Abstract
Background: We have shown previously that the mutated class I MHC molecules abrogate acute and chronic rejection and attenuate transplant vascular sclerosis (TVS) through the early changes (1-7 days post-transplantation) in T cell and dendritic cell molecular response. Here we studied a cohort of long-term (100 days) graft survival recipients for changes in T cell molecular response, and the role of regulatory T cells in the abrogation of chronic rejection in adoptive transfer experiments. Methods: Heterotopic cardiac transplants were performed between donor Wistar Furth (WF) and ACI recipient rats. Controls received no treatment or 6 days therapeutic dose of cyclosporine (CsA 10mg/kg). The experimental group of primary ACI recipient received, peri-operatively, the allochimeric [[?]1h l/u]-RT1.Aa MHC I molecule (1mg/kg) in conjunction with the sub-therapeutic dose of CsA for 3 days. Splenic T cells were isolated from ACI recipient at 100 days post-transplantation and either assessed for changes in the expression of chosen protein markers or, in adoptive transfer experiments; they were injected into lightly irradiated secondary ACI recipients grafted with WF hearts. Secondary cardiac grafts were harvested at 100 days of post-transplantation for assessment of chronic rejection, neointimal index (NI) and apoptosis. Results: Secondary cardiac grafts from recipients exposed to allochimeric MHC I-conditioned splenic total T cells or CD4+ T cells showed significantly reduced NI and apoptosis, and were selectively infiltrated with CD4+Foxp3+ (T regulatory, Treg) cells. Conclusion: Adoptive transfer of allochimeric MHC I-conditioned T cells promotes development of Treg cells and attenuates chronic rejection in rat cardiac model system.
Highlights
Peter Medawar’s studies on the induction of acquired tolerance to foreign tissue using fetal exposure to donor-derived antigens led to numerous studies on protein therapy in abrogating graft rejection and promoting tolerance induction [1]
We showed that allochimeric MHC I treatment caused the inhibition of T cell migration into the graft, restriction of their Vβ-TCR repertoire [3], and induced changes in T cell actin cytoskeleton and down-regulation of numerous molecules involved in actin organization (RhoA, HIPP55), cell polarity (PAR6) and intracellular antigen trafficking (KDEL, GM130; 8-11)
We had previously proposed that some of the anti-rejection effects attributed to allochimeric MHC I therapy rely on acute changes in T cell cytoskeletal organization and in down-regulation of effector molecules involved in actin distribution, T cell motility and Rho GTPases (Rho A and Rock-1) and MAPK signaling pathways [8,9,10]
Summary
Peter Medawar’s studies on the induction of acquired tolerance to foreign tissue using fetal exposure to donor-derived antigens led to numerous studies on protein therapy in abrogating graft rejection and promoting tolerance induction [1]. Numerous studies indicate that the indirect antigen recognition pathway and CD4+ T cells play a major role in both acute and chronic rejection and the development of tolerance [2,3]. We have shown previously that the mutated class I MHC molecules abrogate acute and chronic rejection and attenuate transplant vascular sclerosis (TVS) through the early changes (1-7 days post-transplantation) in T cell and dendritic cell molecular response. We studied a cohort of long-term (100 days) graft survival recipients for changes in T cell molecular response, and the role of regulatory T cells in the abrogation of chronic rejection in adoptive transfer experiments
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