Targeting Resolution Pathways to Rescue Bone Marrow Failure
Abstract
Bone marrow failure (BMF) syndromes can be inherited or acquired, and result in a failure to generate blood. They are almost always 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 these therapies are most effective. Unfortunately, older patients have reduced success with HSC transplantation and poorer responses to IST. Thus, alternative therapies are needed, as immune suppression is not tolerated well and carries increased susceptibility to infection. Using a mouse model of severe aplastic anemia (SAA) 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 promote and/or limit inflammation, and therefore are poised to control inflammation and have the capacity to restore homeostasis after acute inflammatory stress. Indeed, 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 that macrophage dysfunction impairs resolution processes in SAA, suggesting macrophages are an important therapeutic target for treating SAA. We hypothesize that macrophage dysfunction prevents resolution of inflammation and blocks tissue repair processes ultimately driving loss of HSCs in SAA. Therefore, our objectives are to define mechanisms driving macrophage dysfunction (Aim 1) and to test the therapeutic efficacy of improving resolution by administering small pro-resolving lipid mediators (Aim 2). The rationale for the proposed work herein 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. 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. This represents an important departure from the current standard of care of immune suppression. 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 insights relevant to other diseases characterized by prolonged and non-resolved inflammation, and thus will have broad impact to human health.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jun 29, 2021
- Source ID
- W81XWH2010314
Entities
People
- Katherine C MacNamara
Organizations
- Albany Medical College
- United States Army