A novel approach to enhance T cell recovery after bone marrow transplant

Abstract

Abstract Cytoablative treatments such as chemotherapy and radiation are commonly used during allogeneic hematopoietic stem cell (HSC) transplants. After cytoablation, T cells must be replaced to generate effective immune responses. Cytoablative therapies damage the thymic stromal cells (TSC) comprising the lymphopoietic microenvironment necessary for T cell development. Damage to TSCs causes delayed thymic recovery, and corresponding delays in T cell recovery in HSC transplant patients, which directly contribute to increased susceptibility to infection and malignant relapses. However, the mechanisms that cause TSCs to be particularly sensitive to cytoablative therapies are not completely understood. Substantial cellular damage is caused by reactive oxygen species (ROS) generated during radiation and chemotherapy treatments. Our recent work identified a deficiency in the antioxidant enzyme catalase in TSCs, indicating that this population may be particularly sensitive to ROS. We hypothesize that oxidative damage to TSCs during cytoablative therapy is exacerbated by catalase insufficiency, and that this is an important contributor to delayed thymus recovery after treatment. If so, an optimized regimen of antioxidant supplementation during cytoablative therapy may represent a novel approach to enhance immunity after HSC transplant. We have tested this hypothesis using dietary and genetic supplementation of catalase activity in mice receiving bone marrow transplants after irradiation. Our preliminary data support the notions that catalase deficiency increases TSC sensitivity to radiation, and that thymus recovery after bone marrow transplant can be improved by supplementing catalase activity in mice.