Intermittent Antibody-Based Combination Therapy Removes Alloantibodies and Achieves Indefinite Heart Transplant Survival in Presensitized Recipients

Abstract

BACKGROUND: It is well established that primed/memory T cells play a critical role in heart transplant rejection. This contributes to the challenges faced in the transplant clinic since current treatments which are efficient in controlling naïve T cell alloresponses have limited efficacy on primed T cell responders. METHODS: Fully MHC mismatched heart transplantation was performed from BALB/c to C57BL/6 mice pre-sensitised with BALB/c splenocytes 14 days pre-transplantation. A combination therapy comprising CD70-, CD154- and CD8-specific antibodies was administered at day 0 and 4 post-transplantation with Rapamycin on days 0-4. RESULTS: The antibody combination therapy extended heart transplant survival in pre-sensitised recipients from MST 8 days (median survival time) to MST 78 days. A decrease in the number of splenic IFN-γ secreting cells measured by ELISpot assay was seen in the treated group compared to the untreated controls. However, graft-infiltrating CD8(+) and CD4(+) T cells persisted despite treatment and the number of intra-graft CD4(+) T cells increased at day 30 post-transplantation. When an additional “rescue therapy” comprising the same antibodies was re-administered at days 30, 60 and 90 post-transplantation, T cell infiltration was reduced and indefinite graft survival was observed. Furthermore, rescue therapy resulted in gradual decrease in titre and, by day 90 post-transplantation the complete loss of the pre-existing, donor-specific antibodies. CONCLUSION: We conclude that our antibody combination therapy extends allograft survival in pre-sensitised recipients. When combined with intermittent antibody-mediated rescue therapy, this results in indefinite allograft survival and a loss of the pre-existing, donor-specific antibodies from the circulation