Abstract
The rate of graft survival has dramatically increased using calcineurin inhibitors, however chronic graft rejection and risk of infection are difficult to manage. Induction of allograft-specific regulatory T-cells (Tregs) is considered an ideal way to achieve long-term tolerance for allografts. However, efficient in vitro methods for developing allograft-specific Tregs which is applicable to MHC full-mismatched cardiac transplant models have not been established. We compared antigen-nonspecific polyclonal-induced Tregs (iTregs) as well as antigen-specific iTregs and thymus-derived Tregs (nTregs) that were expanded via direct and indirect pathways. We found that iTregs induced via the indirect pathway had the greatest ability to prolong graft survival and suppress angiitis. Antigen-specific iTregs generated ex vivo via both direct and indirect pathways using dendritic cells from F1 mice also induced long-term engraftment without using MHC peptides. In antigen-specific Treg transferred models, activation of dendritic cells and allograft-specific CTL generation were suppressed. The present study demonstrated the potential of ex vivo antigen-specific Treg expansion for clinical cell-based therapeutic approaches to induce lifelong immunological tolerance for allogeneic cardiac transplants.
Highlights
Transplantation is the ultimate treatment for patients with total loss of function of a life-sustaining organ
To induce alloantigen-specific T cells via the indirect pathway, T cells from CBA mice were cultured with Bone Marrow-Derived Dendritic Cells (BMDCs) from CBA mice loaded with the 15-mer (54–68) H-2Kb (Kb) peptide which is located in a hypervariable region of the Kb molecule of the MHC class I of C57BL/6 mice
This peptide was chosen because we have shown that intratracheal delivery of this peptide induced hyporesponsiveness to allogeneic cardiac grafts and generated regulatory cells [4]
Summary
Transplantation is the ultimate treatment for patients with total loss of function of a life-sustaining organ. New immunosuppressive drugs have improved allograft survival rates, but long-term administration of these agents may have serious side-effects, including nephrotoxicity, diabetes, neurotoxicity, and increased risk of infection and cancer [1,2,3]. These complications could be avoided by establishing a technique for donor-specific unresponsiveness or immunologic tolerance to donor alloantigens in transplant recipients. Adoptive transfer of splenocytes from mice pretreated intratracheally with the Kb peptide to naıve secondary recipients prolonged the survival of cardiac grafts, suggesting the generation of allograft antigen-specific regulatory cells. Generation of Tregs specific to the Kb peptide ex vivo as well as adoptive transfer could achieve successful prevention of cardiac allograft rejection
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