Roles of Host Nonhematopoietic Cells in Autoimmunity and Donor Cell Engraftment in Graft-versus-host Disease
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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-2b) or DBA/2 (H-2d)→an unirradiated (C57BL/6×DBA/2) F1(BDF1;H-2b/d) murine model of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Methods: We generated (BDF1→C57BL/6),(BDF1→DBA/2), and (BDF1→BDF1) 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 how MHC disparity on GVHD target organs contribute to the pathogenesis of GVHD.
Abstract
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-2b) or DBA/2 (H-2d)→an unirradiated (C57BL/6×DBA/2) F1(BDF1;H-2b/d) murine model of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Methods: We generated (BDF1→C57BL/6),(BDF1→DBA/2), and (BDF1→BDF1) 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 how MHC disparity on GVHD target organs contribute to the pathogenesis of GVHD.
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