Decreased MHC-II Expression and Immune Dysfunction by Mesenchymal Stem Cells in the Bone Marrow of Patients with Myeloproliferative Disorders.

The etiology of hematological disorders has been studied at the cellular and molecular levels. These studies have led to an understanding of the effects by the bone marrow microenvironment on the pathophysiology of myeloproliferative disorders. The overarching hypothesis states that resident bone marrow Mesenchymal Stem Cells (MSCs) are important in the development of myeloproliferative disorders and are also involved in the development of fibrosis. The specific hypothesis is that MHC-II expression is decreased in patients MSCs. This makes them unable to act as antigen presenting cells and to suppress immune mediated mechanisms that lead to the development of some myeloproliferative disorders. MSCs were expanded from bone marrow aspirates of patients with AML (n=10), CML (n=10), and MDS (n=10). Flow cytometric analysis showed decreased MHC-II expression in MSCs from all patients as compared to MSCs from patients without hematological malignancy. The flow cytometry results were verified in functional studies using the MSCs as stimulators in a one way mixed lymphocyte reaction. Compared to MSCs from non-hematological malignancy patients, MSCs from study subjects showed reduced ability to elicit allogeneic responses. Retrospective analyses of bone marrow biopsies using immunohistochemistry showed an increase in the amount of MSCs in myelofibrosis patients, compared to patients without evidence of fibrosis, alluding to their role in the development of this condition. These results suggest that MSCs may be dysfunctional in patients with hematological disorders. Variations in the immune properties and the increased amount of MSCs in these patients open an avenue for a lingering question on the etiology of the development of some hematological disorders. Do dysfunctions of MSCs precede myeloproliferative disorders and leukemia or does the opposite occur? In summary, we provide insight into the immune-mediated mechanisms related to the pathophysiology of these disorders, which may have clinical implications for future therapies of bone marrow related disease.