Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells that can be isolated from many adult tissues. They can differentiate into cells of the mesodermal lineage, such as adipocytes, osteocytes and chondrocytes, as well as cells of other embryonic lineages. MSCs can interact with cells of both the innate and adaptive immune systems, leading to the modulation of several effector functions. After in vivo administration, MSCs induce peripheral tolerance and migrate to injured tissues, where they can inhibit the release of pro-inflammatory cytokines and promote the survival of damaged cells. This Review discusses the targets and mechanisms of MSC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches.
We studied the immunoregulatory features of murine mesenchymal stem cells (MSCs) in vitro and in vivo. MSCs inhibited T-cell receptor (TCR)-dependent and -independent proliferation but did not induce apoptosis on T cells. Such inhibition was paired with a decreased interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production and was partially reversed by interleukin-2 (IL-2). Thus, we used MSCs to treat myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice. We injected intravenously 1 ؋ 10 6 MSCs before disease onset (preventive protocol) and at different time points after disease occurrence (therapeutic protocol). MSC administration before disease onset strikingly ameliorated EAE. The therapeutic scheme was effective when MSCs were administered at disease onset and at the peak of disease but not after disease stabilization. Central nervous system (CNS) pathology showed decreased inflammatory infiltrates and demyelination in mice that received transplants of MSCs. T-cell response to MOG and mitogens from MSC-treated mice was inhibited and restored by IL-2 administration.
IntroductionAdult bone marrow stromal cells supply the appropriate scaffold for hematopoiesis 1 and hematopoietic-cell homeostasis, 2 but can also differentiate in vitro in most, if not all, somatic cell types. 3,4 Due to their specific capability of generating multiple mesenchymal lineages, bone marrow-derived stromal progenitors have been designated mesenchymal stem cells (MSCs). 5 MSCs are clonogenic because they can be isolated from bone marrow and expanded ex vivo without any apparent modification in phenotype or loss of function. Based on these features, MSCs are considered a promising strategy for tissue engineering, repair of damaged tissues, and gene therapy, but their capacity to trans-differentiate also in vivo is still unresolved.Recently, another unforeseen feature of MSCs has been reported, namely, that MSCs can modulate many T-cell functions including cell activation. 6,7 Based on this, human MSCs (hMSCs) have been administered in vivo to improve the outcome of allogeneic transplantation by promoting hematopoietic engraftment 8 and to hamper graft-versus-host disease. 9 More recently, we have shown that systemic administration of MSCs to mice affected by experimental autoimmune encephalomyelitis (EAE), a prototypical disease mediated by self-reactive T cells, results in striking disease amelioration mediated by the induction of peripheral tolerance. 10 In addition, it has been shown that tolerance induction by MSCs may occur also through the inhibition of dendritic-cell maturation and function, 11-13 thus suggesting that activated T cells are not the only targets of MSCs. In contrast, the effects of hMSCs on B cells are unknown.B-cell development occurs in the bone marrow and is strictly dependent on close interaction of B-cell progenitors with stromal cells that produce cytokines capable of supporting B-cell survival and proliferation. 14,15 Thus, we investigated whether MSCs, which derive from the marrow stroma, affect mature B-cell functions. Here, we demonstrate that hMSCs significantly affect proliferation, differentiation, and chemotactic behavior of normal mature B cells, thus further supporting the possibility that administration of MSCs may represent a novel therapeutic strategy for immune-mediated disorders. Materials and methodsAliquots of bone marrow aspirates were obtained from healthy adult bone marrow donors and peripheral-blood (PB) samples were obtained from healthy adult blood donors after informed consent was obtained, per the Declaration of Helsinki. The ethical board of the G. Gaslini Institute approved the study. B-cell isolation and cultureMononuclear cells (MNCs) were isolated by Ficoll-Hypaque density gradient (Sigma Chemical, St Louis, MO) from the PB of 9 healthy donors. Cell suspensions were first depleted of lymphocytes forming rosettes with sheep red blood cells (T cells) and subsequently treated with magnetic activated cell sorting (MACS) CD19-conjugated microbeads, according to the instructions of the manufacturer (Miltenyi Biotech, Auburn, CA). (mAb). All cell cul...
Interleukin 17-producing T helper cells (T(H)-17 cells) are important in experimental autoimmune encephalomyelitis, but their route of entry into the central nervous system (CNS) and their contribution relative to that of other effector T cells remain to be determined. Here we found that mice lacking CCR6, a chemokine receptor characteristic of T(H)-17 cells, developed T(H)-17 responses but were highly resistant to the induction of experimental autoimmune encephalomyelitis. Disease susceptibility was reconstituted by transfer of wild-type T cells that entered into the CNS before disease onset and triggered massive CCR6-independent recruitment of effector T cells across activated parenchymal vessels. The CCR6 ligand CCL20 was constitutively expressed in epithelial cells of choroid plexus in mice and humans. Our results identify distinct molecular requirements and ports of lymphocyte entry into uninflamed versus inflamed CNS and suggest that the CCR6-CCL20 axis in the choroid plexus controls immune surveillance of the CNS.
Overall, these findings suggest that the beneficial effect of MSCs in experimental autoimmune encephalomyelitis is mainly the result of an interference with the pathogenic autoimmune response.
Mesenchymal stem cells (MSC) are a rare subset of stem cells residing in the bone marrow where they closely interact with hematopoietic stem cells and support their growth and differentiation. MSC can differentiate into multiple mesenchymal and non‐mesenchymal lineages, providing a promising tool for tissue repair. In addition, MSC suppress many T cell, B cell and NK cell functions and may affect also dendritic cell activities. Due to their limited immunogenicity, MSC are poorly recognized by HLA‐incompatible hosts. Based on these unique properties, MSC are currently under investigation for their possible use to treat immuno‐mediated diseases. However, both their condition of immunoprivilege and their immunosuppressive function have recently been challenged when analyzed under particular experimental conditions. Thus, it is likely that MSC effects on the immune system may be deeply influenced not only by cell‐to‐cell interactions, but also by environmental factors shaping their phenotype and functions.
Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen HLA-DR2 or DRB1*1501-DQB1*0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1*15 was strongly associated in families (P=7.8x10(-31)), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4-13.0, P<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P=0.03). Strong evidence for under-transmission of DRB1*14 (P=5.7x10(-6)) even after accounting for DRB1*15 (P=0.03) was present, confirming a protective effect. In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1-14.4, P<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1*15 association observed in primary progressive MS families (P=0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using expanded disease disability score and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.
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