a-1-Antitrypsin (AAT)–modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics

Allogeneic hematopoietic stem cell transplantation is curative in many patients with leukemia and other lymphohematopoietic disorders. However, the immune response of donor cells that mediate the graft-versus-leukemia (GVL) effect, leading to disease eradication, also triggers graft-versus-host disease (GVHD). Preventing GVHDwhile maintaining the GVL effect would be a major advance. Several recent studies suggest that this should be possible. Donor T-cell activation, initiated by host antigen-presenting cells (APCs), is enhanced by proinflammatory cytokines, released from sites of tissue injury following transplant conditioning. These cytokines, including tumor necrosis factor a (TNFa), interleukin 1b (IL-1b), and interferon g (IFN-g), promote T-helper 1 (Th-1) cell differentiation and enhance their proliferation and reactivity against host tissues. The administration of a-1-antitrypsin (AAT), used therapeutically in patients with genetically determined AAT deficiencyrelated emphysema, profoundly alters cytokine profiles and has been shown to suppress GVHD. AAT is a serine protease inhibitor, which in addition to changes in cytokine profiles, also affects the redox status of cells and cell-mediated immunity, among other functions. Taken together, available data indicate that AAT therapy is beneficial in a broad spectrum of inflammatory and immune-mediated diseases not related to genetic AATdeficiency. Therefore, it is of interest that ancillary data suggest that patients transplanted from donors with higher AAT levels were less likely to develop acute GVHD. Hence, we investigated whether exposure of donor cells to (exogenous) AAT would modify cell function and thereby affect GVHD in recipients. However, because AAT also increases expression of cytoprotective factors such as IL10 and IL1Ra, we had to address the concern that AAT exposure might interfere with the desired GVL effect.