The experiments conducted under aim 1 have demonstrated that even relatively mild GVHD can diminish quantitative T cell immune responses to vaccination and functional immune responses to tumors expressing vaccine-targeted antigens. This work has been published (Capitini et al, Blood, 2009) and demonstrated the importance of preventing GVHD if BMT is to be optimized as a platform for immunotherapeutic approaches targeting malignancy.
Under aim 2, we have established that inhibition of interferon gamma signaling can prevent the development of GVHD. Importantly, recipients of donor bone marrow and T cells deficient in interferon gamma receptor prevented the development of GVHD. However, these mice were unable to response to vaccination and could not be protected against tumor development. Interestingly, recipients of bone marrow deficient in interferon gamma receptor could be infused with large number of fully immune competent T cells expressing the interferon gamma receptor did not without inducing GVHD. In addition, these mice generated robust responses to dendritic cell vaccination resulting in protection against tumor. We next studied whether other components of the interferon gamma pathway could be targeted in donor bone marrow to prevent GVHD. Using bone marrow deficient in STAT1, a transcription factor necessary for interferon gamma signaling, we have confirmed that interference with this pathway in bone marrow-derived cells can prevent GVHD with preserved immune competence. To identify the relevant bone-marrow-derived cell population, we have selectively targeted STAT1 by generating mice with a floxed STAT1 gene (obtained from Dr. Lothar Hennighausen) that express the Cre recombinase under non-T cell promoters (CD11c (DC expression), lysozyme (on all phagocytic cells), and CD19 (B cell expression). In recipients of bone marrow from these donors, the STAT1 gene (and, thus, interferon gamma signaling) will be ablated in selective cell populations. Allogeneic transplant experiments using these mice as bone marrow donors are ongoing.
Aim 3 is in the initial stage. We have obtained selective Stat1 inhibitors and are beginning to test these in vitro.
| Capitini, Christian M; Nasholm, Nicole M; Duncan, Brynn B et al. (2013) Graft-versus-host disease impairs vaccine responses through decreased CD4+ and CD8+ T cell proliferation and increased perforin-mediated CD8+ T cell apoptosis. J Immunol 190:1351-9 |
| Capitini, Christian M; Davis, Jessica P E; Larabee, Shannon M et al. (2011) Extracorporeal photopheresis attenuates murine graft-versus-host disease via bone marrow-derived interleukin-10 and preserves responses to dendritic cell vaccination. Biol Blood Marrow Transplant 17:790-9 |
| Capitini, Christian M; Herby, Sarah; Milliron, Matthew et al. (2009) Bone marrow deficient in IFN-{gamma} signaling selectively reverses GVHD-associated immunosuppression and enhances a tumor-specific GVT effect. Blood 113:5002-9 |
