1. Introduction
1.1. Potential mechanisms of pathogenesis of RA
Rheumatoid arthritis (RA) is a chronically systemic inflammatory disorder that ultimately leads to the destruction of joint architecture. RA affects more than two million people in America and about 1% of the world’s population, women are three times more prone to RA than men [1, 2]. About 58 million people suffer from RA all over the world. The disease has a variable course, from a mild, occasionally symptomatic illness requiring only symptomatic therapy to a fully onset requiring aggressive immunosuppressive therapy, surgery or both. The hallmarks of RA is the systemic loss of regulation of immune system characterized by either acute or chronic inflammation, in which the immune system primarily attacks the joints of the body leading to tissue pathology and clinical disease. The etiological factor causes the immune reaction is still unknown. The pathological insult starts with inflammation of the synovium (sinovita), which then takes the form of proliferative nature (pannus) with the damage of cartilage and bones. Plasmatic cells of joint produce antibody that form aggregates of IgG. In turn, IgG aggregates have been recognized by the immune system as foreign antigens and plasmatic cells (B cells, dendritic cells, T cells, and macrophages formed lymphoid follicle-like structures within the synovial membrane) begin to produce autoantibodies against those structures known as rheumatoid factors (RF). Autoantibodies directed against the Fc fragment of IgG. [3, 4]. The most important type of RF is the IgM class, which appears in 70-80% of patients with RA. In the course of the disease, the normal, relatively avascular synovium then becomes heavily infiltrated by a wide variety of cells, including B cells, macrophages, fibroblasts, neutrophil granulocytes, dendritic cells, and many other cells [5]. Because of the autoimmune inflammatory process, which leads to formation of pannus - granulation tissue that occurs from in the inflamed synovium, which is consists of actively proliferating fibroblasts, lymphocytes, macrophages and rich with vessels. The synovial lining increases to a thickness of up to 30 cell layers, presumably through influx of macrophages, and by expansion of synovial fibroblasts. Pannus grows intensively, percolates from the synovial tissue to the cartilage and destroys it by the influence of enzymes, which are induced by the production of high amount of proinflammatory cytokines mainly tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6 within the pannus. Furthermore, many other cytokines such as IL-17, IL-18, IL-15, chemokines, and angiogenic molecules are present in the inflamed synovial membrane and drive the development of the disease. Subsequently, these proinflammatory cytokines activate signal transduction pathways and transcription factors, which, in turn, control the production of cytokines [6]. Gradually, intrasynovial cartilage disappears, it is replaced by granulation tissue and ankylosis develops. Chronic inflammation of periarthric tissues, joint capsule, ligaments and tendons lead to deformation of joints, semiluxations, and contractures. Currently, there is a large body of literature which suggests that autoimmune processes play a central role in the early stages of RA, and in later stages non-immune mechanisms (
2. Current biological therapies for RA
Biologic therapies have brought improved efficacy in the treatment of RA. However, these therapies sometimes fail or produce only partial responses, because of the lack of reliable predictive biomarkers of prognosis, therapeutic response, and toxicity data. Sustained remission is rarely achieved and requires ongoing pharmacological intervention. Although RA often responds to immunosuppressive medication including corticosteroids, methotrexate, azathioprine and cyclophosphamide, or non-steroidal anti-inflammatory drugs, none of these drugs showed a curative effect [25]. Synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, leflunomide, and sulfasalazine, have evidently improved clinical symptoms and reduced joint damage in RA patients. However, despite the effectiveness of synthetic DMARDs, many patients who have been taking those drugs continue to have clinical symptoms of inflammation and progressive joint destruction. Recently, FDA approved many TNF-α inhibitors including infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol in the RA treatment. In randomized clinical trials, all of these agents have been shown effective in reducing clinical symptom of inflammation in RA patients who have failed synthetic DMARDs [26]. Multiple studies have demonstrated significant benefits of early treatment with TNF-α inhibitors combined with methotrexate [27-29]. Other FDA-approved biologic agents for treating moderate-to- severe RA include abatacept, rituximab, and tocilizumab [30-33]. However, all biologic agents carry an increased risk of infections.
