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.

Department of Hematology, University Hospital of Crete School of Medicine, Heraklion, Greece.
Blood (Impact Factor: 9.06). 04/2002; 99(5):1610-9. DOI:10.1182/blood.V99.5.1610
Source: PubMed

ABSTRACT Based on previous reports for impaired hematopoiesis in rheumatoid arthritis (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 (TNF alpha). TNF alpha 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-TNF alpha 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 TNF alpha-mediated effect. The role of these abnormalities on stem cell harvesting and engraftment in RA patients undergoing ASCT remains to be clarified.

0 0
  • [show abstract] [hide abstract]
    ABSTRACT: Mesenchymal stem cells (MSCs) are multipotent progenitor cells which have been shown to possess broad immunoregulatory and anti-inflammatory capabilities, making them a promising tool to treat autoimmune diseases (AID). Nevertheless, as in recent years T cells from AID patients have been found to resist suppression by regulatory T cells, the question of whether they could be regulated by MSCs arises. To use MSCs as a therapeutic tool in human autoimmune diseases, one prerequisite is that T cells from autoimmune patients will be sensitive to these stem cells. The aim of this work was to investigate the ability of healthy donor derived MSCs to inhibit the proliferation of T cells from two pathophysiologically different AIDs: Multiple Sclerosis (MS) and Myasthenia Gravis (MG). We show that MSC-induced inhibition of interferon-γ production and surface expression of the CD3, CD4 and CD28 receptors by activated lymphocytes was similar in the AID patients and healthy controls. Contrarily, the MSCs' ability to suppress the proliferation of T cells of both diseases was significantly weaker compared to their ability to affect T cells of healthy individuals. Although we found that the inhibitory mechanism is mediated through CD14+ monocytes, the faulty cellular component is the patients' T cells. MSC-treated MS and MG lymphocytes were shown to produce significantly more IL-2 than healthy subjects while coupling of the MSC treatment with neutralizing IL-2 antibodies resulted in inhibition levels similar to those of the healthy controls. MSCs were also found to down-regulate the lymphocyte surface expression of the IL-2 receptor (CD25) through both transcription inhibition and induction of receptor shedding. Addition of IL-2 to MSC-inhibited lymphocytes restored proliferation thus suggesting a key role played by this cytokine in the inhibitory mechanism. Taken together, these results demonstrate the potential of a MSC-based cellular therapy for MS, MG and possibly other autoimmune diseases but also highlight the need for a better understanding of the underlying mechanisms for development and optimization of clinical protocols.
    Autoimmunity reviews 10/2013; · 6.37 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The prospective clinical use of multipotent mesenchymal stromal cells (MSCs) holds enormous promise for the treatment of a large number of degenerative and age-related diseases. In particular, autologous MSCs isolated from bone marrow (BM) are considered safe and have been extensively evaluated in clinical trials. Nevertheless, different efficacies have been reported, depending on the health status and age of the donor. In addition, the biological functions of BM-MSCs from patients with various diseases may be impaired. Furthermore, medical treatments such as long-term chemotherapy and immunomodulatory therapy may damage the BM microenvironment and affect the therapeutic potential of MSCs. Therefore, a number of practical problems must be addressed before autologous BM-MSCs can be widely applied with higher efficiency in patients. As such, this review focuses on various factors that directly influence the biological properties of BM-MSCs, and we discuss the possible mechanisms of these alterations.
    Cytotherapy 06/2013; · 3.06 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The regenerative abilities and the immunosuppressive properties of mesenchymal stromal cells (MSCs) make them potentially the ideal cellular product of choice for treatment of autoimmune and other immune mediated disorders. Although the usefulness of MSCs for therapeutic applications is in early phases, their potential clinical use remains of great interest. Current clinical evidence of use of MSCs from both autologous and allogeneic sources to treat autoimmune disorders confers conflicting clinical benefit outcomes. These varied results may possibly be due to MSC use across wide range of autoimmune disorders with clinical heterogeneity or due to variability of the cellular product. In the light of recent genome wide association studies (GWAS), linking predisposition of autoimmune diseases to single nucleotide polymorphisms (SNPs) in the susceptible genetic loci, the clinical relevance of MSCs possessing SNPs in the critical effector molecules of immunosuppression is largely undiscussed. It is of further interest in the allogeneic setting, where SNPs in the target pathway of MSC's intervention may also modulate clinical outcome. In the present review, we have discussed the known critical SNPs predisposing to disease susceptibility in various autoimmune diseases and their significance in the immunomodulatory properties of MSCs.
    BioMed research international. 01/2013; 2013:929842.