Augmented Regulatory T Cell Response After Photochemical Treatment Alleviates Acute Graft-Versus-Host Disease and Improves Survival.

Abstract 3740

Graft-versus-Host disease (GVHD) causes significant morbidity and mortality after allogeneic transplantation. Regulatory T cells of both donor and host origin can limit GVHD. Acute GVHD early post transplantation is heralded by a cytokine storm induced by a dominant T helper type 1(Th1) response, which damages host tissues like skin, gut, liver and lungs. We hypothesized that co-transplantation of photochemically (S-59) treated T cells modulates T cell effecter subsets and their cytokine milieu, and thereby reduces acute GVHD. To this end, we transplanted whole bone marrow cells in a major histocompatibility complex (MHC) antigen mismatched murine model using marrow with T cells from C57BL/6J AKR (acute GVHD model), with and without S-59 treatment. We observed equivalent elevation of CD4⁺Th1 (IL-2 and IFN-g), cytotoxic CD8⁺ (FAS, IFN-g and TNF-a) and CD4⁺Th2 (IL-4, IL-5, IL-6, IL-13) cytokines in recipients of both groups during the first week after transplantation. While the Th1 cytokines persisted as long as 10 days after transplantation, there was a shift to a regulatory T cell (Treg) cytokine profile (Transforming growth factor b [TGF-b] and IL-10) in the group that received the S-59 treated T cells. TGF-b and IL-10 levels were higher in the peripheral blood and bone marrow of the study group compared to controls (table). This was accompanied by the appearance of FoxP3^High CD4⁺ CD25⁺ Tregs in the spleen and CD4⁺ Th17 cytokine (IL-17) elevation in the thymic compartment of recipients that received S-59 treated T cells (mean-28.44pg/ml versus 1.45pg/ml, p=0.0059). In-vivo tracking of S-59 treated T cells demonstrated the disappearance of these cells in the peripheral blood, spleen, bone marrow and thymus by 48 hours after transplantation. Nonetheless, we noted that recipients of S-59 treated T cells had significantly less acute GVHD and better overall survival (p=0.0001). In summary, our experiments indicate that there is an initial dominance of inflammatory and CD4 Th1 cytokines immediately post transplantation. Co-transplantation of S-59 treated T cells shifts the effecter CD4 T cell profile to resemble a Treg phenotype. Despite the absence of circulating photochemically treated T cells, significant alterations in the recipient cytokine milieu persisted after transplantation. Thus, S-59 treated T cells appear to exert an important immunomodulatory effect to ameliorate GVHD and improve survival after MHC-mismatched allogeneic transplantation.