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

Administration of the immunosuppressive drug cyclosporine after syngeneic o r autologous bone marrow transplantation elicits a T-lymphocyte-dependent a utoimmune syndrome similar to graft-versus-host disease (GVHD). The onset o f this autoaggression syndrome,termed syngeneic GVHD, is associated with th e development of a highly restricted repertoire of CD8(+) autoreactive T ce lls that recognize a peptide from the invariant chain, termed CLIP, present ed by major histocompatibility complex (MHC) class II molecules. Clonal ana lysis reveals 2 distinct subsets of autoreactive T cells defined by their a ctivation requirement for either the N-terminal or the C-terminal flanking regions of CLIP and by their cytokine profile. The studies here reveal that the autoreactive T-cell clones requiring the N-terminal flanking region of CLIP produce type 1 cytokines (interferon [IFN]-gamma, interleukin [IL]-2, and tumor necrosis factor-alpha). In contrast, the autoreactive T-cell clo nes that require the C-terminal flanking region of CLIP produce type 2 cyto kines (IL-4, IL-10, transforming growth factor-beta). As assessed in a loca l graft-versus-host reaction assay, the N-terminal flanking-restricted clon es mediate changes consistent with acute GVHD, whereas the clones responsiv e to the C-terminal flanking region do not. Moreover, the autoreactive T-ce ll clones restricted by the C-terminal flanking region of CLIP ameliorate t he pathogenic potential of the cells responsive to the N-terminal flanking region of CLIP. The mechanism accounting for this regulatory affect appears to be the downregulation of mRNA message for type 1 cytokines (IFN-gamma a nd IL-2). The C-terminal-restricted autoreactive T-cell clones, however, co uld manifest disease with dermal changes similar to those seen in chronic s yngeneic GVHD, provided that IFN-gamma was present. Consistent with these o bservations was the demonstration that type 1 cytokines are preferentially detected during the acute phase of syngeneic GVHD, whereas type 2 cytokines dominate during the chronic phase. The results suggest that acute and chro nic syngeneic GVHD is mediated by distinct autoreactive T cells, which are separated by their fine specificity for the CLIP-MHC class II complex and b y their cytokine profiles.