Prolonged Islet Graft Survival in NOD Mice by Blockade of the CD40-CD154 Pathway of T-Cell Costimulation

Abstract

Allorejection and recurrence of autoimmunity are the major barriers to transplantation of islets of Langerhans for the cure of type 1 diabetes in humans. CD40-CD154 (CD40 ligand) interaction blockade by the use of anti-CD154 monoclonal antibody (mAb) has shown efficacy in preventing allorejection in several models of organ and cell transplantation. Here we report the beneficial effect of the chronic administration of a hamster anti-murine CD154 mAb, MR1, in prolonging islet graft survival in NOD mice. We explored the transplantation of C57BL/6 islets into spontaneously diabetic NOD mice, a combination in which both allogeneic and autoimmune components are implicated in graft loss. Recipients were treated either with an irrelevant control antibody or with MR1. MR1 administration was effective in prolonging allograft survival, but did not provide permanent protection from diabetes recurrence. The autoimmune component of graft loss was studied in spontaneously diabetic NOD mice that received syngeneic islets from young male NOD mice. In this combination, a less dramatic yet substantial delay in diabetes recurrence was observed in the MR1-treated recipients when compared with the control group. Finally, the allogeneic component was explored by transplanting C57BL/6 islets into chemically induced diabetic male NOD mice. In this setting, long-term graft survival (>100 days) was achieved in MR1-treated mice, whereas control recipients rejected their grafts within 25 days. In conclusion, chronic blockade of CD154 results in permanent protection from allorejection and significantly delays recurrence of diabetes in NOD mice.

IddLoci Synergize to Prolong Islet Allograft Survival Induced by Costimulation Blockade in NOD Mice

“…The synergy observed between Idd5 and Idd3 that results in nearly complete protection from diabetes and insulitis and increases islet allograft survival to a C57BL/6-like frequency is dependent on the B10-derived Idd5. 2 Idd3, which is partially protective of diabetes, significantly improves islet allograft survival in the NOD mouse, with the strongest effect seen in the NOD.B6 Idd3 B10 Idd5 congenic strain. The Idd3 effect likely results from differential expression of IL-2 that modulates CD4 ϩ CD25…”

“…These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process. Diabetes 58: 165-173, 2009 T he NOD mouse is a model of type 1-like autoimmune diabetes and is used to study costimulation blockade-based transplantation tolerance within the context of autoimmunity (1)(2)(3)(4). However, costimulation blockade protocols fail in NOD mice.…”

Suppressor of Cytokine Signaling 1 Inhibits Cytokine Induction of CD40 Expression in Macrophages

“…Recently, increased numbers of CD40-positive microglia were detected in HIV-1-infected brain tissue (16). Because CD40 is functionally critical and nonredundant for the activation of immune responses, blocking the interaction between CD40-CD154 with anti-CD154 or CD40-Ig has been shown to be significantly beneficial in animal models of autoimmune diseases such as experimental autoimmune encephalomyelitis (17)(18)(19)(20), graft-vs-host disease (21,22), and atherosclerosis (23). These findings collectively illustrate the importance of CD40-CD154 interactions for homeostasis of immune responses.…”

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

“…We have previously reported that simultaneous administration of mAb targeting CD45RB and CD154 protected islet allografts in mice and allowed for the induction of tolerance in a large proportion of recipients in a nonautoimmune background (21). In addition, monotherapy with anti-CD154 mAb significantly prolonged survival of syngeneic and allogeneic islet transplants in spontaneously diabetic NOD mice (21).…”