Dendritic Cells, Aging, and Graft-verus-Host Disease
Host dendritic cells (DC) are known to initiate graft-versus-host disease (GVHD) in response to an allogeneic bone marrow transplant. Older patients experience increased incidence and severity of GVHD, and this finding can be reproduced in a mouse model. Through the use of such a murine model of GVHD, I aim to characterize alterations in older host DC that render older mice more susceptible to severe GVHD. This aim will first be addressed through the analysis of co-stimulatory and inhibitory molecule expression, as well as cytokine production.
Prophylactic treatment with host derived regulatory DC (DCreg) has been shown to reduce the severity of GVHD following complete MHC mismatched transplants in both young and older mice. Over 90% of young mice survive GVHD when treated with DCreg (compared to 100% mortality when untreated); older mice also respond to this treatment, although with somewhat lower efficacy depending on the strain combination. I am investigating the mechanisms of GVHD induction and long-term maintenance of a disease free state following DCreg treatment to understand the relative role of Treg, in addition to, host and donor-derived DC in this process. In addition, I aim to develop a murine model of GVHD that facilitates induction of less severe disease that more closely mimics the majority of human patients with GVHD and allows for therapeutic intervention with DCreg.
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