Transplant Tolerance and Myeloid Supressor Cells

Abstract

The successful organ transplantation is currently dependent on chronic administration of immunosuppressive drugs to non-specifically suppress immune response, causing severe side effects, including infection and cancer. Induction of specific tolerance is ideal solution, which, indeed, naturally occurs. Thus, ˜1/4 liver transplants in farm pigs were spontaneously accepted, inducing systemic specific tolerance. In humans, weaning off, leading to complete stop of immunosuppressive has achieved in ˜1/4 liver transplant patients. The underlying mechanisms remain unclear. We have investigated mouse liver transplant tolerance, and noted that, different from liver transplants that are spontaneously accepted, hepatocyte transplants are acutely rejected, suggesting immune regulatory activity of liver non-parenchymal cells. Hepatic stellate cells (HSC) turn out to be potent immunosuppressors. Cotransplantation with HSC effectively protects islet allografts from rejection. We demonstrated in this study that, in contrast to myeloid (CD11b+) cells in islet alone grafts that were CD11c+, CD11b+ cells in HSC/islet grafts expressed low CD11c and costimulatory molecules, but high arginase 1 and iNOS, and markedly inhibited T cell response - sharing many properties with myeloid derived suppressor cells (MDSC). MDSCconsisting of heterogeneous cell populations were initially identified in cancer patients contributing to immune evasion. The impact of MDSC on transplant tolerance has not been extensively studied. MDSC. Induction of MDSC by cotransplantation with HSC was dependent on IFN-g stimulation since HSC deficient in IFN-gR1 largely lost the ability to induce MDSC, and failed to protect islet allografts. The induction of MDSC by HSC was also confirmed by addition of HSC into BM-derived DC culture. The harvested floating cells were predominantly CD11b+CD11c− (not CD11c+), expressed high arginase 1 and iNOS, but low CD40, CD80 and CD86. They expressed Gr-1, F4/80, Ly6C, suggesting heterogeneous nature. Transwell culture data suggested that induction of MDSC by HSC was mediated by soluble factors. They demonstrated potent inhibitory activity against T cell response. Cotransplantation with in vitro-generated MDSC achieved long-term survival in 64% islets allografts as effective as cotransplantation with HSC, associated with reduction of graft CD8 T cells via apoptosis (annexin V), and expansion of antigen-specific Treg cells, which was mediated by B7-H1 expressed on MDSC since the MDSC generated from mice deficient in B7-H1 expression markedly reduced their ability to protect the cotransplanted islet allografts due to failure to induce sufficient Treg cells. In conclusion, MDSC play a crucial role in induction of transplant tolerance. IFN-γ/B7-H1 pathway appears to be crucial in establishing peripheral tolerance. Large amounts of MDSC can be generated in vitro, and can potentially be used for induction of transplant tolerance.