Rheumatoid Arthritis and Stem Cell Therapy
Stem Cell Treatmenst for Rheumatoid Arthritis is available. The Disease process often leads to the decay of articular cartilage and ankylosis of the joints. Rheumatoid Arthritis can also produce diffuse inflammation in the lungs, pericardium, pleura, and sclera, and also nodular lesions, most common in subcutaneous tissue.
Although the cause of Rheumatoid Arthritis is unknown, autoimmunity plays a pivotal role in both its chronic status and progression. RA is considered a systemic autoimmune disease.
STEM CELL RESEARCH
Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications.
Yi T, Song SU.
2012 Feb;35(2):213-21. Epub 2012 Feb 28.
Clinical Research Center, Inha Research Institute, Inha University School of Medicine, Incheon, 400-712, Korea.
Mesenchymal stem cells (MSCs) are adult stem cells that can be isolated from most adult tissues, including bone marrow, adipose, liver, amniotic fluid, lung, skeletal muscle and kidney. The term MSC is currently being used to represent both mesenchymal stem cells and multipotent mesenchymal stromal cells. Numerous reports on systemic administration of MSCs leading to functional improvements based on the paradigm of engraftment and differentiation have been published. However, it is not only difficult to demonstrate extensive engraftment of cells, but also no convincing clinical results have been generated from phase 3 trials as of yet and prolonged responses to therapy have been noted after identification of MSCs had discontinued. It is now clear that there is another mechanism by which MSCs exert their reparative benefits. Recently, MSCs have been shown to possess immunomodulatory properties. These include suppression of T cell proliferation, influencing dendritic cell maturation and function, suppression of B cell proliferation and terminal differentiation, and immune modulation of other immune cells such as NK cells and macrophages. In terms of the clinical applications of MSCs, they are being tested in four main areas: tissue regeneration for cartilage, bone, muscle, tendon and neuronal cells; as cell vehicles for gene therapy; enhancement of hematopoietic stem cell engraftment; and treatment of immune diseases such as graft-versus-host disease, rheumatoid arthritis, experimental autoimmune encephalomyelitis, sepsis, acute pancreatitis and multiple sclerosis. In this review, the mechanisms of immunomodulatory effects of MSCs and examples of animal and clinical uses of their immunomodulatory effects are described.
Haematopoietic stem cell gene therapy as a treatment for autoimmune diseases.
Mol Pharm. 2011 Jul 6;
Authors: Alderuccio F, Nasa Z, Chung J, Ko H, Chan J, Toh BH
A key function of the immune system is to protect us from foreign pathogens such as viruses, bacteria and parasites. However, it is also important in many other aspects of human health such as cancer surveillance, tissue transplantation, allergy and autoimmune disease. Autoimmunity can be defined as a chronic immune response that targets self-antigens leading to tissue pathology and clinical disease.
As a group of diseases that include type 1 diabetes, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus, there are no effective cures and treatment is often based on long-term broad-spectrum immunosuppressive regimes.
While a number of strategies aimed at providing disease specific treatments are being explored, one avenue of study involves the use of haematopoietic stem cells to promote tolerance. In this manuscript, we will review the literature in this area but in particular examine the relatively new experimental field of gene therapy and haematopoietic stem cells transplantation as a molecular therapeutic to combat autoimmune disease.
PMID: 21732672 [PubMed - as supplied by publisher]
Mesenchymal stem cells: Re-establishing immunological tolerance in autoimmune rheumatic diseases.
Arthritis Rheum. 2011 Jun 6;
Authors: Macdonald GI, Augello A, De Bari C
Immunological tolerance is critical in preventing autoimmune disease and maintaining immune homeostasis. Increased understanding regarding cytokine networks led to the development of neutralizing antibodies against TNF alpha, IL-1 and IL-6 signalling in the treatment of rheumatoid arthritis (RA). However, there remains an unmet need given the significant number of patients not achieving remission nor responding to these drugs. Mesenchymal (stromal) stem cells (MSCs) are promising tools for the repair of damaged joint tissues such as cartilage, bone and tendons.
They also have potent anti-inflammatory and immunomodulatory properties both in vitro and in vivo . Research into MSC therapy for Crohn's disease, type I diabetes, graft-versus-host disease (GvHD) and multiple sclerosis continues apace with phase II/III trials ongoing. There have been conflicting reports regarding their effects in the autoimmune rheumatic diseases, particularly in the collagen-induced arthritis mouse model of RA [2-8].
