Relationship of cyclosporine A-mediated inhibition of clonal deletion and development of syngeneic graft-versus-host disease.

Abstract

We have described a strain-specific graft-vs-host disease (GVHD)-like syndrome in syngeneic mouse radiation chimeras that developed in two of seven strains tested after cyclosporine A (CsA) therapy. It has been suggested, recently, that autoreactive T cells that develop as a result of CsA treatment may result from inhibition of clonal deletion and could be responsible for the development of this disease. To test this hypothesis, TCR expression, as a measure of tolerance induction, was analyzed in a series of syngeneic radiation chimeras (inducible and noninducible for syngeneic GVHD), with and without CsA treatment. Clonal deletion, as assessed by anti-TCR V beta chain mAb, appeared to occur normally in strains of mice inducible for syngeneic GVHD. Conversely, animals in which T cells bearing self-reactive TCR could be detected, did not develop the disease. This discrepancy did not appear to be due to a generalized difference in the effects of CsA on the various strains of mice used, as the effects of the drug (i.e., decreased mitogen responsiveness, inhibition of thymocyte maturation, etc.) appeared similar in all strains tested. Therefore, the development of CsA-induced autoreactive T cells as assessed by V beta TCR expression showed strain variation that did not correlate with the induction of syngeneic GVHD and suggested that other mechanisms may be involved in the development of this autoimmune phenomenon.