title: Approach to withdrawal from tacrolimus in a fully allogeneic murine skin graft model.
abstract: With few exceptions, transplant patients must take immunosuppressants throughout their lives. In this study, we used anti-T-cell receptor (TCR/CD3) monoclonal antibodies (mAbs) to induce immunological tolerance to alloantigens after withdrawal from tacrolimus in a fully allogeneic murine skin graft model. Skin grafts from AKR donor mice were maintained in C57BL/6 recipients by administering tacrolimus for one month. Anti-T-cell receptor (TCR) alphabeta mAb was administered to recipient mice on the day of withdrawal from tacrolimus administration. Seven days after mAb administration, the recipient mice were treated with various combinations of the following treatments: low-dose whole body irradiation, AKR bone marrow transfer (BMT), and anti-CD3 mAb administration. The control recipient mice did not receive treatment with either mAb, nor any other treatment. All the control recipient mice showed rejection of AKR skin grafts 42 days after tacrolimus withdrawal (mean skin graft survival: 77 days). Mice treated with a combination of anti-TCR alphabeta antibody, low-dose irradiation and AKR BMT showed stable chimerism in their peripheral blood lymphocytes and significantly prolonged skin graft survival (mean skin graft survival: >151.2+/-15.3 days). Mice given the combination of anti-TCR alphabeta mAb, anti-CD3 mAb, low-dose irradiation, and AKR BMT exhibited more stable chimerism but had earlier skin graft rejection (mean skin graft survival: 116.7+/-17.6 days) than the mice that did not receive anti-CD3 mAb. These results suggest that anti-TCR alphabeta mAb, but not anti-CD3 mAb, in combination with low-dose irradiation and BMT, is useful for long-lasting allograft survival after withdrawal from tacrolimus in mice with fully allogeneic skin grafts.
authors.affiliation: Department of Immunology, Medical Institute of Bioregulation, Kyushu University; Surgery II, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Uchiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Kong
authors.forename: K
authors.initials: K
authors.lastname: Kishihara
authors.forename: K
authors.initials: K
authors.lastname: Sugimachi
authors.forename: K
authors.initials: K
authors.lastname: Nomoto
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D005260:Female; D006085:Graft Survival / Q000276:immunology* / Q000528:radiation effects; D007166:Immunosuppressive Agents; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016038:Skin Transplantation / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016559:Tacrolimus; D014916:Whole-Body Irradiation
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2; D016559:Tacrolimus