Conversely, promising results in patients with systemic lupus erythematosus (SLE) were recently reported  even in the face of conflicting results in murine models of SLE. In this article we will examine MSCs as a possible cellular therapy for RA, SLE and systemic sclerosis (SSc) and critically review possible reasons for conflicting results in the literature. We will also address whether MSC dysfunction could play a role in the aetiopathogenesis of these conditions.
Finally, we will examine the possible mechanisms of MSCs at a cellular level including the effects on regulatory T (Treg) cells and type 17 T helper (Th17) cell populations.
PMID: 21647863 [PubMed - as supplied by publisher]
Autologous hematopoietic stem cell transplantation in autoimmune diseases.
Expert Rev Hematol. 2009 Dec;2(6):699-715
Authors: Annaloro C, Onida F, Lambertenghi Deliliers G
The term 'autoimmune diseases' encompasses a spectrum of diseases whose clinical manifestations and, possibly, biological features vary widely. The results of conventional treatment are considered unsatisfactory in aggressive forms, with subsets of patients having short life expectancies.
Relying on wide experimental evidence and more feeble clinical data, some research groups have used autologous hematopoietic stem cell transplantation (HSCT) in the most disabling autoimmune diseases with the aim of resetting the patient's immune system.
Immunoablative conditioning regimens are preferred over their myeloablative counterparts, and some form of in vivo and/or ex vivo T-cell depletion is generally adopted.
Despite 15 years' experience, published controlled clinical trials are still lacking, with the evidence so far available coming from pilot studies and registry surveys.
In multiple sclerosis, clinical improvement, or at least lasting disease stabilization, can be achieved in the majority of the patients; nevertheless, the worst results are observed in patients with progressive disease, where no benefit can be expected from conventional therapy.
Concerning rheumatologic diseases, wide experience has been acquired in systemic sclerosis, with long-term improvements in cutaneous disease being frequently reported, although visceral involvement remains unchanged at best. Autografting has proved to be barely effective in rheumatoid arthritis and quite toxic in juvenile idiopathic arthritis, whereas it leads to clinical remission and the reversal of visceral impairment in the majority of patients with systemic lupus erythematosus.
A promising indication is Crohn's disease, in which long-term endoscopic remission is frequently observed. Growing experience with autologous HCST in autoimmune diseases has progressively reduced concerns about transplant-related mortality and secondary myelodysplasia/leukemia.
Therefore, a sustained complete remission seems to be within the reach of autografting in some autoimmune diseases; in others, the indications, risks and benefits of autografting need to be better defined. Consequently, the search for new drugs should also be encouraged.
Rationale and Design of the ARREST Trial Investigating Mesenchymal Stem Cells in the Treatment of Small AAA.
Related Articles Rationale and Design of the ARREST Trial Investigating Mesenchymal Stem Cells in the Treatment of Small AAA. Ann Vasc Surg. 2017 Sep 12;: Authors: Wang SK, Green LA, Gutwein AR, Drucker NA, Motaganahalli RL, Fajardo A, Babbey CC, Murphy MP Abstract BACKGROUND: Abdominal aortic aneurysms (AAA) are a major source of morbidity and mortality despite continuing advances in surgical technique and care. Although the inciting factors for AAA development continue to be elusive, accumulating evidence suggests a significant peri-aortic inflammatory response leading to degradation and dilation of the aortic wall. Previous human trials have demonstrated safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of inflammation-related pathologies such as rheumatoid arthritis, graft vs host disease, and transplant rejection. Therefore, herein we describe the ARREST trial, a Phase I investigation into the safety of MSC infusion for patients with small AAA and the cells' effects on modulation of AAA-related inflammation. METHODS: ARREST is a Phase I, single-center, double-blind, randomized controlled trial (RCT) investigating infusion both dilute and concentrated MSCs compared to placebo in 36 small AAA (35-45 mm) patients. Subjects will be followed by study personnel for 12 months to ascertain incidence of adverse events, immune cell phenotype expression, peripheral cytokine profile, and peri-aortic inflammation. Maximum transverse aortic diameter will be assessed regularly for 5 years by a combination of CT and duplex sonography. RESULTS: Four patients have thus far been enrolled, randomized, and treated per protocol. We anticipate the conclusion of the treatment phase within the next 24 months with ongoing long-term follow up. CONCLUSION: ARREST will be pivotal in assessing the safety of MSC infusion and provide preliminary data on the ability of MSCs to favorably modulate the pathogenic AAA host immune response. The data gleaned from this Phase I trial will provide the groundwork for a larger, Phase III RCT which may provide the first pharmaceutical intervention for AAA. PMID: 28916304 [PubMed - as supplied by publisher]Read more...