Induction of cell transplant tolerance: a roadmap from bench to bedside (P2220)

Abstract

Abstract Organ transplants have worked for decades, but outcomes of cell transplants remain disappointing. Enlightened by mouse liver allografts being spontaneously accepted, but hepatocyte transplants acutely rejected (suggesting lack of non-parenchymal cell protection), we identified strong regulatory activity of hepatic stellate cells (HpSC). Islet allografts (300) mixed with HpSC (3x105) achieved long survival without immunosuppression, associated with apoptosis of CD8 T cells, enhancement of Tregs, which depends on IFNγ/B7-H1 pathway. However, co-transplanted HpSC have to be syngeneic to recipients - a hurdle for clinical application. We revealed that HpSC did not directly induce Tregs, but induce MDSC. Addition of HpSC in DC culture (1:40) generated MDSC (instead of DC) with high iNOS and argenase 1 and potent suppressive activity. The induction of MDSC was found to be mediated by soluble factors, particularly retinoic acid and iC3b. Islet allografts mixed with (or followed by iv injection of) generated MDSC (3x106) were protected as effectively as HpSC, associated with elimination of effector T and enhancement of Tregs, which also required intact IFNγ/B7-H1 signaling. Human HpSC were tested showing markedly T cell suppression in MLR, which was reversed by B7-H1 blocking Ab. Human HpSC also induced MDSC in vitro. We will reexamined these in vivo in a humanized NOD/SCID mouse model before pursue to clinical trial.