The immunobiology of inductive anti-CD40L therapy in transplantation: allograft acceptance is not dependent upon the deletion of graft-reactive T cells.
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 long-term 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.
Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor 48109, USA.
Meera J
MJ
Nathan
Dengping
D
Yin
Ernst J
EJ
Eichwald
D Keith
DK
Bishop
D000818:Animals; D023201:CD40 Ligand / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013997:Time Factors; D014181:Transplantation Immunology; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology
D007376:Interleukin-2; D023201:CD40 Ligand; D007371:Interferon-gamma