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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3793-3803.
Prepublished online as a Blood First Edition Paper on August 8, 2007; DOI 10.1182/blood-2007-04-086470.
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TRANSPLANTATION
Regulatory dendritic cells protect against cutaneous chronic graft-versus-host disease mediated through CD4+CD25+Foxp3+ regulatory T cells
Shigeharu Fujita1,2,
Yumiko Sato1,
Kaori Sato1,
Kawori Eizumi1,
Tomohiro Fukaya1,
Masato Kubo3,
Naohide Yamashita2, and
Katsuaki Sato1
Laboratories for 1 Dendritic Cell Immunobiology, Rikagaku Kenkyusho (RIKEN) Research Center for Allergy and Immunology, Yokohama;
2 Department of Advanced Medical Science, The Institute of Medical Science, The University of Tokyo, Tokyo, and
3 Laboratory for Signal Network, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan
Chronic graft-versus-host disease (cGVHD) is a common cause of morbidity and mortality in allogeneic bone marrow transplantation (alloBMT). However, effective strategies for the treatment of cGVHD have not been established. In this study, we examined the therapeutic utility of modified dendritic cells (DCs) with a greater capacity to regulate immune responses than previously known tolerogenic DCs, regulatory DCs (DCregs), in the major histocompatibility complex-compatible, and multiple minor histocompatibility antigen-incompatible model of cGVHD in alloBMT. Treatment of the recipient mice after alloBMT with the recipient-type DCregs led to greater suppression of the incidence and severity of cutaneous cGVHD than rapamycin, whereas treatment with the recipient-type mature DCs promoted the pathogenesis. Analysis of the recipient mice suggested that the protective effect of the recipient-type DCregs involved the peripheral generation of alloreactive CD4+CD25+Foxp3+regulatory T (TR) cells from donor-derived CD4+CD25–Foxp3– T cells. Thus, immunotherapy with DCregs is a promising strategy for the treatment of cGVHD in alloBMT mediated through the induction of a dominant tolerance involving CD4+CD25+Foxp3+ TR cells.
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