Graft-versus-host disease (GVHD) remains a major cause of mortality after allogeneic hematopoietic stem cell transplantation (HSCT) and response to first-line therapy with glucocorticoids is often limited. 
To identify novel therapeutic targets for treatment and/or prophylaxis of GVHD, we performed RNA sequencing and Differentially Expressed Gene (DEG) analysis on sequentially isolated T cells of HSCT recipients. In recipients who later developed GVHD, we observed early up-regulation of the anti-apoptotic molecule BCL2, which is targeted in chronic lymphocytic leukemia with a recently approved small molecule inhibitor.
Furthermore, gastrointestinal tract, liver and skin affected by acute and/or chronic GVHD showed higher BCL2 mRNA expression compared to matched control groups. BCL2 protein levels were elevated in overall leukocytes and pathogenic cell subsets including CD8+ T lymphocytes in peripheral blood and skin of GVHD patients. Notably, high Bcl-2 expression levels correlated to steroid-refractory GVHD and increased transplant-related mortality. In vitro inhibition of BCL2 in allo-reactions led to dose-dependent apoptosis of T cells and increase of CD4/CD8 ratio.
Our results highlight the role of BCL2 as survival factor of GVHD-mediating lymphocytes. Selective inhibition of BCL2 may present a novel and urgently needed targeted therapy in treatment of steroid-refractory GVHD.

Expansion of BCL2+ lymphocytes in cutaneous graft-versus host disease is associated with steroid resistance and poor prognosis