Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 1020-1024
Direct Alloreactivity by Human Cytotoxic T Lymphocytes Can Be
Inhibited by Altered Peptide Ligand Antagonism
Scott R. Burrows,
Rajiv Khanna, and
Denis J. Moss
From the Queensland Institute of Medical Research and University of
Queensland Joint Oncology Program, Brisbane, Australia.
Alloreactive T lymphocytes that respond directly to foreign major
histocompatibility complex (MHC) molecules and bound peptide are known
to be central mediators of graft-versus-host disease (GVHD) and
allograft rejection. We have recently identified a peptide from the
human protein, cytochrome P450 (isotypes IIC9, 10, or 18), that is
recognized in association with human leukocyte antigen (HLA) B*3501 by
alloreactive cytotoxic T lymphocytes (CTLs). These CTLs with this
specificity were isolated from several unrelated individuals and were
found to express a common T-cell receptor (TCR). Synthetic analogs of
the cytochrome P450 peptide were generated by introducing single amino
acid substitutions at putative TCR contact positions. Four altered
peptide ligands were powerful competitive antagonists of these CTL
clones, reducing lysis levels of target cells expressing the
alloantigen HLA B*3501 by over 80%. This first demonstration that it
is possible to suppress CTL alloreactivity with structural variants of
allodeterminants raises the prospect that such TCR antagonists could be
exploited within the clinical arena to specifically modulate GVHD and
allograft rejection.
