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Cytotoxic T-Lymphocyte-Defined Human Minor Histocompatibility
Antigens With a Restricted Tissue Distribution
Edus H. Warren,
Philip D. Greenberg, and
Stanley R. Riddell
From the Fred Hutchinson Cancer Research Center, Seattle, WA; and the
University of Washington, Seattle, WA.
Cytotoxic T lymphocytes (CTL) specific for human minor
histocompatibility (H) antigens can be isolated from the blood of major histocompatibility complex (MHC)-matched allogeneic bone marrow transplant (BMT) recipients and may play a prominent role in the graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactions (Tsoi
et al, J Immunol 125:2258, 1980; Tsoi et al, Transplant Proc 15:1484, 1983; Goulmy et al, Nature 302:159, 1983;
Irle et al, Transplantation 40:329, 1985; and Niederwieser et
al, Blood 81:2200, 1993). The identification of
minor H antigens that are expressed in hematopoietic cells, including
leukemic cells, but not in fibroblasts and other tissue types has
suggested that such tissue-restricted antigens could potentially serve
as targets for T-cell immunotherapy to enhance GVL activity without
inducing GVH disease (de Bueger et al, J Immunol 149:1788,
1992; van der Harst et al, Blood 83:1060, 1994; and Dolstra et
al, J Immunol 158:560, 1997). To explore the feasibility of
this strategy, donor CD3+CD8+ CTL clones
specific for recipient minor H antigens were isolated and characterized
from allogeneic BMT recipients. CTL clones were obtained from the
majority of donor/recipient pairs. Seventeen distinct minor H antigens
distinguishable by their MHC-restricting allele, population frequency,
and/or distribution of tissue expression were defined by 56 CD3+CD8+ CTL clones isolated from these
patients. The MHC-restricting alleles for these CTL clones included
HLA-A2 and HLA-B7, which had previously been shown to present minor H
antigens to CTL, as well as HLA-A3, -A11, -B8, -B53, and -Cw7, which
had not previously been described to present minor H antigens to CTL.
Estimated phenotype frequencies for these 17 distinct minor H antigens
range from 0.17 to 0.92. In vitro cytotoxicity assays using
hematopoietic cells and fibroblasts as target cells showed that 5 of
the 17 minor H antigens were expressed in both hematopoietic cells and fibroblasts. However, 12 were presented for CTL recognition only by
hematopoietic cells and not by dermal fibroblasts derived from the same
donors. These results significantly extend the spectrum of CTL-defined
human minor H antigens that could potentially serve as target antigens
for cellular immunotherapy to promote GVL activity after allogeneic
BMT.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2197-2207
© 1998 by The American Society of Hematology.
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