The Suppressive Effect of Bone Marrow Mesenchymal Stem Cells on T Cell Activation, Is Deficient in Patients with Severe Aplastic Anemia.

Abstract

Normal bone marrow derived mesenchymal stem cells (MSC) suppress T cell function, and may provide an immunoprotected environment for hemopoietic stem cells. In this study we compare the suppressive activity on T cell function of MSC from 23 patients with severe aplastic anemia (SAA) patients, at diagnosis (n=3), following immunosuppressive therapy (IS) (n=16) or after an allogeneic bone marrow transplant (BMT) (n=4), and normal individuals. As shown in Figure 1 increasing numbers of control MSC (25, 50 and 100x10^3 cells) produced a dose dependent suppression of PHA induced T cell proliferation; when MSC were derived from SAA patients, they exhibited significantly less suppressive activity (37% vs 6%, 81% vs 24%, 96% vs 35%). The reduced ability of SAA MSC to suppress mitogen induced T cell proliferation, was seen irrespective of disease phase. Paired experiments on mixed lymphocyte reaction confirmed the inability of SAA MSC to suppress T cell function. Other abnormalities of SAA MSC included: (a) impaired capacity to down regulate CD38 expression on PHA primed T cells, (b) impaired ability to suppress gamma-IFN production in PHA coltures, which resulted in a 11 fold different gamma-IFN concentration in the cultures; (c) no effect on T cell mediated inhibition of hemopietic colony formation. Finally SAA MSC produced significantly (1 log) less adenosin diphosphate -ribosyl cyclase (cADPR), a promoter of in vitro hematopoiesis. MSC mediated suppression of PHA induced T cell proliferation, was restored to control levels in 3 of 4 patients post-BMT. In conclusion, the ability of MSC to down regulate T cell priming, proliferation and cytokine release is deficient in patients with SAA, persists indefinitively after immunosuppressive therapy, but may be restored after BMT. Whether this defect plays a role in the pathogenesis of marrow failure, remains to be determined. Figure Figure

Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells

“…It is tempting to postulate that MSCs may play an important immunoregulatory role in the bone marrow microenvironment to create an immuneprivileged site in which primitive stem cells and APCs coexist. A recent observation in patients with aplastic anemia indicate diminished immunosuppressive potential of MSCs obtained from these patients compared to normal donors, implicating MSCs and their immunoregulatory function in the pathogenesis of this autoimmune disorder [12].…”