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 Blood, 21 January 2010, Vol. 115, No. 3, pp. 724-735.
Prepublished online as a Blood First Edition Paper on November 18, 2009; DOI 10.1182/blood-2009-06-229708.

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TRANSPLANTATION

Immunization with host-type CD8{alpha}+ dendritic cells reduces experimental acute GVHD in an IL-10–dependent manner

Tomomi Toubai1, Chelsea Malter1, Isao Tawara1, Chen Liu2, Evelyn Nieves1, Kathleen P. Lowler1, Yaping Sun1, and Pavan Reddy1

1 Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor; and 2 Department of Pathology, University of Florida College of Medicine, Gainesville

Little is known about the role of active immunization in suppressing undesirable immune responses. Because CD8{alpha}+ dendritic cells (DCs) suppress certain immune responses, we tested the hypothesis that immunization of donors with host-derived CD8{alpha}+ DCs will reduce host-specific donor T-cell responses. BALB/c T cells from the animals that were immunized with B6 CD8{alpha}+ DCs demonstrated, in vitro and in vivo, significantly reduced proliferation and secretion of inflammatory cytokines but showed enhanced secretion of interleukin-10 (IL-10). The responses against third-party and model antigens were preserved demonstrating antigen specificity. The in vivo relevance was further demonstrated by the reduction on graft-versus-host disease (GVHD) in both a major histocompatibility complex–mismatched clinically relevant BALB/c -> B6 model and major histocompatibility complex–matched, minor-mismatched C3H.SW -> B6 model of GVHD. Immunization of the donors that were deficient in IL-10 (IL-10–/–) or with CD8{alpha}+ DCs from B6 class II (class II–/–) failed to reduce T-cell responses, demonstrating (1) a critical role for secretion of IL-10 by donor T cells and (2) a direct contact between the T cells and the CD8{alpha}+ DCs. Together, these data may represent a novel strategy for reducing GVHD and suggest a broad counterintuitive role for vaccination strategies in mitigating undesirable immune responses in an antigen-specific manner.


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