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Publication Detail
The host environment regulates the function of CD8+ graft-versus-host-reactive effector cells.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Chakraverty R, Flutter B, Fallah-Arani F, Eom H-S, Means T, Andreola G, Schwarte S, Buchli J, Cotter P, Zhao G, Sykes M
  • Publication date:
  • Pagination:
    6820, 6828
  • Journal:
    J Immunol
  • Volume:
  • Issue:
  • Status:
  • Country:
    United States
  • PII:
  • Language:
  • Keywords:
    Animals, Bone Marrow Transplantation, CD8-Positive T-Lymphocytes, Flow Cytometry, Graft vs Host Disease, Graft vs Leukemia Effect, Lymphocyte Activation, Mice, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Transplantation Chimera
We have examined how the host environment influences the graft-vs-leukemia (GVL) response following transfer of donor T cells to allogeneic chimeras. Donor T cells induce significant GVL when administered in large numbers to established mixed chimeras (MC). However, when using limiting numbers of T cells, we found that late transfer to MC induced less GVL than did early transfer to freshly irradiated allogeneic recipients. Late donor T cell transfer to MC was associated with marked accumulation of anti-host CD8 cells within the spleen, but delayed kinetics of differentiation, reduced expression of effector molecules including IFN-gamma, impaired cytotoxicity, and higher rates of sustained apoptosis. Furthermore, in contrast to the spleen, we observed a significant delay in donor CD8 cell recruitment to the bone marrow, a key location for hematopoietic tumors. Increasing the numbers of T cells transferred to MC led to the enhancement of CTL activity and detectable increases in absolute numbers of IFN-gamma(+) cells without inducing graft-vs-host disease (GVHD). TLR-induced systemic inflammation accelerated differentiation of functional CTL in MC but was associated with severe GVHD. In the absence of inflammation, both recipient T and non-T cell populations impeded the full development of GVHD-inducing effector function. We conclude that per-cell deficits in the function of donor CD8 cells activated in MC may be overcome by transferring larger numbers of T cells without inducing GVHD.
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