Roles of Host Nonhematopoietic Cells in Autoimmunity and Donor Cell Engraftment in Graft-versus-host Disease

BACKGROUND: Graft-versus-host disease (GVHD) is initiated when alloreactive donor T cells are primed by host APCs to undergo clonal expansion and maturation. Since there is a controversy regarding the role of nonhematopoietic cells in GVHD, we wanted to investigate the influence of MHC disparity on nonhematopoietic cells on the pathogenesis of GVHD in the MHC-haplomismatched C57BL/6 (H-2(b)) or DBA/2 (H-2(d))→unirradiated (C57BL/6×DBA/2) F(1)(BDF(1); H-2(b/d)) murine model of acute GVHD (aGVHD) or chronic GVHD (cGVHD). METHODS: We generated (BDF(1)→C57BL/6), (BDF(1)→DBA/2), and (BDF(1)→BDF(1)) chimeras and examined GVHD-related parameters and donor cell engraftment in those chimeras. RESULTS: Using this experimental system, we found that 1) severe aGVHD across MHC Ag barrier depends on the expression of nonhematopoietically rather than hematopoietically derived alloAgs for maximal GVHD manifestations; 2) host APCs were sufficient to break B cell tolerance to self molecules in cGVHD, whereas host APCs were insufficient to induce autoimmunity in aGVHD; 3) donor cell engraftment was greatly enhanced in the host with MHC-matched nonhematopoietic cells. CONCLUSION: Taken together, our results provide an insight into how MHC disparity on GVHD target organs contribute to the pathogenesis of GVHD.