Current Stem Cell Research & Therapy - Volume 6, Issue 1, 2011

The immune system is challenged with the task of protecting us from unknown foreign pathogens such as viruses and bacteria. This is achieved through a complex system of physical, soluble and cellular factors that can be roughly divided into innate and adaptive immune systems. An underlying feature that enables recognition and responses to unknown targets is the generation of antigen receptors on lymphocytes through the process of random gene recombination. However, a consequence of this is the generation of self-reactive receptors capable of responding to self-antigens and causing pathology. Although a number of mechanisms such as clonal deletion and regulation have evolved to eliminate or counter the action of these self-reactive clones, self-reactive clones still exist and cause pathology. Five to six percent of the population suffers from autoimmunity, with over 60 different types of autoimmune diseases described, including the more readily recognised diseases such type 1 diabetes, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus to name a few [1]. While different in clinical symptoms and pathology, an underlying similarity of autoimmune diseases is a chronic adaptive immune response to self-tissues that ultimately leads to clinical illness. At present, the standard treatment for autoimmunity involves immunosuppressive agents designed to dampen the immune response but this is often associated with unwanted side effects such as increased susceptibility to infection. As yet, a cure has not been described and thus a challenge for the medical and clinical research communities is devising treatments and strategies that are specific for autoimmune diseases and do not render the recipient immunecompromised. This quest is the goal of many approaches that include the use and manipulation of stem cells. In this series of reviews, we focus on the use of haematopoietic and mesenchymal stems cells in the treatment of autoimmune disease, highlighting the promises, potential and challenges that lie ahead. While the immunological importance of the bone marrow compartment has been known for half a century, it is only in the past 15 years or so that the strategy of bone marrow or haematopoietic stem cell transfer (HSCT) to specifically treat autoimmunity has been trialed in humans. In the first series of papers, three leading groups in the field of HSCT review and provide their experience in clinical trials in treating three quite different autoimmune diseases. Delemarre et al. [2] targets the chronic joint disease known as juvenile idiopathic arthritis, Couri and Voltarelli [3] address type 1 diabetes, an autoimmune diseases that destroys the insulin secreting cells of the pancreas, and lastly Milanetti and colleagues [4] review the extensive studies they and others have generated in treating systemic sclerosis. While much still need to be learnt about the mechanism(s) involved with the beneficial effects observed in many patients treated with autologous HSCT and why some relapse, this general strategy is proving to be very exciting and providing the first glimpse of potentially long-term medication free remission. As mentioned, our understanding of the mechanisms associated with the benefits associated with HSCT is not complete and whether many mechanisms may in fact be in action. Focusing on type 1 diabetes, LoCascio and colleagues [5] explore various mechanisms associated with immune tolerance that may be involved or associated with HSCT as a treatment. It has been shown in a number of settings that driving the ectopic expression of autoantigens can promote immune tolerance. This theme forms the basis of studies describe by Scott [6] and Chan et al. [7] that show manipulating the haematopoietic stem cell system through retroviral transduction can promote autoantigen specific tolerance and suppress disease expression. The generation of tolerogenic B cells is a particular focus of the work by Scott with a historical journey describing the genesis of this research direction. It is of particular interest that this strategy has been used in a number of disease models, suggesting that the underlying mechanism involved is applicable across different antigens and disease settings. In contrast, our studies in the mouse model of experimental autoimmune encephalomyelitis (EAE) are of importance, reflecting current human trials and relapse rates that are still an issue. We have found that while HSCT alone can promote remission, it does not impart immune tolerance and thus whether this translates to the current human experience is of particular relevance. The final group of reviews highlights the potential role of mesenchymal stem cells in treating autoimmunity. Only recently their potential as a therapeutic agent has been identified, and in the context of autoimmunity it is their immunomodulatory features which are of most interest. EAE as a model for multiple sclerosis is a popular model to examine the role of mesenchymal stem cells. Payne and colleagues [8] present a comprehensive overview of MS and EAE and how mesenchymal stem cells may have a role in disease treatment. Many of these themes are discussed in more detail by Kassis et al. [9] which examines the immunomodulatory influences of MSCs on various immune functions. Last but not least, Uccelli et al. [10], present their view on the controversial topic of MSC transdifferentiation into neural cells and their importance in the broader area of MSCs as a therapeutic agent to treat MS. I am grateful to the editors of Current Stem Cell Research & Therapy for the opportunity to participate in this special issue of CSCRT and highlight the potential of stem cells in the treatment of autoimmunity. I believe this series of reviews will not only provide a valuable reference point for researchers and students in the field of autoimmunity and tolerance but also to those with a wider interest in stem cell biology and eager to learn how stem cells may provide avenues for therapies in diverse disease settings.

