Blockade of CD40-Mediated Signaling Is Sufficient for Inducing Islet But Not Skin Transplantation Tolerance

Abstract

Treatment of mice with a single donor-specific transfusion (DST) plus a brief course of anti-CD154 mAb to block CD40-mediated signaling uniformly induces donor-specific transplantation tolerance. Survival of islet allografts in treated mice is permanent, but skin grafts eventually fail unless recipients are thymectomized. The nature of the cellular mechanisms involved and the basis for the difference in survival of islet vs skin allografts are not known. In this study, we used CD40 knockout mice to investigate the role of CD40-mediated signaling in each component of the tolerance induction protocol: the DST, the graft, and the host. When CD40-mediated signaling was eliminated in only the DST or the graft, islet allografts were rapidly rejected. However, when CD40 signaling was eliminated in the host, ∼40% of the islet allografts survived. When CD40 signaling was eliminated in the DST, the graft, and the host, islet grafts survived long term (>84 days), whereas skin allografts were rapidly rejected (∼13 days). We conclude that transplantation tolerance induction in mice treated with DST and anti-CD154 mAb requires blockade of CD40-mediated signaling in the DST, the graft, and the host. Blockade of CD40-mediated signaling is necessary and sufficient for inducing islet allograft tolerance and is necessary but not sufficient for long-term skin allograft survival. We speculate that a requirement for regulatory CD4+ T cells in skin allograft recipients could account for this differential response to tolerance induction.

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

“…CD40-CD40L interactions at the pancreatic duct cell level could therefore contribute to beta cell damage in Type 1 diabetes and after islet transplantation. So far, the beneficial effects of CD40L blockade in preventing experimental autoimmune diabetes [28,29] and islet graft rejection [54,55,56] has been attributed to disruption of the interactions between antigen-presenting cells and T lymphocytes [26]. We suggest that CD40-CD40L targeted therapy could also act by preventing the local release of inflammatory cytokines by duct cells in the vicinity of pancreatic islets.…”

A functional CD40 receptor is expressed in pancreatic beta cells

“…In light of our findings, the inhibition of spontaneous diabetes reported in NOD mice treated with anti-CD154 antibody (anti-CD40L) [13] might be explained not only as a result of costimulatory blockade in APCs but also in beta cells. Likewise, blockade of the CD40 pathway promotes islet allograft survival in rodent transplantation models [44], and this effect could be partially dependent on the blockade of CD40 signalling in beta cells.…”

Immunoglobulin-Like Transcript 3-Fc Suppresses T-Cell Responses to Allogeneic Human Islet Transplants in hu-NOD/SCID Mice

“…There is evidence that the constitutive and selective expression of CD40 on the surface of ␤-cells contributes to autoimmunity and islet allograft rejection by providing costimulatory signals to infiltrating lymphocytes (6,8,10,12,39,40). It is, therefore, possible that in addition to suppressing islet allograft rejection in diabetic patients, ILT3-Fc may also prevent recurrence of diabetes by inhibiting the CD40-CD40L interaction between pancreatic islet cells and autoaggressive T-cells, primed to diabetagenic islet cell peptides presented by self-APCs.…”