Kate MacNamara, PhD | Aplastic Anemia and MDS International Foundation

Kate MacNamara, PhD

Macrophages in the Pathogenesis of Aplastic Anemia
Original Research Center: 
Albany Medical College
Pubmed Author Name: 
MacNamara K
Current Position/Title: 
Assistant Professor

Bone marrow failure is the rare but devastating collapse of blood production, and if left untreated the disease is invariably fatal. Our current therapies are inadequate in the sense that they involve general immunosuppression or highly invasive treatments via bone marrow transplantation. In both genetic and acquired cases of bone marrow failure, excessive inflammation ultimately causes destruction of the stem cells required to maintain daily production of all blood cells. Inflammatory molecules such as interferon gamma (IFN-gamma) are known to contribute to pathology, yet exactly how stem cell function is compromised by these factors is not clear and remains an important question in understanding the pathogenesis of bone marrow failure.

We utilized a mouse model of bone marrow failure to investigate the mechanisms whereby IFN-gamma drives hematopoietic failure. We made the unexpected observation that IFN-gamma signaling in stem cells themselves was not required for the loss of blood stem cells. We identified macrophages, key phagocytic cells of the immune system, as the direct targets of IFN-gamma in driving the decline of stem cells during bone marrow failure. Ablation of the macrophage population during disease preserved stem cell function and prevented death caused by hematopoietic failure. Preventing IFN-gamma signaling exclusively in macrophages was also able to rescue disease. Our observation was particularly striking because we observed similar numbers of activated T lymphocytes and similar levels of pro-inflammatory cytokines, including IFN-gamma, in mice with severe disease, relative to those rescued through manipulation of the macrophage population. We identified one factor, the chemokine CCL5, to be selectively increased during severe disease in manner that required both macrophages and IFN-gamma. Neutralization of this factor was able to rescue the loss of hematopoietic stem cells seen during aplastic anemia. Thus, we have revealed a previously unknown mechanism whereby IFN-gamma and macrophages contribute to hematopoietic failure. Here we propose to investigate further how macrophages and CCL5 contribute to aplastic anemia. Our ultimate goal is to identify novel pathways that can be targeted to rescue hematopoiesis in patients with bone marrow failure.

2016
First Year Report: 

Bone marrow failure is the rare but devastating collapse of blood production, and if left untreated the disease is invariably fatal. Our current therapies are inadequate in the sense that they involve general immunosuppression or highly invasive treatments such as bone marrow transplantation. In both genetic and acquired cases of bone marrow failure, excessive inflammation ultimately causes destruction of the stem cells required to maintain daily production of all blood cells. Interferon gamma (IFN-gamma) is known to contribute to pathology, yet exactly how stem cell function is compromised by IFN-gamma is not clear and remains an important question in understanding the pathogenesis of bone marrow failure. We utilized a mouse model of bone marrow failure to investigate the mechanisms whereby IFN-gamma drives hematopoietic failure. We made the unexpected observation that IFN-gamma signaling in stem cells themselves was not required for the loss of blood stem cells. We identified macrophages, key phagocytic cells of the immune system, as the direct targets of IFN-gamma in driving the decline of stem cells during bone marrow failure. Ablation of the macrophage population during disease preserved stem cell function and prevented death caused by hematopoietic failure. Preventing IFN-gamma signaling exclusively in macrophages was also able to rescue disease. Our observation was particularly striking because we observed similar numbers of activated T lymphocytes and similar levels of pro-inflammatory cytokines, including IFN-gamma, in mice with severe disease, relative to those rescued through manipulation of the macrophage population. The chemokine CCL5 was significantly elevated in mice with bone marrow failure and its increase required both IFN-gamma and macrophages. We are currently investigating the signals, including CCL5, that maintain macrophages during severe aplastic anemia and the mechanisms whereby macrophages drive the loss of hematopoietic cells and hematopoiesis.