GVHD Abrogates T Cell Responses to Dendritic Cell Vaccines but Not Vaccine-Induced Proliferation.

BACKGROUND: Allogeneic bone marrow transplant (BMT) is a potent form of immunotherapy against hematopoietic and potentially solid tumors, but relapse of malignancy and Graft versus Host Disease (GVHD) remain a major cause of morbidity and mortality. Dendritic cell (DC) vaccines represent a potential strategy to enhance the potency and efficacy of the Graft versus Tumor (GVT) effect without exacerbating GVHD, but little is known regarding the impact of the allogeneic BMT environment on vaccine responses. Previous work in our lab has shown that DC can effectively expand tumor-antigen specific T cells following minor-mismatched allogeneic transplantation, resulting in delay of tumor growth. However, GVHD completely abrogates these responses. We hypothesized that the mechanism behind the loss of DC vaccine responses was through diminished T cell proliferation in the setting of GVHD.

METHODS: We established a minor histocompatibility antigen mismatched BMT model by transplanting B6 x C3H.SW (F1) thymectomized mice with either CD45.1+ B6 (allogeneic) or CD45.1+/45.2+ F1 (syngeneic) T cell-depleted bone marrow on day 0, followed by a donor lymphocyte infusion at day 14 to induce GVHD. On day 28, we adoptively transferred transgenic CD8+ (CD45.2, V beta 8.3+) or CD4+ (CD45.2, V beta 6+) T cells that only recognize components of the HY antigen to avoid cross-reactivity with allogeneic antigens. The T cells were labeled with CFSE prior to transfer to explore the impact of vaccine-induced proliferation in the presence or absence of GVHD.

RESULTS: In the allogeneic BMT setting, both CD8+ and CD4+ HY-transgenic T cells given with a DC vaccine begin proliferating 5 days (CD8+ 40%, CD4+ 65% divided) after adoptive transfer. The syngeneic BMT vaccinated control mice show similar kinetics (CD8+ 38%, CD4+ 65% divided), suggesting GVHD does not decrease T cell proliferation. Interestingly, although HY transgenic T cells do not normally undergo homeostatic peripheral expansion (HPE) during lymphopenia, the CD4+ T cells proliferate in lymph nodes even in the absence of a vaccine (50% divided), but this was not observed in the respective syngeneic BMT unvaccinated control mice (0% divided).

CONCLUSIONS: DC vaccines represent a strategy to improve the efficacy of the GVT response following allogeneic BMT, however, GVHD can abrogate DC vaccine responses. The negative impact of GVHD on vaccine responses does not appear to result from impaired DC vaccine-driven proliferation. Indeed, even in the absence of a vaccine, non-alloreactive CD4+ T cells proliferate via a mechanism that appears to be distinct from HPE. This data provides important insights towards optimizing antigen-specific vaccines administered in the allogeneic BMT setting.