NIH Research Festival
FARE Award Winner
GvHD is an immune mediated reaction that can occur after hematopoietic stem cell transplantation in which donor T cells recognize the host antigens as foreign, destroying host tissues. Establishment of a tolerogenic immune environment while preserving immune response to infectious agents is required for successful transplantation and GvHD is a significant obstacle. PSG1 is a protein synthesized by the placenta at the onset of pregnancy. PSG1 is essential to maintaining a tolerogenic immune environment to prevent rejection of the fetus by the maternal immune system. PSG1 has been shown to increase secretion of transforming growth factor-β (TGFβ), a cytokine essential for the differentiation of tolerance inducing FoxP3+ regulatory T-cells (Tregs), a cell population shown to be important in the prevention of GvHD. We thus hypothesized that PSG1 could be used to treat GvHD by inducing immune tolerance. In vitro data using naïve mouse T-cells showed that upon treatment with PSG1, 18% of T-cells expressed FoxP3 compared to only 2% in untreated controls. FoxP3 expression was effectively blocked by TGFβ inhibitors, further supporting the hypothesis that PSG1 induces expression of Tregs through regulation of TGFβ. Using a GvHD murine model, we further showed that mice receiving PSG1 had reduced numbers of tissue-infiltrating inflammatory CD3+ T-cells and showed a marked improvement histologically over untreated controls. These same PSG1 treated mice also showed expression of FoxP3 in 30% of splenic T-cells when compared to approximately 5-10% expression in untreated controls. Combined, this data strongly suggests that PSG1 induces immune tolerance in GvHD.
Scientific Focus Area: Immunology
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