

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