Antibody-induced transplantation tolerance that is dependent on thymus-derived regulatory T cells.
Targeting of the CD45RB isoform by mAb (anti-CD45RB) effectively induces donor-specific tolerance to allografts. The immunological mechanisms underlying the tolerant state remain unclear although some studies have suggested the involvement of regulatory T cells (T-regs). Although their generative pathway remains undefined, tolerance promoting T-regs induced by systemic anti-CD45RB treatment have been assumed to originate in the peripheral immune system. We demonstrate herein that separable effects on the peripheral and central immune compartments mediate graft survival induced by anti-CD45RB administration. In the absence of the thymus, anti-CD45RB therapy is not tolerogenic though it retains peripheral immunosuppressive activity. The thymus is required for anti-CD45RB to produce indefinite graft survival and donor-specific tolerance, and this effect is accomplished through thymic production of donor-specific T-regs. These data reveal for the first time an Ab-based tolerance regimen that relies on the central tolerance pathway.
Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
Shaoping
S
Deng
Daniel J
DJ
Moore
Xiaolun
X
Huang
Mohammad
M
Mohiuddin
Major K
MK
Lee
Ergun
E
Velidedeoglu
Moh-Moh
MM
Lian
Meredith
M
Chiaccio
Samsher
S
Sonawane
Anton
A
Orlin
Jing
J
Wang
Haiying
H
Chen
Andrew
A
Caton
Robert
R
Zhong
James F
JF
Markmann
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology; D007274:Injections, Intraperitoneal; D017493:Leukocyte Common Antigens / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
D000911:Antibodies, Monoclonal; D017493:Leukocyte Common Antigens