ISSN: 1574-888X

Current Stem Cell Research & Therapy
Volume 6, Number 1, March 2011

Contents

Hot Topic

Stem Cell Based Therapy for Autoimmunity
Guest Editor: Frank Alderuccio


Editorial Pp. 1-2
[PMID: 20955162 PubMed - indexed for MEDLINE]


Restoration of the Immune Balance by Autologous Bone Marrow Transplantation in Juvenile Idiopathic Arthritis Pp. 3-9
Eveline Delemarre, Sarah Roord, Nico Wulffraat, Femke van Wijk and Berent Prakken
[Abstract] [Purchase Article] [PMID: 20955161 PubMed - indexed for MEDLINE]


Stem Cell-Based Therapies and Immunomodulatory Approaches in Newly Diagnosed Type 1 Diabetes Pp. 10-15
Carlos Eduardo Barra Couri and Júlio César Voltarelli
[Abstract] [Purchase Article] [PMID: 20955160 PubMed - indexed for MEDLINE]


Autologous Hematopoietic Stem Cell Transplantation for Systemic Sclerosis Pp. 16-28
Francesca Milanetti, Jurate Bucha, Alessandro Tesori and Richard K. Burt
[Abstract] [Purchase Article] [PMID: 20955159 PubMed - indexed for MEDLINE]


Hematopoietic Stem Cell Transplantation for the Treatment of Autoimmunity in Type 1 Diabetes Pp. 29-37
Samuel A. LoCascio, Joia Spinelli and Josef Kurtz
[Abstract] [Purchase Article] [PMID: 20955158 PubMed - indexed for MEDLINE]


Gene Therapy for Immunologic Tolerance: Using Bone Marrow-Derived Cells to Treat Autoimmunity and Hemophilia Pp. 38-43
David W. Scott
[Abstract] [Purchase Article] [PMID: 20955157 PubMed - indexed for MEDLINE]


Transplantation of Genetically Modified Haematopoietic Stem Cells to Induce Antigen-Specific Tolerance as a Cure for Autoimmune Diseases Pp. 44-49
James Chan, Frank Alderuccio and Ban-Hock Toh
[Abstract] [Purchase Article] [PMID: 20955156 PubMed - indexed for MEDLINE]


The Prospect of Stem Cells as Multi-Faceted Purveyors of Immune Modulation, Repair and Regeneration in Multiple Sclerosis Pp. 50-62
Natalie Payne, Christopher Siatskas, Adele Barnard and Claude C.A. Bernard
[Abstract] [Purchase Article] [PMID: 20955155 PubMed - indexed for MEDLINE]


Bone Marrow Mesenchymal Stem Cells: Agents of Immunomodulation and Neuroprotection Pp. 63-68
Ibrahim Kassis, Adi Vaknin-Dembinsky and Dimitrios Karussis
[Abstract] [Purchase Article] [PMID: 20955154 PubMed - indexed for MEDLINE]


Mesenchymal Stem Cells for Multiple Sclerosis: Does Neural Differentiation Really Matter? Pp. 69-72
Antonio Uccelli, Sara Morando, Ivan Bonanni, Alessandro Leonardi and Gianluigi Mancardi
[Abstract] [Purchase Article] [PMID: 20955153 PubMed - indexed for MEDLINE]


General Article


Stem Cell Plasticity, Neuroprotection and Regeneration in Human Eye Diseases Pp. 73-81
F. David Rodríguez and Elena Vecino
[Abstract] [Purchase Article] [PMID: 21190534 PubMed - indexed for MEDLINE]




Abstracts


[Back to top] [Purchase Article] [PMID: 20955161 PubMed - indexed for MEDLINE]
Restoration of the Immune Balance by Autologous Bone Marrow Transplantation in Juvenile Idiopathic Arthritis
Eveline Delemarre, Sarah Roord, Nico Wulffraat, Femke van Wijk and Berent Prakken

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.


[Back to top] [Purchase Article] [PMID: 20955160 PubMed - indexed for MEDLINE]
Stem Cell-Based Therapies and Immunomodulatory Approaches in Newly Diagnosed Type 1 Diabetes
Carlos Eduardo Barra Couri and Júlio César Voltarelli

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.


[Back to top] [Purchase Article] [PMID: 20955159 PubMed - indexed for MEDLINE]
Autologous Hematopoietic Stem Cell Transplantation for Systemic Sclerosis
Francesca Milanetti, Jurate Bucha, Alessandro Tesori and Richard K. Burt

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.


[Back to top] [Purchase Article] [PMID: 20955158 PubMed - indexed for MEDLINE]
Hematopoietic Stem Cell Transplantation for the Treatment of Autoimmunity in Type 1 Diabetes
Samuel A. LoCascio, Joia Spinelli and Josef Kurtz

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 donor-specific 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.


[Back to top] [Purchase Article] [PMID: 20955157 PubMed - indexed for MEDLINE]
Gene Therapy for Immunologic Tolerance: Using Bone Marrow-Derived Cells to Treat Autoimmunity and Hemophilia
David W. Scott

Bone marrow derived cells, especially B lymphocytes, have been shown to function as tolerogenic antigen-presenting 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 antigen-presenting 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.


[Back to top] [Purchase Article] [PMID: 20955156 PubMed - indexed for MEDLINE]
Transplantation of Genetically Modified Haematopoietic Stem Cells to Induce Antigen-Specific Tolerance as a Cure for Autoimmune Diseases
James Chan, Frank Alderuccio and Ban-Hock Toh

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.


[Back to top] [Purchase Article] [PMID: 20955155 PubMed - indexed for MEDLINE]
The Prospect of Stem Cells as Multi-Faceted Purveyors of Immune Modulation, Repair and Regeneration in Multiple Sclerosis
Natalie Payne, Christopher Siatskas, Adele Barnard and Claude C.A. Bernard

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 long-approved 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.


[Back to top] [Purchase Article] [PMID: 20955154 PubMed - indexed for MEDLINE]
Bone Marrow Mesenchymal Stem Cells: Agents of Immunomodulation and Neuroprotection
Ibrahim Kassis, Adi Vaknin-Dembinsky and Dimitrios Karussis

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.


[Back to top] [Purchase Article] [PMID: 20955153 PubMed - indexed for MEDLINE]
Mesenchymal Stem Cells for Multiple Sclerosis: Does Neural Differentiation Really Matter?
Antonio Uccelli, Sara Morando, Ivan Bonanni, Alessandro Leonardi and Gianluigi Mancardi

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 anti-apoptotic, 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.


[Back to top] [Purchase Article] [PMID: 21190534 PubMed - indexed for MEDLINE]
Stem Cell Plasticity, Neuroprotection and Regeneration in Human Eye Diseases
F. David Rodríguez and Elena Vecino

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 back-wards. 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.