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

Abstract

Reported effects of anti-CD154 treatment on autoimmunity, alloreactivity, and inf lammatory events mediated by macrophages and endothelial cells indicated that it might be an ideal agent for the prevention of intrahepatic islet allograft failure. This hypothesis was tested in MHCmismatched rhesus monkeys. Transplantation of an adequate number of viable islets resulted in engraftment and insulin independence in six of six recipients treated with anti-CD154 (hu5c8) induction plus monthly maintenance therapy (postoperative day >125, >246, >266, >405, >419, >476). Anti-CD154 (hu5c8) displayed no inhibitory effect on islet cell function. For monkeys followed for >100 days, continued improvement in graft function, as determined by first phase insulin release in response to intravenous glucose, was observed after the first 100 days post-transplant. No evidence of toxicity or infectious complications has been observed. All recipients treated with anti-CD154 became specifically nonresponsive to donor cells in mixed lymphocyte reactions. Furthermore, three monkeys are now off therapy (>113, >67, and >54 days off anti-CD154), with continued insulin independence and donor-specific mixed lymphocyte reaction hyporeactivity. In striking contrast to all previously tested strategies, transplantation of an adequate number of functional islets under the cover of anti-CD154 (hu5c8) monotherapy consistently allows for allogeneic islet engraftment and long-term insulin independence in this highly relevant preclinical model.Islet cell transplantation for patients with type 1 diabetes can result in the reversal of hyperglycemia and normalization of metabolic control (1-7). Broad-based application of curative islet cell transplantation has been limited, however, by the inability of current, generalized immunosuppressive reagents to reliably support long-term islet graft survival and function. The CD40-CD154 costimulation pathway has proven to be a critical interaction in the generation of a T-dependent immune response (8-10), and blockade of this pathway has prevented allograft rejection (11-16), graft versus host disease (17-19), and autoimmunity (20-29) in rodent models. Humanized anti-CD154 (30) (hu5c8, Biogen) has been shown to prevent renal allograft rejection in a rigorous non-human primate model (31). Additionally, blockade of the CD40-CD154 costimulation pathway can prevent production of proinflammatory mediators by activated macrophages (32-34) and endothelial cells (35)(36). Blockade of this pathway, therefore, has the potential to prevent allograft rejection, recurrent autoimmunity, and the nonspecific inflammatory events that occur on transplantation of islets into the liver, without the adverse effects of conventional, generalized immunosuppressive drugs on islet function (37). This study was undertaken to determine whether anti-CD154 (hu5c8) monotherapy would prevent the rejection of allogeneic islets in a preclinical, non-human primate model of pancreatectomy-induced diabetes.

Prolonged Blockade of CD40-CD40 Ligand Interactions by Gene Transfer of CD40Ig Results in Long-Term Heart Allograft Survival and Donor-Specific Hyporesponsiveness, But Does Not Prevent Chronic Rejection

“…Blockade of CD40-CD40L interactions by the use of anti-CD40L mAbs in mice (12)(13)(14)(15)(16)(17)(18) and primates (19,20) has resulted in prolongation of allograft survival. However, in only some of these studies, a fraction of the recipients showed long-term engraftment (12,17,19,20).…”

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.…”

CTLA-4Ig in Combination with Anti-CD40L Prolongs Xenograft Survival and Inhibits Anti-Gal Ab Production in GT-Ko Mice

“…CD40 ligand (CD154) monoclonal antibodies (Anti-CD40L mAbs), alone or in combination with CTLA-4-immunoglobulin fusion protein (CTLA-4Ig), have been reported to induce long-term allograft survival and tolerance in a number of transplantation models (1)(2)(3)(4)(5)(6). The efficacy of these treatments can be variable and has been reported to be affected by the strain of the mouse recipient, the type of tissue transplanted, the age of the recipient and whether the response is a memory or naïve one (7)(8)(9)(10).…”