Improving Inflammation Resolution to Mitigate Acquired Bone Marrow Failure

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Improving Inflammation Resolution to Mitigate Acquired Bone Marrow Failure Bone marrow failure is the devastating collapse of blood production, and current treatments are inadequate. First line therapies include immunosuppressive therapies, and when feasible, bone marrow transplantation. These therapies are often efficacious in the short-term, especially for young patients, however they are much less effective in older patients. Immune suppression is not well tolerated, especially in the elderly, and carries increased susceptibility to infection. Therefore, alternative therapies are needed. It is well established that bone marrow failure is associated with non-resolving inflammation. The resolution of inflammation requires the balance between pro-inflammatory leukotrienes or prostaglandins and w3-derived specialized pro-resolving mediators (SPMs), like resolvins. Using a mouse model of acquired severe aplastic anemia (SAA) that mirrors key features of human disease, we established a role for impaired inflammation resolution programs in disease pathogenesis. Our preliminary work demonstrates the effectiveness of SPMs in ameliorating SAA. The rationale for the proposed work is that rather than blunting inflammatory responses, promoting resolution and reparative processes may be an ideal therapeutic strategy for bone marrow failure. The proposed studies will address a fundamental gap in our understanding of the physiologically relevant process of inflammation resolution in the bone marrow. We propose three integrated, but independent, Aims to: (1) address mechanisms of impaired resolution, (2) determine the impact of SPMs in the marrow in SAA, and (3) evaluate the effect of SPMs on function of hematopoietic stem cells. The proposed work will support a novel approach to treat BMF without the use of immune suppression, representing an important departure from the current standard of care. We believe these studies will be impactful therapeutic options for BMF patients, particularly older patients where IST has failed, and wherein host defenses are already weakened. At the same time, the proposed studies may provide new mechanistic insight relevant to other diseases characterized by prolonged and non-resolved inflammation, and thus will have broad impact to human health.