The Immunoregulatory and Hematopoietic Effects of Momelotinib in a Murine Bone Marrow Failure Model.

Abstract

BACKGROUND: Immune-mediated bone marrow failure (AA) is characterized by T cell-mediated destruction of hematopoietic stem and progenitor cells (HSPCs). The JAK-STAT signaling pathway plays a crucial role in regulating immune responses, and JAK inhibitors have shown potential in treating immune-mediated disorders. This study investigates the effects of MMB, a JAK inhibitor, in a mouse model of immune-mediated bone marrow failure to evaluate its impact on hematopoiesis and immune cell function. METHODS: In this study, immune-mediated AA was induced in B6D2F1 female mice through irradiation and lymphocyte infusion. The mice were treated with MMB monotherapy at doses of 6.25 and 12.5 mg/kg for 14 days. Peripheral blood cell counts, bone marrow cell counts, plasma cytokine levels, T lymphocyte subsets, Fas/FasL expression, and hematopoietic stem and progenitor cell (HSPC) levels were analyzed to assess the effects of MMB treatment on immune function and hematopoiesis. RESULTS: MMB treatment exacerbated the reduction in peripheral blood cell counts in marrow failure mice and decreased bone marrow hematopoietic cell numbers. Concurrently, MMB also reduced cytokine levels. The treatment also led to a significant reduction in CD4T cells and Tregs in both the spleen and bone marrow, while the low-dose MMB group exhibited a decrease in CD8+ T cell count. Additionally, MMB did not significantly improve HSPC levels, and a decrease in the more primitive LSK and LT-HSC populations was observed. However, later-stage stem and progenitor cells, such as ST-HSCs, MPPs, and CMPs, showed an increase in numbers. The treatment also resulted in downregulation of Fas expression on non-T cells, while FasL expression on lymphocytes increased. CONCLUSION: MMB treatment exacerbated peripheral blood cell reduction and impaired bone marrow hematopoiesis in the immune-mediated AA mouse model. Although MMB modulated T lymphocyte subsets, it did not significantly improve hematopoietic stem and progenitor cell function. These findings highlight the need for further research to explore the potential and limitations of JAK inhibitors like MMB in the treatment of immune-mediated bone marrow failure.