Complexity of effector mechanisms in cyclosporine-induced syngeneic graft-versus-host disease.

Administration of the immunosuppressive drug cyclosporine after syngeneic or autologous bone marrow transplanta- tion elicits a T-lymphocyte-dependent autoimmune syndrome similar to graft-versus-host disease (GVHD). The onset of this autoaggression syndrome, termed syngeneic GVHD, is associated with the development of a highly restricted re p e rt o i re of CD8 + a u t o reactive T cells that recognize a peptide from the invariant chain, termed CLIP, p resented by major histocompatibility complex (MHC) class II molecules. Clonal analysis reveals 2 distinct subsets of a u t o reactive T cells defined by their activation re q u i rement for either the N-terminal or the C-terminal fla n k i n g regions of CLIP and by their cytokine pro file. The studies here reveal that the autoreactive T-cell clones re q u i r i n g the N-terminal flanking region of CLIP produce type 1 cytokines (interf e ron (IFN)-γ , interleukin (IL)-2, and tumor n e c rosis factor-α). In contrast, the autoreactive T-cell clones that re q u i re the C-terminal flanking region of CLIP p roduce type 2 cytokines (IL-4, IL-10, transforming growth factor-β). As assessed in a local graft-versus-host re a c- tion assay, the N-terminal fla n k i n g - restricted clones mediate changes consistent with acute GVHD, whereas the clones responsive to the C-terminal flanking region do not. More o v e r, the autoreactive T-cell clones restricted by the C - t e rminal flanking region of CLIP ameliorate the pathogenic potential of the cells responsive to the N-term i n a l flanking region of CLIP. The mechanism accounting for this re g u l a t o ry affect appears to be the downregulation of mRNA message for type 1 cytokines (IFN-γ and IL-2). The C-term i n a l - restricted autoreactive T-cell clones, how- e v e r, could manifest disease with dermal changes similar to those seen in chronic syngeneic GVHD, provided that I F N -γ was present. Consistent with these observations was the demonstration that type 1 cytokines are pre f e re n t i a l l y detected during the acute phase of syngeneic GVHD, whereas type 2 cytokines dominate during the chronic phase. The results suggest that acute and chronic syngeneic GVHD is mediated by distinct autoreactive T cells, which are separated by their fine specificity for the CLIP-MHC class II complex and by their cytokine pro fil e s .