title: Anti-CD25 mAb administration prevents spontaneous liver transplant tolerance.
abstract: Liver allografts are accepted spontaneously in all mouse strain combinations without immunosuppressive therapy. The mechanisms underlying this phenomenon remain largely undefined. In this study, we examined the effect of CD4+ CD25+ T regulatory cells (Treg) on the induction of mouse liver transplant tolerance. Orthotopic liver transplantation was performed from B10 (H2b) to C3H (H2k) mice. Depleting rat anti-mouse CD25 mAb (PC61) was given to the donors or recipients (250 microg/d IP) pretransplant or to the recipients postoperatively. At day 5 posttransplantation, both effector T cells (mainly CD8) and CD4+ CD25+ Treg were increased in the liver allografts and host spleens compared to naïve mice. Anti-CD25 mAb administration, either pretransplantation or posttransplantation, reduced the ratio of CD4+ CD25+ Treg to the CD3 T cells of liver grafts and recipient spleens and induced liver allograft acute rejection compared to IgG treatment. Anti-CD25 mAb administration elevated anti-donor T-cell proliferative responses and CTL and NK activities of graft infiltrates and host splenocytes; reduced CTLA4, Foxp3, and IDO mRNA levels; increased IL-10 and IFN-gamma; and decreased IL-4 mRNA levels in the livers or host spleens. The number of apoptotic T cells was reduced significantly in the liver grafts and treated host spleens. Therefore, anti-CD25 mAb administration changed the balance of CD4+ CD25+ Treg to activated T cells of liver graft recipients, preventing liver transplant tolerance. This was associated with enhanced anti-donor immune reactivity, downregulated Treg gene expression, and reduced T cell apoptosis in the grafts and host spleens.
authors.affiliation: Division of Transplantation, Department of Surgery, University of Washington Medical Center, Seattle, Washington 98195, USA. weili8@u.washington.edu
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Carper
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.forename: X X
authors.initials: XX
authors.lastname: Zheng
authors.forename: C S
authors.initials: CS
authors.lastname: Kuhr
authors.forename: J D
authors.initials: JD
authors.lastname: Reyes
authors.forename: D L
authors.initials: DL
authors.lastname: Perkins
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
authors.forename: J D
authors.initials: JD
authors.lastname: Perkins
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D023001:Transplantation Tolerance / Q000187:drug effects / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D053645:Interleukin-2 Receptor alpha Subunit