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Donor APCs are required for maximal GVHD but not for GVL

Abstract

Graft-versus-host disease (GVHD) is a major source of morbidity in allogenic stem cell transplantation1. We previously showed that recipient antigen-presenting cells (APCs) are required for CD8-dependent GVHD in a mouse model across only minor histocompatibility antigens (minor H antigens)2. However, these studies did not address the function of donor-derived APCs after GVHD is initiated. Here we show that GVHD develops in recipients of donor major histocompatibility complex class I–deficient (MHC I) bone marrow. Thus, after initial priming, CD8 cells caused GVHD without a further requirement for hematopoietic APCs, indicating that host APCs are necessary and sufficient for GHVD. Nonetheless, GVHD was less severe in recipients of MHC I bone marrow. Therefore, once initiated, GVHD is intensified by donor-derived cells, most probably donor APCs cross-priming alloreactive CD8 cells. Nevertheless, donor APCs were not required for CD8-mediated graft-versus-leukemia (GVL) against a mouse model of chronic-phase chronic myelogenous leukemia. These studies identify donor APCs as a new target for treating GVHD, which may preserve GVL.

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Figure 1: Recipients of B2m−/− bone marrow (BM) develop less GVHD.
Figure 2: Splenic DCs in mice with GVHD were donor-derived.
Figure 3: MHC II+ cells in skin and bowel are donor-derived.
Figure 4: Donor APCs are not required for CD8-mediated GVL.

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Acknowledgements

We thank M. Shlomchik for discussions and reading of the manuscript. This work was supported by National Institutes of Health RO1 grants CA96943 and HL66279. W.D.S. was supported by National Institutes of Health grant K08 HL03979 and B.E.A. was supported by National Institutes of Health grant T32 AI071019-23-25.

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Correspondence to Warren D Shlomchik.

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Matte, C., Liu, J., Cormier, J. et al. Donor APCs are required for maximal GVHD but not for GVL. Nat Med 10, 987–992 (2004). https://doi.org/10.1038/nm1089

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