Soluble antigen and cyclosporine-induced specific unresponsiveness in rats. Frequency of alloantigen-specific T cytotoxic cells in normal, sensitized, and unresponsive rats.
The cellular mechanisms of unresponsiveness induced with a combined KCl-extracted donor antigen (HAg) and CsA regimen were dissected by limiting-dilution (LD) assay. While untreated Wistar-Furth (WFu, RT1u) rats reject Buffalo (BUF, RT1b) heart allografts within a mean survival time of 6.6 +/- 0.5 days, recipients treated with 3 cycles of CsA alone (-1,0,1; 7,8,9; 15,16,17) maintained BUF heart allografts up to an MST of 22.5 +/- 8.9 days. When CsA was combined with BUF HAg (-1), BUF heart survival was further prolonged up to an MST of 34.2 +/- 6.6 days, while third-party BN HAg was ineffective (MST of 21.5 +/- 2.1 days). On day 10 postgrafting, the frequency of T cytotoxic cells (fTc) within the splenic pan-T-cell population was 1:1437 +/- 301 in CsA and 1:1087 +/- 438 in CsA/HAg treated recipients. In contrast, on day 30 postgrafting, both CsA and CsA/HAg treated WFu rats bearing functional BUF hearts showed within their splenic pan-T-cell populations a profound decrease in fTc to 1:2966 +/- 824 with CsA alone and to 1:4946 +/- 938 with CsA/HAg treatment. In contrast, both untreated WFu rats who rejected BUF heart allografts and CsA-treated WFu recipients who had rejected their BUF heart allografts on day 20 displayed an increased fTc to 696 +/- 243 and to 1:1169, respectively, when examined at day 30 postgrafting. Additionally, both the W3/25+ and OX8+ T cell subsets specifically suppressed the proliferative response of normal WFu T cells against BUF and, to a lesser degree, third-party BN irradiated stimulators. Thus, CsA-treated animals develop a potent specific-suppressor mechanism that is augmented by pretreatment with donor soluble antigen. This suppressor activity may decrease the frequency of alloantigen-specific Tc cells and thereby prolong the survival of BUF heart allografts.
Ito
T
T
Department of Surgery, University of Texas Medical School, Houston 77030.
Stepkowski
S M
SM
Kahan
B D
BD
D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D007111:Immunity, Cellular / Q000187:drug effects; D007114:Immunization; D007519:Isoantigens / Q000276:immunology*; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors
D003524:Cyclosporins; D007519:Isoantigens