title: Early presence of regulatory cells in transplanted rats rendered tolerant by donor-specific blood transfusion.
abstract: Mechanisms by which donor-specific blood transfusion (DSBT) promotes organ allograft acceptance are unclear. In a rat fully mismatched cardiac allograft model, we found that DSBT alone (without immunotherapy) induces the development of regulatory T cells (DSBT-Tregs) posttransplant, thereby shedding new light in the mechanisms of the transfusion effect. Compartments and timing of expansion, requirements, and phenotype of DSBT-Tregs are unknown. It is generally assumed that some time is necessary before Tregs develop. However, we show-by adoptive transfer from DSBT-tolerant into naive recipients: 1) the presence of DSBT-Tregs at 5 days posttransplant in spleen and lymph nodes; 2) their gradual expansion in these compartments; and 3) their presence in the graft 14 of 30 days posttransplant. DSBT-Tregs are donor specific and do not protect third-party allografts. Splenocytes from DSBT-treated nontransplanted recipients or from transplanted DSBT-untreated (rejecting) recipients do not transfer tolerance, indicating that both DSBT and graft are required for sufficient numbers of DSBT-Tregs to develop. Thymectomy (or splenectomy) before DSBT (not at transplantation) abrogate DSBT-Tregs generation and tolerance, showing that thymus (and spleen) are required for DSBT-Tregs generation (not for expansion/maintenance). In contrast with other Tregs models, DSBT-Tregs activity is not restricted to CD4(+)CD25(+) but to CD4(+)CD45RC(-) cells, whereas CD4(+)CD45RC(+) cells act as effector cells and accelerate rejection. In conclusion, DSBT alone induces-rapidly posttransplant-the development of alloantigen-specific Tregs in lymphoid tissues and in the graft. DSBT, graft, thymus, and spleen are required for DSBT-Tregs generation. DSBT-Tregs in this model are CD4(+)CD45RC(-) (identical to Tregs protecting from autoimmunity in rats).
authors.affiliation: Laboratory for Experimental Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kitade
authors.forename: Masaru
authors.initials: M
authors.lastname: Kawai
authors.forename: Omer
authors.initials: O
authors.lastname: Rutgeerts
authors.forename: Willy
authors.initials: W
authors.lastname: Landuyt
authors.forename: Mark
authors.initials: M
authors.lastname: Waer
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Jacques
authors.initials: J
authors.lastname: Pirenne
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001803:Blood Transfusion; D015704:CD4 Antigens / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008297:Male; D051381:Rats; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D023001:Transplantation Tolerance
chemical_list: D015704:CD4 Antigens; D017493:Leukocyte Common Antigens