Induction of Accommodation by Anti–complement Component 5 Antibody-based Immunosuppression in ABO-incompatible Heart Transplantation

Abstract

Background. Plasmapheresis in combination with immunoglobulin and rituximab is often used to induce accommodation in ABO-incompatible (ABOi) living-donor transplantation; however, this regimen cannot be applied to cases of ABOi deceased-donor transplantation. Here, we investigated whether an anti–complement component 5 (C5) antibody-based regimen can induce accommodation in ABOi heart transplantation. Methods. Both IgM and IgG anti-blood type A antibodies were induced in wild-type mice by sensitization using human blood type A antigen. Heterotopic ABOi heart transplantation was performed from human blood type A-transgenic C57BL/6J mice to sensitized wild-type DBA/2 mice. Results. Either anti-C5 antibody or conventional triple immunosuppressants (corticosteroid, tacrolimus, mycophenolate mofetil) alone did not induce accommodation in majority of ABOi heart allografts, whereas their combination induced accommodation in more than 70% of cases despite the presence of anti-A antibodies. The combination therapy markedly suppressed the infiltration of T cells and macrophages into ABOi allografts, despite mild deposition of IgG and C4d. T-cell activation and differentiation into Th1, Th2, and Th17 cells were suppressed along with CD49dhighCD4+ T and follicular helper T cells in the combination treatment group. CD24+ B cells, including both CD24+CD23+ marginal zone B cells and CD24+CD23− T2-marginal zone B cells, were increased in the accommodation group. Conclusions. C5 inhibitor-based immunosuppression induced accommodation in murine ABOi heart transplantation, presenting a promising strategy for ABOi deceased-donor transplantation.

Anti-C5 Antibody Tesidolumab Reduces Early Antibody-mediated Rejection and Prolongs Survival in Renal Xenotransplantation

“…Tacrolimus-based immunosuppression is the industry standard for renal allotransplantation, and was able to prolong survival to at least 56 days in the Park's ABO incompatible mouse cardiac allograft model. 12 We tested tesidolumab for its ability to prolong survival of GGTA1/ b4GalNt2 KO pig kidneys and the results were clear. Although tesidolumab delayed the onset of AMR, it did not provide enough protection to allow tacrolimus to prolong survival in the rhesus monkey to the point where an argument could be made that clinical success was likely.…”

“…Having circumvented the initial obstacle in the preclinical model using an acceptable clinical intervention with anti-C5, our next task was to evaluate whether prolonged renal xenograft survival could be achieved using a clinically acceptable baseline immunosuppressive reagent instead of the anti-CD154 (5c8) that is not a clinically acceptable drug based on thromboembolic complications encountered in clinical trials in renal allotransplantation. Tacrolimus-based immunosuppression is the industry standard for renal allotransplantation, and was able to prolong survival to at least 56 days in the Park's ABO incompatible mouse cardiac allograft model 12 . We tested tesidolumab for its ability to prolong survival of GGTA1/β4GalNt2 KO pig kidneys and the results were clear.…”

“…In this model, if early AMR was avoided the cardiac allografts were able to survive in recipients treated with a clinically available immunosuppressive regimen of tacrolimus, mycophenolic acid, and steroids. 12 If temporary anti-C5 therapy can prevent early AMR of renal xenografts in a preclinical model that would be significant since eculizumab is readily available and there is clinical experience with this drug in renal allotransplantation. 13 As eculizumab does not bind to NHP C5, we tested anti-C5 antibody tesidolumab for its ability to prevent early AMR in the pig-to-Rhesus kidney xenotransplant model.…”

“…Anti-C5 antibodies have been used to prevent early AMR in a mouse model of ABO incompatible model of heart allotransplantation. In this model, if early AMR was avoided the cardiac allografts were able to survive in recipients treated with a clinically available immunosuppressive regimen of tacrolimus, mycophenolic acid, and steroids 12 . If temporary anti-C5 therapy can prevent early AMR of renal xenografts in a preclinical model that would be significant since eculizumab is readily available and there is clinical experience with this drug in renal allotransplantation 13 .…”

Suppressive effects of vitamin C-treated induced-regulatory T cells on heart allograft rejection under vitamin C-deficient or –sufficient conditions

“…Hearts from BALB/c mice were transplanted into the abdomen of WT or Gulo-KO B6 mice (S1 Appendix) [23]. One day prior to transplantation, iTreg cells from CD45.1 + Foxp3 GFP KI B6 mice (2 × 10 6 ) were intravenously transferred into CD45.2 + recipient mice.…”