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* Transplantation Immunology Group, Department of Hematology, University College London, London, U.K.;
Center for Immunology and Inflammatory Disease and
Transplantation Biology Research Center, Bone Marrow Transplantation Section, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129
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-
, 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-+ 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Leukemia Research, U.K., and by National Institutes of Health Grants PO1 CA111519 and RO1 CA79989, and by a Senior Research Award from the Multiple Myeloma Foundation.
2 R.C. and B.F. contributed equally to this work.
3 Current address: Hematology-Oncology Clinic, National Cancer Center, Goyang, Korea.
4 Address correspondence and reprint requests to Dr. Megan Sykes, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, MGH-East, Building 149-5102, 13th Street, Boston, MA 02129. E-mail address: Megan.Sykes{at}tbrc.mgh.harvard.edu
5 Abbreviations used in this paper: BMT, bone marrow transplantation; AV, annexin V; BM, bone marrow; DLI, donor leukocyte infusion; GVH, graft-vs-host; GVHD, graft-vs-host disease; GVL, graft-vs-leukemia; MC, mixed chimera; MST, median survival time; SC, splenocyte; TBI-allo, freshly irradiated allogeneic recipients; TBI-syn, freshly irradiated syngeneic recipients; TCD, T cell-depleted.
6 The online version of this article contains supplemental material.
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