Juvenile idiopathic arthritis (JIA) is one of the most frequent autoimmune diseases in childhood and is characterized by chronic inflammation of the synovial fluid in joints. Several drugs are available for the treatment of JIA, including various biological agents that interfere with critical cytokine pathways. Though very effective in suppressing disease activity, none of these drugs can cure the disease and induce a lasting medication free remission. A small proportion of JIA patients will become or are unresponsive to any form of medical treatment. For these severely ill patients autologous bone marrow transplantation (aBMT) is a last resort treatment. aBMT is remarkably effective in suppressing disease activity, with beneficial outcome reported in around 70% of these previously refractory patients. Moreover aBMT is the only treatment that can induce a lasting medication-free-disease remission in these patients. In the very long term (after 7 years of remission) however, some disease relapses are observed, with the disease returning in a less severe form compared to prior aBMT. The exact mechanism of how aBMT is inducing this lasting disease remission is still largely unknown, but data from both animal models and humans suggest a prominent role for regulatory T cells. In this review we reviewed the current views of the cellular mechanisms that lay beneath disease induction of JIA and the disease remission caused by aBMT therapy.

Type 1 diabetes mellitus is an autoimmune disease against pancreatic β cells. The autoimmune response begins months or years before the clinical presentation. At the time of hyperglycemic symptoms a small amount of β cell mass still remains. The main therapeutic option to type 1 diabetes mellitus is daily insulin injections which is shown to promote tighter glucose control and to reduce much of diabetic chronic complications. Subgroup analysis of the Diabetes Control and Complication Trial (DCCT) showed another important aspect related to long term complications of diabetes, ie, patients with initially larger residual β cell mass suffered less microvascular complications and less hypoglycemic events than those patients with small amounts of β cells at diagnosis. In face of this, β cell preservation has become another important target in the management of type 1 diabetes and its related complications. In this review, we summarize various immunomodulatory regimens ever used in humans, including stem cell-based strategies, aiming at blocking autoimmunity against pancreatic β cells and at promoting β cell preservation and/or possible β cell regeneration in recent-onset type 1 diabetes.

Systemic sclerosis is a rare disorder manifesting as skin and internal organ fibrosis, a diffuse vasculopathy, inflammation, and features of autoimmunity. Patients with diffuse cutaneous disease or internal organ involvement have a poor prognosis with high mortality. To date no therapy has been shown to reverse the natural course of the disease. Immune suppressive drugs are commonly utilized to treat patients, but randomized trials have generally failed to demonstrate any long-term benefit. In phase I/II trials, autologous hematopoietic stem cell transplantation (HSCT) has demonstrated impressive reversal of skin fibrosis, improved functionality and quality of life, and stabilization of internal organ function, but initial studies were complicated by significant treatment-related mortality. Treatment-related mortality was reduced by better pre-transplant evaluation to exclude patients with compromised cardiac function and by treating patients earlier in disease, allowing selected patients the option of autologous HSCT treatment. There are currently three ongoing randomized trials of autologous HSCT for systemic sclerosis: ASSIST (American Systemic Sclerosis Immune Suppression versus Transplant), SCOT (scleroderma cyclophosphamide versus Transplant), and ASTIS (Autologous Stem cell Transplantation International Scleroderma). The results from these trials should clarify the role of autologous HSCT in the currently limited therapeutic arsenal of severe systemic sclerosis.

Type 1 diabetes (T1D) is an autoimmune disease that leads to the destruction of the insulin-producing pancreatic β cells. While there is no current cure, recent work in the field of allogeneic hematopoietic stem cell transplantation (HSCT) and the induction of mixed chimerism, a state in which multilineage hematopoietic populations of both recipient and donor co-exist, has demonstrated that it is possible to provide protection from disease onset, as well as reverse the autoimmune state in spontaneously diabetic mice. Furthermore, the establishment of mixed chimerism induces donorspecific tolerance, providing the potential to normalize glucose regulation via pancreatic islet transplantation without the requirement of life-long immunosuppression. Current studies are aimed at understanding the mechanisms involved in both the reversal of autoimmunity and the induction of tolerance, with the aim of moving this promising approach to curing T1D into the clinic.

Bone marrow derived cells, especially B lymphocytes, have been shown to function as tolerogenic antigenpresenting cells (APC's) both in vivo and in vitro. In addition, it is well established that immunoglobulins can function as potent tolerogenic carriers for associated epitopes. We have taken advantage of these properties to develop a gene therapy approach to induce unresponsiveness in a number of animal models for clinical diseases. In our system, we engineered target peptide-IgG constructs into retroviral vectors and transduced hematopoietic cells to create tolerogenic antigenpresenting cells. In this review, we discuss the strategies and mechanism of our gene therapy approach mediated by B cells, as well as by bone marrow cells, for tolerance acquisition in various mouse models for autoimmune disease and hemophilia A. Our results show that MHC class II and co-stimulatory molecules must be expressed on the tolerogenic antigen presenting cells for efficacy. This therapy requires regulatory T cells for both the induction and maintenance of tolerance. The putative role of epitopes provided by the IgG carrier in this process is emphasized. Studies in non-human primates and with human T cell clones in vitro are in progress to transition this approach to the clinic. The use of stem cells and B cell-delivered gene therapy in human clinical diseases may soon become a reality.

