The Immunobiology of Inductive Anti-CD40L Therapy in Transplantation: Allograft Acceptance is Not Dependent Upon the Deletion of Graft-Reactive T Cells

Abstract

CD40-CD40L costimulatory interactions are crucial for allograft rejection, in that treatment with anti-CD40L mAb markedly prolongs allograft survival in several systems. Recent reports indicate that costimulatory blockade results in deletion of graft-reactive cells, which leads to allograft tolerance. To assess immunologic parameters that were influenced by inductive CD40-CD40L blockade, cardiac allograft recipients were treated with multiple doses of the anti-CD40L mAb MR1, which was remarkably effective at prolonging allograft survival. Acute allograft rejection responses such as IL-2 producing helper cell priming, Th1 priming, and alloantibody production were abrogated by anti-CD40L treatment. Interestingly, the spleens of mice bearing long-term cardiac allografts following inductive anti-CD40L treatment retained precursor donor alloantigen-reactive CTL, IL-2 producing helper cells, and Th1 in numbers comparable to those observed in naïve mice. These mice retained the ability to reject donor-strain skin allografts, but were incapable of rejecting the original cardiac allograft, or a second donor-strain cardiac allograft. Further, differentiated effector cells were incapable of mediating rejection following adoptive transfer into mice bearing longterm allografts, suggesting that regulatory cell function, rather than effector cell deletion was responsible for long-term graft acceptance. Collectively, these data demonstrate that inductive CD40-CD40L blockade does not result in the deletion of graft-reactive T cells, but induces the maintenance of these cells in a quiescent precursor state. They further point to a tissue specificity of this hyporesponsiveness, suggesting that not all donor alloantigen-reactive cells are subject to this regulation.

CD4+ T Regulatory Cell Induction and Function in Transplant Recipients after CD154 Blockade Is TLR4 Independent

“…In fact, this has been the major controversial issue in the mechanism of CD154 blockade in promoting allograft survival (14,15,17). The results of our experiments in in vivo setting of primary tolerant recipients have confirmed several previous findings primarily from adoptive transfer cell systems, that CD4…”

“…To identify the type of CD4 ϩ Treg that controls alloreactive CD8 ϩ T cells and maintains graft survival in our model, we used anti-CD25 mAb treatment, which has been shown to efficiently deplete CD4 ϩ CD25 ϩ T cells in both autoimmune disease and tumor models (14,15). Depletion of CD4 ϩ CD25 ϩ cells resulted in the rejection of donor-type skin grafts in ϳ70% of long-term hosts, albeit with somewhat delayed kinetics (MST Ϯ SD ϭ 14 Ϯ 2 days; n ϭ 4, Fig.…”

Blockade of CD27/CD70 pathway to reduce the generation of memory T cells and markedly prolong the survival of heart allografts in presensitized mice

“…This was consistent with previous studies showing that blocking the CD27/70 pathway effectively inhibited the function and generation of memory T cells [28,29]. Furthermore, we found that this treatment regimen abrogated the production of IgG1/IgG2a alloantibodies in recipient mice, were consistent with a prior study by Nathan et al demonstrating that anti-CD154 treatment could abrogate the production of alloantibodies [30]. CD154 is a key molecule in the contact-mediated signaling required for B cell activation and differentiation and can induce Ig isotype switching [31,32], while the CD27/CD70…”

Memory Alloreactive B Cells and Alloantibodies Prevent Anti-CD154-Mediated Allograft Acceptance

“…One approach to successfully achieving long-term graft survival in murine cardiac allograft models is with anti-CD154 (MR1) mAb therapy (3)(4)(5)(6)(7)(8). Blocking CD40-CD154 interactions abrogates both naive B cell responses and T cell priming (9).…”