3. Current concept of stem cell therapy in RA
The natural healing process for RA requires a combination of stem cells, growth factors, and matrix to optimize tissue repair and regeneration. The use of these bioactive cells to supplement and hasten the natural healing process is considered by many to be a new era of clinical treatment. This ideal cell population for the treatment of RA should have a series of properties, namely a high osteogenic and chondrogenic potential, and at the same time, it should be easily expanded,
4. MSC based stem cell therapy in RA
MSCs are the non-hematopoietic progenitor cells found in various adult tissues. MSCs have been characterized by the ease of isolation and rapid growth
5. HSC (hematopoietic stem cell)-based therapy in RA
Out of several advantages of HSC-based therapy, one potential of using HSC lines for transplantation in patients with autoimmune diseases is that these cells can be recovered from unaffected individuals. Thus, genetic makeup is defined and will not be affected by genetic influence whereas ESCs will be affected by genetic influences [62]. In addition, by using genetically selected or engineered cell types may further limit the possibility of disease progression or re-emergence. There are several studies in the past that used cell-based approaches to treat active, destructive, refractory and inflammatory arthritis that involved HSC transplantation (HSCT) [62-65] and juvenile idiopathic arthritis [66, 67]. Although this treatment was curative for some patients, prolonged immunosuppression after HSCT was associated with a significant risk of infection, which limited the potential of this therapy [68, 69]
6. Regulatory T cell-based therapy in RA
Tregs play an important role in the prevention of autoimmunity, and have ability to modulate the severity of CIA [71, 72]. Deficiencies in Treg function have been identified in a wide variety of human autoimmune disorders, including RA [73-76]. The majority of the reports suggested that biological or stem cells therapy will induce a potent population of Tregs in patients with RA [57, 59, 60], but the natural Treg defect will persist in responding patients after anti-TNF treatment [77]. A few studies suggested that Tregs isolated from patients with active RA were competent at suppressing conventional T cell proliferation but not cytokine production [73]. A recent report suggested that reduced expression and functional abnormalities in Tregs associated with cytotoxic T lymphocyte-associated antigen 4 (CTLA-4] could account for the Treg defect in patients with RA [78].
Tregs comprise about 5-10% of the mature CD4+ T helper cell subpopulation in mice and about 1-2% of CD4+ T cells in human. Tregs are composed of thymus-derived, naturally occurring CD4+CD25+Foxp3+ Tregs (nTregs) as well as adaptive (also called ‘induced’) Tregs (iTregs) that are generated from CD4+CD25−Foxp3− naive T cells in the periphery. Unlike other cell-surface markers used to identify Tregs, Foxp3 is not up-regulated upon activation, and discriminates Tregs from activated effectors T cells. On the other hand, Foxp3 is also expressed in T cells without conferring any regulatory functions. nTregs are characterized by the expression of CD25, CD45RB, CD62L, CD103, CD95 (Fas), MHC class II, CD127, neuropiln-1 lymphocyt activation gene-3 (LAG-3), CTLA-4, glucocorticoid-induced TNFR family related gene (GITR), and Foxp3. iTreg cells are also characterized as expressing the same markers as nTreg cells but arise from CD4+D25+FoxP3- precursor cells. iTreg cells are further classified into two subgroups on the basis of TGF-β or IL-10 production. Recently, it was reported that human CD4+FoxP3+ T cells have three distinct populations with precise phenotypes and fates which includes, CD25++ CD45RA+ (Foxp3lo) resting Tregs (rTreg cells), CD25+++ CD45RA- (Foxp3hi) activated Tregs (aTregs), and CD25++ CD45RA- (Foxp3hi) cytokines-secreting T cells which lack suppressive activity [79]. The first two groups of phenotypes represent different stages of Treg cell differentiation and are both playing suppressive function
One critical factor in Treg cell-based therapy is the survival of Tregs. Tregs are highly susceptible to apoptosis in the absence of common gamma chain (γc) cytokines (
Several studies have shown improvement of inflammation,
7. Concept of stem cell-derived Treg-based therapy in RA
Because of the intrinsic resistance of Tregs to exogenous expansion and a high number of Tregs are required to perform the Treg-based immunotherapy, it becomes imminent to isolate a larger Treg cell subset for exogenous expansion and adoptive transfer, as discussed above, there are number problem and limitations to generate a large number of Tregs regardless of an increasing number of protocols for isolating subsets of Tregs, no approach to date has been confirmed the capacity to isolate the entire Treg cell population with 100 percent specificity. ESCs or iPSCs have the remarkable potential to develop into many different cell types in the body during early life and growth. ES or iPSC can give rise to all the blood cell types including myeloide (
Previously, pluripotent stem cells (
8. Conclusion
Biologic agents have revolutionized the treatment of RA by reducing the signs and symptoms and improving physical function and quality of life in affected patients, and also showed promising data to treat many diseases. However, question remains for their side effects. Improved knowledge of the pathophysiology will lead to the recognition of more reliable and practical predictors of the disease course and treatment response. Stem cell-based therapies offer many exciting opportunities for the development of novel treatment and cure for autoimmune diseases. The multipotent autologous stem cells have potential to treat disorders involving connective tissue because of their differentiation potential. In addition, the multipotent autologous stem cells have significant effects on a variety of autoimmune diseases because of their immunomodulatory immune response. Despite of the great potential and convincing evidence that primary MSCs inhibit human T-cell proliferation
Acknowledgement
This project was funded, in part, under grants with the Grant Number K18CA151798 from the National Cancer Institute (NCI) and the Melanoma Research Foundation to J.S.
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