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Studies on the mechanism of tolerance or graft-versus-host disease in
allogeneic bone marrow recipients at the level of cytotoxic T-cell
precursor frequencies
EU Irschick, F Hladik, D Niederwieser, W Nussbaumer, E Holler, E Kaminski and C Huber
Department of Internal Medicine, University of Innsbruck, Austria.
Previous studies demonstrated that the frequency of donor-versus-host-
reactive cytotoxic T-cell precursors (CTL-p) before allogeneic bone marrow
transplantation (BMT) from matched unrelated donors correlates with the
incidence of graft-versus-host disease (GvH-D). We investigated whether
clinical manifestations of GvH-D after HLA- identical sibling BMT are
accompanied by an increased frequency of minor histocompatibility antigen
(HA)-specific CTL-p. We further asked whether changes of
third-party-reactive CTL-p as a measure of overall immunocompetence are
related to infectious complications frequently seen immediately after BMT.
Eighteen patients (16 with an HLA-identical bone marrow graft, two with
either one HLA-A or one HLA-DR mismatch) were studied. Limiting dilution
analysis (LDA) was used to assess donor CTL-p frequencies against recipient
pre-BMT, donor, and third-party targets in a follow-up study. Eight cases
receiving HLA-identical marrow grafts never developed signs of GvH-D.
Undetectable or very low frequencies (1/131,458) of minor HA-specific CTL-p
were demonstrated pre-BMT. Two recipients, one of an HLA-A- and one of an
HLA-DR- mismatched graft, exhibited low frequencies of recipient-specific
CTL-p (1/66,920 and 1/85,577, respectively) before transplantation, which
further decreased despite mild GvH-D grade I, or decreased within 3 months
after grafting in the other case. Eight patients receiving HLA- identical
grafts developed GvH-D. Recipient-specific CTL-p were less than 1/300,000
in five patients during limited GvH-D (four with grade I and one with grade
II disease of the skin), but were detectable in three patients presenting
with extensive GvH-D grades II to III and ranged from 1/7,993 to 1/210,108.
The differences in post-BMT recipient- specific CTL-p frequencies between
patients with GvH-D grades 0 to I (median, less than 1/300,000) and those
with GvH-D grades II to III (median, 1/111,970) were statistically
significant (P less than .05). Posttransplant lymphocytes from all 18
patients contained less than 1/300,000 CTL-p with specificity for donor
targets. Comparison of third- party-reactive CTL-p frequencies between
donor and post-BMT recipient lymphocytes showed a severe and long-lasting
depletion subsequent to BMT, which was not related to infectious
complications. Again, these differences reached the level of statistical
significance (median CTL-p before BMT, 1/4,417; after BMT, 1/14,289; P less
than .005).(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 79,
Issue 6,
pp. 1622-1628,
03/15/1992
Copyright © 1992 by The American Society of Hematology
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E. Goulmy, R. Schipper, J. Pool, E. Blokland, F. Falkenburg, J. Vossen, A. Gratwohl, G. B. Vogelsang, H. C. van Houwelingen, and J. J. van Rood
Mismatches of Minor Histocompatibility Antigens between HLA-Identical Donors and Recipients and the Development of Graft-Versus-Host Disease after Bone Marrow Transplantation
N. Engl. J. Med.,
February 1, 1996;
334(5):
281 - 285.
[Abstract]
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J. den Haan, N. Sherman, E Blokland, E Huczko, F Koning, J. Drijfhout, J Skipper, J Shabanowitz, D. Hunt, V. Engelhard, et al.
Identification of a graft versus host disease-associated human minor histocompatibility antigen
Science,
June 9, 1995;
268(5216):
1476 - 1480.
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