title: Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy.
abstract: Regulatory T cells (Tregs) are essential for the establishment and maintenance of immune tolerance, suggesting a potential therapeutic role for Tregs in transplantation. However, Treg administration alone is insufficient in inducing long-term allograft survival in normal hosts, likely due to the high frequency of alloreactive T cells. We hypothesized that a targeted reduction of alloreactive T effector cells would allow a therapeutic window for Treg efficacy. Here we show that preconditioning recipient mice with donor-specific transfusion followed by cyclophosphamide treatment deleted 70-80% donor-reactive T cells, but failed to prolong islet allograft survival. However, infusion of either 5 × 10(6) Tregs with direct donor reactivity or 25 × 10(6) polyclonal Tregs led to indefinite survival of BALB/c islets in more than 70% of preconditioned C57BL/6 recipients. Notably, protection of C3H islets in autoimmune nonobese diabetic mice required islet autoantigen-specific Tregs together with polyclonal Tregs. Treg therapy led to significant reduction of CD8(+) T cells and concomitant increase in endogenous Tregs among graft-infiltrating cells early after transplantation. Together, these results demonstrate that reduction of the donor-reactive T cells will be an important component of Treg-based therapies in transplantation.
authors.affiliation: Department of Surgery, University of California, San Francisco, San Francisco, CA; Department of Biochemistry and Molecular Biology, Korea University, Seoul, Republic of Korea.
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: V
authors.initials: V
authors.lastname: Nguyen
authors.forename: K-M
authors.initials: KM
authors.lastname: Lee
authors.forename: S-M
authors.initials: SM
authors.lastname: Kang
authors.forename: Q
authors.initials: Q
authors.lastname: Tang
mesh_terms: D064591:Allografts / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000637:transplantation; D003520:Cyclophosphamide / Q000627:therapeutic use; D006085:Graft Survival; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D050378:T-Lymphocytes, Regulatory / Q000637:transplantation*; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000379:methods
chemical_list: D003520:Cyclophosphamide
keywords: CD8+ T cell; T cell deletion; Treg therapy; diabetes