title: The synergistic effect of total-lymphoid irradiation with extracted donor alloantigen in inducing transplantation unresponsiveness.
abstract: The synergistic effect of total lymphoid irradiation with KCl-extracted donor type antigen (H-Ag) was examined in the rat cardiac graft model. TLI therapy alone of 10, 16, and 20 Gy achieved by a 2 Gy daily treatment of WFu recipients produced modest prolongation of BUF heart survival to median survival times (MST) of 11, 26, and 30 days, respectively, in comparison with normal control (MST = 6). The TLI immunosuppressive effect was significantly potentiated with donor H-Ag when combined with 16 (greater than 100 days) but not with 10 or 20 Gy TLI therapy. This effect was specific: 16 Gy TLI treated recipients of BUF hearts rejected their grafts in a MST of 27 days when treated with third-party BN H-Ag. The state of unresponsiveness was transferable to 6 Gy total-body-irradiated WFu recipients of BUF hearts with 60 x 10(6) purified T cells isolated from TLI/H-Ag-treated rats (greater than 100) but not from normal controls (MST = 6). In vitro analysis of nontransplanted WFu rats 1-4 weeks after completion of 16 Gy TLI therapy alone demonstrated a nonspecifically reduced MLR proliferative response as well as the presence of potent nonspecific suppressor cells (NSC). By 3 or even 6 months post-TLI, W3/25- NSC displayed persistent suppressive activity and inhibited normal proliferative response to alloantigens. Limiting dilution assay revealed that the frequency of T cytotoxic cells (fTc) was severely decreased to 1:63111 at one day and to 1:16488 at one week postirradiation in comparison with normal control (1:2551). At 3 and 6 months the fTc of 1:2301 and 1:2040, respectively, approximated normal levels. These combined in vivo and in vitro results demonstrate that 16 Gy TLI therapy induces an unresponsiveness mediated by NSC and that the administration of donor type H-Ag facilitates the generation of potent regulatory T cells capable of inducing prolonged heart allograft survival.
authors.affiliation: Department of Surgery, University of Texas Medical School, Houston 77030.
authors.forename: L S
authors.initials: LS
authors.lastname: Florence
authors.forename: T
authors.initials: T
authors.lastname: Ito
authors.forename: K K
authors.initials: KK
authors.lastname: Ang
authors.forename: G L
authors.initials: GL
authors.lastname: Jiang
authors.forename: C S
authors.initials: CS
authors.lastname: Wong
authors.forename: S
authors.initials: S
authors.lastname: Goto
authors.forename: R
authors.initials: R
authors.lastname: Didlake
authors.forename: E K
authors.initials: EK
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Stepkowski
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
mesh_terms: D000818:Animals; D005720:Gamma Rays; D006085:Graft Survival; D016027:Heart Transplantation; D006649:Histocompatibility Antigens / Q000276:immunology*; D007111:Immunity, Cellular; D007116:Immunization, Passive; D007165:Immunosuppression Therapy / Q000379:methods*; D008208:Lymphatic System / Q000528:radiation effects*; D007959:Lymphocyte Culture Test, Mixed; D051381:Rats; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014019:Tissue Donors
chemical_list: D006649:Histocompatibility Antigens