SUSCEPTIBILITY TO CLINICALLY MANIFEST CYCLOSPORINE-A (CSA)-INDUCED AUTOIMMUNE-DISEASE IS ASSOCIATED WITH INTERFERON-GAMMA (IFN-GAMMA)-PRODUCING CD45RC(-) T-HELPER CELLS() RT6()

Lethally irradiated Lewis (LEW) rats reconstituted with syngeneic bone marrow and given CsA for a 4-week period, develop, upon withdrawal of CsA, a graft-versus-host-like disease, so-called CsA-induced autoimmu nity (CsA-AI). This T cell-mediated autoimmune disease is thymus-depen dent; it is generally held that this disease is a consequence of aberr ant T cell recovery brought about by CsA. In this study we determined mononuclear cell subsets phenotypically by tri-colour flow cytometry. A strong decrease in recent thymic emigrants (Thy1.1(+), TCR alpha bet a(+)) was observed as a consequence of CsA treatment, eventually resul ting in decreased absolute peripheral T cell numbers. In these rats no altered CD4:CD8 T cell ratio was observed before onset of CsA-AI; CD4 (+) and CD8(+) cells consisted predominantly of monocytes (CD4(dim+), TCR alpha beta(-)) and natural killer cells (CD8(+), TCR alpha beta(-) ), respectively. LEW rats, x-irradiated, syngeneic bone marrow-reconst ituted and treated with CsA, showed a marked and persistent, relative expansion of mature CD45RC(+), RT6(-) Th cells. In contrast, Brown-Nor way rats treated in a similar fashion, or LEW rats subjected to either CsA treatment or x-irradiation, did not show a comparable expansion o f mature CD45RC(+), RT6(-) Th cells, nor did these animals develop CsA -AI. The CD45RC(+), RT6(-) Th cells produced IL-2, and moreover consti tuted the only Th subset producing IFN-gamma upon stimulation, and the refore were considered as Th1-like effector cells. These results are c onsistent with the view that a persistent preponderance of Th1 cells a nd not the mere presence of autoreactive cells determines whether or n ot clinically manifest CsA-AI will occur.