Donor-Specific Regulatory T Cell-Mediated Immune Tolerance in an Intrahepatic Murine Allogeneic Islet Transplantation Model with Short-Term Anti-CD154 mAb Single Treatment

Abstract

Anti-CD154 blockade-based regimens remain unequaled in prolonging graft survival in various organ transplantation models. Several studies have focused on transplantation tolerance with the anti-CD154 blockade, but none of these studies has investigated the mechanisms associated with its use as the sole treatment in animal models, delaying our understanding of anti-CD154 blockade-mediated immune tolerance. The purpose of this study was to investigate the mechanism underlying the anti-CD154 monoclonal antibody (mAb) blockade in inducing immune tolerance using an intrahepatic murine allogeneic islet transplantation model. Allogeneic BALB/c AnHsd (BALB/c) islets were infused into the liver of diabetic C57BL/6 (B6) mice via the cecal vein. Anti-CD154 mAb (MR1) was administered on −1, 0, 1, 3, 5, and 7 d posttransplantation at 0.5 mg per mouse. We showed that short-term MR1 monotherapy could prolong the allogeneic islet grafts to more than 250 d in the murine intrahepatic islet transplantation model. The second islet grafts transplanted under the kidney capsule of the recipients were protected from rejection. We also found that rejection of same-donor skin grafts transplanted to the tolerant mice was modestly delayed. Using a DEREG mouse model, FoxP3+ regulatory T (Treg) cells were shown to play important roles in transplantation tolerance. In mixed lymphocyte reactions, Treg cells from the tolerant mice showed more potency in suppressing BALB/c splenocyte-stimulated Teff cell proliferation than those from naïve mice. In this study, we demonstrated for the first time that a short-term anti-CD154 mAb single treatment could induce FoxP3+ Treg cell-mediated immune tolerance in the intrahepatic murine allogeneic islet transplantation model.

Long-term survival and induction of operational tolerance to murine islet allografts through the co-transplantation of cyclosporine A eluting microparticles

“…However, C3H skin (third-party skin) rejection was comparable between islets + CsA microparticles + CTLA4-Ig treated recipients and control recipients. Our skin grafts results are consistent with previous reports whereby naïve B6 mice rejected BALB/c skin allografts at 14 days posttransplant whereas intrahepatic islet transplanted tolerant B6 mice showed a modest prolongation of skin allograft survival for up to 17 days posttransplant (19). Our observations, align with others that reported that tolerance to Fas ligand chimeric with streptavidin (SA-FasL)-engineered islet grafts is donor-specific and systemic at the induction phase.…”

In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways

“…Using a DEREG mouse model Lee et al. demonstrated that a short-term blockade of CD154 could lead to Treg mediated immune tolerance in the intrahepatic murine allogeneic islet transplantation model ( 196 ). Animal studies are supported by clinical data where CD154 blockade in relapsing-remitting multiple sclerosis patient demonstrated an increase of CD25+ T cells and anti-inflammatory cytokines ( 197 ).…”

The Influence of Microenvironment on Survival of Intraportal Transplanted Islets

“…Immune tolerance induction is a promising strategy to accept histocompatibility complex (MHC)-mismatched allografts without reducing resistance to infection or increasing other complications ( 67 ). For immunological tolerance to allografts, the high proportion of MHC alloreactive T cell is considered as a major barrier to tolerance induction.…”

“…And in the intrahepatic mouse allogeneic islet transplantation model, Lee et al. demonstrated for the first time that short-term single administration of anti-CD154 monoclonal antibody could induce FoxP3+ Treg cell-mediated immune tolerance ( 67 ).…”