A Critical Role of Sema4d (cd 100) in Reducing Graft-Versus-Host Disease in A Murine Major Mismatch Transplant

Sema4D (CD100) is a 150 kDa transmembrane protein member of the class IV semaphorin family that has immunomodulatory functions, and is essential for the activation and differentiation of antigen specific T cells. We investigated the effects of CD100 expression on T cells in allotransplantation. In vitro studies showed that T cells from genetically engineered CD100−/− mice expanded ten fold less than B6 wild type (wt) T cells (10800 ± 1229.9 vs. 1600 ± 258 cpm P < .01) in response to BALB/c allogeneic stimulators. We then evaluated the role of CD100 in vivo utilizing a well characterized experimental model of graft-versus-host disease (GvHD) where donor and recipient are mismatched at both major and minor histocompatibility antigens [B6 (H2b)→BALB/c (H2d)]. Recipient BALB/c animals were irradiated with 8 Gy and transplanted with 5.0 × 106 million bone marrow (BM) cells from B6 animals together with 0.5 million T cells from either B6 wild type (wt) or CD100 −/− donors. As shown in Table 1, at day 60 after transplant, mice that received CD100 −/− T cells had significantly less clinical GvHD scores and improved survival (P = .08) compared to allogeneic wt T cells. Recipients of CD100−/− T cells also demonstrated significantly reduced GvHD pathology in the intestine, liver and skin on day 60. All of BMT recipients showed complete donor engraftment. Examination of T cells in the spleen on day 14 showed that CD100 −/− T cells expanded fourfold less than wild type (P < .01). Together our data show that Sema4D is a co-stimulatory molecule that modulates T cell allogeneic responses both in vitro and in vivo and may represent a novel target for the prevention of GvHD (Table 1). Tabled 1Day post Transplantwt T CellsnCD100−/− T CellsnP ValueGvHD clinical score+604.6 ± 0.861.8 ± 0.26<.02Survival+6067%6100%6.08Liver pathology+6017.0 ± 1.549.0 ± 1.34<.01Skin pathology+601.5 ± 0.240.8 ± 0.24.02Intestinal pathology+607.8 ± 0.884.8 ± 1.08.03T cell expansion (×106)+143.95 ± 0.7850.83 ± 0.165<.0195% confidence interval. Open table in a new tab 95% confidence interval.