Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: evidence for a tumor necrosis factor alpha–mediated effect

Abstract

Based on previous reports for impaired hematopoiesis in rheumatoid arhrtitis (RA), and in view of the current interest in exploring the role of autologous stem cell transplantation (ASCT) as an alternative treatment in patients with resistant disease, we have evaluated bone marrow (BM) progenitor cell reserve and function and stromal cell function in 26 patients with active RA. BM progenitor cells were assessed using flow cytometry and clonogenic assays in short-term and long-term BM cultures (LTBMCs). BM stroma function was assessed by evaluating the capacity of preformed irradiated LTBMC stromal layers to support the growth of normal CD34+ cells. We found that RA patients exhibited low number and increased apoptosis of CD34+ cells, defective clonogenic potential of BM mononuclear and purified CD34+ cells, and low progenitor cell recovery in LTBMCs, compared with healthy controls (n = 37). Patient LTBMC stromal layers failed to support normal hematopoiesis and produced abnormally high amounts of tumor necrosis factor alpha (TNFα). TNFα levels in LTBMC supernatants inversely correlated with the proportion of CD34+ cells and the number of colony-forming cells, and positively with the percentage of apoptotic CD34+ cells. Significant restoration of the disturbed hematopoiesis was obtained following anti-TNFα treatment in 12 patients studied. We concluded that BM progenitor cell reserve and function and BM stromal cell function are defective in RA probably due, at least in part, to a TNFα-mediated effect. The role of these abnormalities on stem cell harvesting and engraftment in RA patients undergoing ASCT remains to be clarified.