title: Effect of infusion of monoclonal antibodies to tumour necrosis factor-receptor super family 25 on graft rejection in allo-immune mice receiving autologous marrow transplantation.
abstract: Significant barriers to transplantation exist for individuals who are pre-sensitized to donor antigen and have high titres of donor-reactive antibody. We report the effect of autologous bone marrow transplantation (BMTx) after myeloablation in pre-sensitized mice along with the use of monoclonal antibodies (mAbs) to tumour necrosis factor-receptor super family 25 (TNFRSF25), expressed on regulatory T (Treg) cells. C57BL/6 mice, which had been sensitized earlier with BALB/c skin allografts, received secondary BALB/c grafts after the primary grafts had been rejected. Subsequently, recipient mice underwent myeloablation with cyclophosphamide and busulphan and were injected with T-cell-depleted bone marrow from CD45.1 congenic donors (BMTx). Recipient mice underwent immunosuppressive treatment with rapamycin. A subgroup of mice was also treated with mAbs to TNFRSF25. Control mice were pre-sensitized mice that received cyclophosphamide and busulphan followed by rapamycin. BMTx-treated mice had significantly prolonged skin graft survival versus control mice. These mice also showed attenuated donor-specific mixed lymphocyte co-culture responses relative to controls, increased splenic Treg cells and markedly diminished serum anti-donor IgG. Infusion of anti-TNFRSF25 mAbs further augmented graft survival and increased graft-infiltrating Treg cells. These mAbs also expanded murine and human Treg cells in vitro with the capacity to attenuate mixed lymphocyte co-cultures using fresh peripheral blood mononuclear cells. Overall, this study delineates the roles of autologous BMTx and anti-TNFRSF25 mAbs in expanding Treg cells and attenuating alloimmune responses in pre-sensitized mice.
authors.affiliation: Transplant Research Division, University Health Network and Toronto General Hospital, Toronto, ON, Canada.|Department of Immunology and Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Reginald M
authors.initials: RM
authors.lastname: Gorczynski
authors.affiliation: Transplant Research Division, University Health Network and Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Hassan
authors.initials: H
authors.lastname: Sadozai
authors.affiliation: Transplant Research Division, University Health Network and Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Transplant Research Division, University Health Network and Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Ismat
authors.initials: I
authors.lastname: Khatri
mesh_terms: D064591:Allografts / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy / Q000379:methods*; D007518:Isoantibodies / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D007518:Isoantibodies; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse
keywords: bone marrow transplantation; donor-reactive antibodies; myeloablation; regulatory T cells; tumour necrosis factor-receptor super family 25