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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-09-2859.
Submitted September 20, 2002
Accepted December 13, 2002
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*
Department of Microbiology and Immunology, University of Miami, Miami, FL, USA
Burnham Institute, La Jolla, CA, USA
Basic Research Program, National Cancer Institute Frederick, Frederick, MD, USA
* Corresponding author; email: rlevy{at}med.miami.edu.
Engraftment failure following allogeneic BMT is of clinical concern particularly involving T cell depleted inoculum and transplants for aplastic anemia. Immune resistance by lymphoid and NK populations with "barrier" function is well established. 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 MiHA prior to BMT. Host resistance was sensitively evaluated by CFU assays to directly assess for donor progenitor cells (PC) and peripheral chimerism. B6 host CD8+ T-cells but not CD4+ or NK1.1+ cells effected rejection of primitive (CFU-HPP) and lineage-committed (CFU-IL3/GM) allogeneic donor progenitors. To address complementation by the cytotoxic pathways existing in singly deficient (perforin or Fas-L) recipients, cytotoxically double (perforin plus Fas-L) 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 transplant of TNFR1-/- progenitor grafts did not diminish the ability of B6-cdd recipients to reject allografts. Finally, injection of anti-TRAIL 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 progenitor cells via alternative effector pathway(s) independent of perforin, Fas-L, 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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