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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-09-2859.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 3991-3999
IMMUNOBIOLOGY
Antigen-primed CD8+ T cells can mediate resistance,
preventing allogeneic marrow engraftment in the simultaneous absence of
perforin-, CD95L-, TNFR1-, and TRAIL-dependent
killing
Masanobu Komatsu,
Michele Mammolenti,
Monica Jones,
Roland Jurecic,
Thomas J. Sayers, and
Robert B. Levy
From the Department of Microbiology and Immunology,
University of Miami School of Medicine, Miami, FL; Burnham Institute,
La Jolla, CA; Basic Research Program, SAIC-Frederick,
National Cancer Institute at Frederick, MD.
Engraftment failure following allogeneic bone marrow (BM)
transplantation is of clinical concern particularly involving
T-cell-depleted inoculum and transplantations for aplastic anemia.
Immune resistance by lymphoid and natural killer (NK)
populations with "barrier" function is well established. Major
histocompatibility complex (MHC)-identical marrow allografts
were examined to investigate effector pathways in non-NK-mediated
resistance. Barrier function was examined in cytotoxic normal and
deficient B6 (H-2b) recipients primed to donor minor
histocompatibility antigen (MiHA) prior to BM transplantation.
Host resistance was sensitively evaluated by colony-forming
unit (CFU) assays to directly assess for donor progenitor
cell (PC) and peripheral chimerism. B6 host CD8+ T
cells but not CD4+ or NK1.1+ cells effected
rejection of primitive (CFU-HPP [high-proliferative potential]) and lineage-committed (CFU-IL3/GM [interleukin
3/granulocyte macrophage]) allogeneic donor progenitors. To
address complementation by the cytotoxic pathways existing in singly
deficient (perforin or FasL) recipients, cytotoxically double (perforin
plus FasL) deficient (cdd) recipients were used. Resistance in B6-cdd
recipients was comparable to that of wild-type B6 recipients
and was also dependent on CD8+ T cells. A "triple"
cytotoxic deficient model, involving transplantation of
TNFR1 / (tumor necrosis factor receptor 1)
progenitor grafts did not diminish the ability of B6-cdd recipients to
reject allografts. Finally, injection of anti-TRAIL (tumor necrosis
factor-related apoptosis-inducing ligand) monoclonal antibody
(mAb) in B6-cdd recipients also failed to inhibit rejection of
TNFR1/ marrow grafts. In total, these studies
demonstrate that CD8+ host T cells can effectively resist
MHC-matched MiHA-mismatched donor PCs via alternative effector
pathway(s) independent of perforin-, FasL-, TNFR-1-, and
TRAIL-dependent cytotoxicity. Therefore, inhibition of these
effector pathways in sensitized recipients is unlikely to result in
stem cell engraftment following PC allografts.
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