Autoimmune diseases are incurable and are managed using therapeutic agents. Bone marrow transplantation is being trialled as a treatment for these diseases. While allogeneic bone marrow transplantation shows impressive benefit, its application is hindered by GVHD and high mortality. On the other hand, autologous bone marrow transplantation has lower mortality rate and no GVHD but is associated with higher relapse rates. Given that autoimmune diseases are a result of a failure of immune tolerance and that bone marrow-derived dendritic cells play an important role in establishing immune tolerance, the transplantation of genetically modified haematopoietic stem cells to generate molecular chimerism to induce antigen-specific tolerance offers the potential for developing a cure for autoimmune diseases. In this review, we will discuss key findings from clinical data and animal studies to provide evidence to support the above concept.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is characterised by an autoimmune attack on components of the myelin sheath and axons leading to neurological disability. Although longapproved current treatments for MS have so far only targeted immune components of the disease in a non-specific manner, the efficacy of these immunomodulatory treatments is limited given that they are only immunosuppressive and / or immunoregulatory and do not prevent long-term disease progression. As such, there is a clear need for more effective therapies that are capable of targeting other aspects of the disease including neurodegeneration, demyelination and the underlying causes of the autoimmune state. Emerging data suggest that hematopoietic, mesenchymal and neural stem cells have the promise to restore self-tolerance, to provide in situ immunomodulation and neuroprotection as well as to promote regeneration. This review will summarise burgeoning experimental and clinical evidence supporting the application of these stem cell populations for the treatment of MS.

Mesenchymal stromal cells (MSC) are part of the bone marrow stem cells repertoire which also includes the main stem cells population of the bone marrow, the hematopoietic stem cells. The main role of MSCs is to support hematopoiesis but they can also give rise to cells of the mesodermal layers. Recently, significant interactions between MSCs and cells from the immune system have been demonstrated: MSCs were found to downregulate T and B lymphocytes, natural killer cells (NK) and antigen presenting cells through various mechanisms, including cell-to cell interaction and soluble factor production. Besides the immunomodulatory effects, MSCs were shown to possess additional stem cells features, such as the self-renewal potential and multipotency. Their debatable transdifferentiation potential to cells of the endo- and exo-dermal layer, including cells of the CNS, may explain in part their reported neuroprotective effects. Studies in vitro and in vivo (in cells cultures and in animal models) have indicated neuroprotective effects. MSCs are believed to promote functional recovery following CNS injury or inflammation, by producing trophic factors that may facilitate the mobilization of endogenous neural stem cells and promote the regeneration or the survival of the affected neurons. These immunomodulatory and neuroprotective features could make MSCs potential candidates for future therapeutic modalities in immune-mediated and neurodegenerative diseases.

The lack of therapies fostering remyelination and regeneration of the neural network deranged by the autoimmune attack occurring in multiple sclerosis (MS) is raising great expectations about stem cells therapies for tissue repair. Mesenchymal stem cells (MSCs) have been proposed as a possible treatment for MS due to the reported capacity of transdifferentiation into neural cells and their ability at modulating immune responses. However, recent studies have demonstrated that many other functional properties are likely to play a role in the therapeutic plasticity of MSCs, including antiapoptotic, trophic and anti-oxidant effects. These features are mostly based on the paracrine release of soluble molecules, often dictated by local environmental cues. Based on the modest evidence of long-term engraftment and the striking clinical effects that are observed immediately after MSCs administration in the experimental model of MS, we do not favor a major role for transdifferentiation as an important mechanism involved in the therapeutic effect of MSCs.

Regeneration and plasticity refer to the ability of certain progenitor cells to produce cell lineages with specific morphological and functional settings. The pathway from a less delineated or immature phenotype to a mature or specialized one follows intricate routes where a monumental array of molecular elements, basically transcription factors and epigenetic regulators that turn off or on a specific phenotypic change, play a fundamental role. Nature itself offers procedures to healing strategies. Therapy approaches to pathologies in the realm of ophthalmology may benefit from the knowledge of the properties and mechanisms of activation of different routes controlling the pathways of cell definition and differentiation. Specification of cell identity, not only in terms of phenotypic traits, but also regarding the mechanisms of gene expression and epigenetic regulation, will provide new tools to manipulating cell fates and status, both forward and backwards. In the human eye, two main locations shelter stem cells: the limbus, which is situated in the limit of the cornea and the conjuctiva, and the ciliary body pars plana. Transplantation of limbal cells is currently used in certain pathologies where corneal epithelium is damaged. Therapeutic applications of retina progenitors are not yet fully developed due to the complexity of the cellular components of the multilayer retinal architecture. Animal models of Retinitis pigmentosa or Glaucoma offer an interesting approach to validate certain techniques, such as the direct injection of progenitors into the vitreal compartment, aimed to restoring retinal function.