Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154.

Abstract

Clinical islet cell transplantation has resulted in insulin independence in a limited number of cases. Rejection, recurrence of autoimmunity, and impairment of normal islet function by conventional immunosuppressive drugs, e.g., steroids, tacrolimus, and cyclosporin A, may all contribute to islet allograft loss. Furthermore, intraportal infusion of allogeneic islets results in the activation of intrahepatic macrophages and endothelial cells, followed by production of proinflammatory mediators that can contribute to islet primary nonfunction. We reasoned that the beneficial effects of anti-CD154 treatment on autoimmunity, alloreactivity, and proinflammatory events mediated by macrophages and endothelial cells made it an ideal agent for the prevention of islet allograft failure. In this study, a nonhuman primate model (Papio hamadryas) was used to assess the effect of humanized anti-CD154 (hu5c8) on allogeneic islet engraftment and function. Nonimmunosuppressed and tacrolimus-treated recipients were insulin independent posttransplant, but rejected their islet allografts in 8 days. Engraftment and insulin independence were achieved in seven of seven baboon recipients of anti-CD154 induction therapy administered on days -1, 3, and 10 relative to the islet transplant. Three of three baboons treated with 20 mg/kg anti-CD154 induction therapy experienced delayed rejection episodes, first detected by elevations in postprandial blood glucose levels, on postoperative day (POD) 31 for one and on POD 58 for the other two. Re-treatment with three doses of anti-CD154 resulted in reversal of rejection in all three animals and in a return to normoglycemia and insulin independence in two of three baboons. It was possible to reverse multiple episodes of rejection with this approach. A loss of functional islet mass, as detected by reduced first-phase insulin release in response to intravenous glucose tolerance testing, was observed after each episode of rejection. One of two baboons treated with 10 mg/kg induction therapy became insulin independent post-transplant but rejected the islet graft on POD 10; the other animal experienced a reversible rejection episode on POD 58 and remained insulin independent and normoglycemic until POD 264. Two additional baboon recipients of allogeneic islets and donor bone marrow (infused on PODs 5 and 11) were treated with induction therapy (PODs -1, 3, 10), followed by initiation of monthly maintenance therapy (for a period of 6 months) on POD 28. Rejection-free graft survival and insulin independence was maintained for 114 and 238 days, with preservation of functional islet mass observed in the absence of rejection. Prevention and reversal of rejection, in the absence of the deleterious effects associated with the use of conventional immunosuppressive drugs, make anti-CD154 a unique agent for further study in islet cell transplantation.

Successful Reversal of Streptozotocin-Induced Diabetes With Stable Allogeneic Islet Function in a Preclinical Model of Type 1 Diabetes

“…This group has now been expanded to 13 patients, the large majority of whom are insulin-independent at 1 year (Rajotte R, personal communication). Notably, prolonged reversal of type 1 diabetes with novel immunosuppressive and tolerogenic strategies has also been reported after isolated islet transplantation in four nonhuman primate series (2)(3)(4)(5). Kenyon et al (3,4) reported long-term survival in seven of seven baboon and six of six rhesus monkey recipients using monthly maintenance immunosuppressive therapy with anti-CD154 (hum58Biogen).…”

Prolonged Islet Allograft Survival in Diabetic NOD Mice by Targeting CD45RB and CD154

“…Treatment with anti-CD154 mAb induced long-term allograft acceptance in several transplantation models (13)(14)(15)(16) and efficiently prevented autoimmune diseases (17,18), including diabetes (19 -21). CD154 is a tumor necrosis factor receptor family member involved (via binding to CD40) in T-cell co-stimulation (signal 2) after antigen recognition.…”

A self-immunomodulating myoblast cell line for erythropoietin delivery

“…40,41 A maintenance therapy with agents blocking T cell costimulation was required for the long-term survival of islets and kidneys allografted in non-human primate models. 5,9,10 The constant expression of CTLA4Ig may provide a means to prevent the late rejection events without the constraints of systemic treatments. However, the long-term efficacy of a sustained localized delivery remains to be tested with non-dividing cells.…”

“…7 CD154 blockade allowed the long-term survival of mouse islet allografts when combined with injections of donor small lymphocytes 8 and was recently reported to permit the acceptance of allogeneic islets in two non-human primate models. 9,10 Fewer studies, however, have evaluated the effect of these molecules on transplantation of other cell types. Intraperitoneal injections of CTLA4Ig combined with anti-CD4 monoclonal antibodies improved the efficiency of myoblast allotransplantation.…”