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Division of Immunology and Hematopoiesis, Oncology Center, Johns Hopkins University, Baltimore, MD 21287
Administration of the immunosuppressive drug cyclosporine after
syngeneic bone marrow transplantation paradoxically elicits a systemic
autoimmune syndrome resembling graft-vs-host disease (GVHD). This
syndrome, termed syngeneic GVHD, is associated with the development of
CD8+ cytolytic T lymphocytes that promiscuously recognize
MHC class II molecules in association with a peptide from the invariant
chain (CLIP). Clonal analysis reveals a major subset of cells that are
pathogenic and require the N-terminal flanking region of CLIP for
activation, while there is a minor subset of nonpathogenic T cells that
require the C-terminal flanking region. The present studies show that
pathogenic T cells produce type 1 cytokines (IL-2; IFN-
), while the
nonpathogenic clones produce type 2 cytokines (IL-4; IL-10). Moreover,
the repertoire of the pathogenic T cells is highly conserved with
respect to Vß and V
TCR gene expression. The vast majority of
clones express Vß8.5 (12/12) and V11 (11/12). Although a limited
number was evaluated, the nonpathogenic clones have only a V
restriction. Sequence analysis of the pathogenic T cell clones reveals
a marked heterogeneity in the complementarity-determining region 3
domain and differential J region gene expression for both TCR - and
ß-chains. Evaluation of the specificity of these clones suggests that
the functional interaction between the N-terminal flanking region of
CLIP (defined by the amino acid sequence -KPVSP-) and the V region of
the TCR is critical, allowing effective target cell recognition and
tissue destruction in syngeneic GVHD.
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