Harnessing RvE1 to Treat Bone Marrow Failure
Abstract
Bone marrow failure (BMF) syndromes can be inherited or acquired and result in the failure to generate blood and immune cells. They are fatal if left untreated and the current therapeutic approach revolves around immunosuppressive therapies (IST) and hematopoietic stem cell (HSC) transplantation. There have been many successes in treating BMF in recent years, particularly for young patients where therapies are most effective. Unfortunately, older patients have reduced success with HSC transplantation and poorer responses to IST. Alternative therapies are needed because immune suppression is not tolerated well and carries increased risk of infection. Using a mouse model of severe aplastic anemia (AA) that mirrors many of the features of human disease, we identified a novel role for macrophages in the interferon-gamma-dependent loss of HSCs. Macrophages are equipped with machinery to induce and limit inflammation, and therefore have the capacity to restore homeostasis after acute inflammatory stress. In healthy tissues macrophages play an essential role in resolving inflammation by removing dead cells and releasing factors that aid in tissue repair. Our preliminary studies demonstrate macrophage dysfunction impairs resolution processes in AA, and reduced resolution correlates with an imbalance in pro-inflammatory and pro-resolving lipid mediators. Administration of pro- resolving lipid mediators was able to mitigate disease, demonstrating therapeutic efficacy of targeting resolution. We hypothesize that enhancing resolution ameliorates BMF and will improve IST by modulating macrophage function and lymphocyte activity in the BM and result in durable improvement of HSC function. The rationale for the proposed work is that rather than blunting inflammatory responses, promoting resolution and reparative processes may improve HSC function and normal blood production without impacting immunity and host defense. We will investigate how exogenous RvE1 impacts inflammation resolution, T cell function, and HSC function in an established mouse model of disease. The proposed studies are rooted in the conceptually innovative idea that resolution processes are delayed or absent in BMF, and the results of the proposed work may provide a novel approach to treat BMF without the use of immune suppression. We will also examine the ability of RvE1 to improve suboptimal IST treatments. These studies will be impactful by providing new therapeutic options for BMF patients, particularly older patients where IST has failed, and wherein host defenses are already weakened.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310435
Entities
People
- Katherine C MacNamara
Organizations
- Albany Medical College
- United States Army