RÉSUMÉ
PURPOSE: Mesenchymal stem/progenitor cells (MSCs) have regenerative and immunomodulatory properties, exerted by cell-cell contact and in a paracrine fashion. Part of their immunosuppressive activity has been ascribed to their ability to promote the induction of CD4+CD25+FoxP3+ T lymphocytes with regulatory functions (Treg). Here the authors studied the effect of MSCs on the induction of Treg and on the development of autoimmunity, and they examined the possibility that MSC-mediated Treg induction could be attributed to the secretion of soluble factors. METHODS: The authors induced experimental autoimmune uveitis (EAU) in mice by immunization with the 1-20 peptide of the intraphotoreceptor binding protein. At the same time, some of the animals were treated intraperitoneally with syngeneic MSCs. The authors checked T-cell responses and in vitro Treg conversion by cell proliferation and blocking assays, in cell-cell contact and transwell settings. TGFß and TGFß receptor gene expression analyses were performed by real-time PCR. RESULTS: The authors found that a single intraperitoneal injection of MSCs was able to significantly attenuate EAU and that a significantly higher percentage of adaptive Treg was present in MSC-treated mice than in MSC-untreated animals. In vitro blocking of antigen presentation by major histocompatibility complex class II precluded priming and clonal expansion of antigen-specific Treg, whereas blockade of TGFß impaired the expression of FoxP3, preventing the conversion of CD4+ T cells into functionally active Treg. CONCLUSIONS: The authors demonstrated that MSCs can inhibit EAU and that their immunomodulatory function is due at least in part to the induction of antigen-specific Treg in a paracrine fashion by secreting TGFß.
Sujet(s)
Maladies auto-immunes/thérapie , Immunomodulation , Transplantation de cellules souches mésenchymateuses/méthodes , Lymphocytes T régulateurs/immunologie , Uvéite/thérapie , Animaux , Maladies auto-immunes/immunologie , Maladies auto-immunes/anatomopathologie , Modèles animaux de maladie humaine , Études de suivi , Cellules souches mésenchymateuses , Souris , Souris de lignée C57BL , Uvéite/immunologie , Uvéite/anatomopathologieRÉSUMÉ
In reconstructive surgery, implantable devices are used to supply a missing function. In tissue engineering, biomaterials serve to guide and eventually deliver cells and/or molecules where a tissue regenerative response is needed. The host organism always reacts to implants of any biomaterial, in some instances even triggering a local cascade of events called the foreign body response (FBR), whose mechanisms are well defined. What has yet to be completely unraveled are the biomarkers systemically mirroring the FBR and the regeneration processes, which would be helpful for assessing the therapeutic efficacy of the bioscaffold. Our goal was to identify a biomarker fingerprint of the systemic reaction of host response to bioscaffold implants. Different biomaterials chosen for their osteoconductive properties, including collagen, hydroxyapatite, in foam or granules, and poly-ε-caprolactone, were implanted in immunocompetent mice. We analyzed serum concentrations of cells and cytokines involved in the inflammatory/immune response, and the histological features of grafts. Within two weeks after implantation, a wave of proinflammatory cytokines was flowing in the blood stream and the concentration of blood cells changed, revealing specific patterns depending on the chemistry and structure of the implanted biomaterials. Cells secreting pro-inflammatory, chemoactractant, and pro-angiogenic cytokines required for the early events in tissue repair were locally recruited because of the presence of a bioscaffold.
Sujet(s)
Matériaux biocompatibles , Réaction à corps étranger/étiologie , Structures d'échafaudage tissulaires/effets indésirables , Animaux , Marqueurs biologiques/sang , Collagène de type I/effets indésirables , Cytokines/sang , Durapatite/effets indésirables , Réaction à corps étranger/immunologie , Réaction à corps étranger/anatomopathologie , Immunité humorale , Médiateurs de l'inflammation/sang , Souris , Souris de lignée BALB C , Polyesters/effets indésirables , Conception de prothèse , Facteurs tempsRÉSUMÉ
BACKGROUND: Colorectal cancer can be efficiently treated when found at early stages, thus the search for novel markers is of paramount importance. Since inflammation is associated with cancer progression and angiogenesis, we investigated expression of cytokines like IL-6 and other mediators that play a key role in the innate immune system, in particular toll like receptor 4 (TLR4), in the microenvironment of lesions from different stages of colon disease progression, from ulcerative colitis to adenoma and adenocarcinoma to find useful markers. METHODS: The presence of inflammatory cells and expression of key cytokines involved in the inflammation process were quantified by immunohistochemistry in specific tissue compartments (epithelial, stromal, endothelial) by immunohistochemistry. A murine azoxymethane/dextran sulfate model in which Tir8, a negative regulator of the inflammatory response, was ablated was used to confirm the clinical observations. 116 Archival tissue samples from patients with different stages of colorectal disease: 13 cases of ulcerative colitis (UC), 34 tubular or tubulo-villous adenomas (AD), and 53 infiltrating adenocarcinomas. 16 specimens of healthy mucosa surgically removed with the cancerous tissue were used as a control. RESULTS: The differences between healthy tissues and the diverse lesions was characterized by a marked inflammatory-angiogenic reaction, with significantly (P < 0.05) higher numbers of CD68, CD15, and CD31 expressing cells in all diseased tissues that correlated with increasing grade of malignancy. We noted down-regulation of a potential modulator molecule, Hepatocyte Growth Factor, in all diseased tissues (P < 0.05). TLR-4 and IL6 expression in the tumor microenvironment were associated with adenocarcinoma in human samples and in the murine model. We found that adenocarcinoma patients (pT1-4) with higher TLR-4 expression in stromal compartment had a significantly increased risk in disease progression. In those patients with a diagnosis of pT3 (33 cases) colon cancer, those with very high levels of TLR-4 in the tumor stroma relapsed significantly earlier than those with lower expression levels. CONCLUSIONS: These data suggest that high TLR-4 expression in the tumor microenvironment represents a possible marker of disease progression in colon cancer.
Sujet(s)
Tumeurs colorectales/anatomopathologie , Récepteur de type Toll-4/métabolisme , Animaux , Antigènes CD/immunologie , Tumeurs colorectales/immunologie , Tumeurs colorectales/métabolisme , Cytokines/métabolisme , Modèles animaux de maladie humaine , Humains , Immunohistochimie , Souris , Souris knockout , PronosticRÉSUMÉ
Lipocalin-2 (LCN2) is a member of the lipocalin family, small secreted proteins functioning as modulators of many different physiological processes including cell differentiation, proliferation and apoptosis. LCN2 expression is also up-regulated in several pathological conditions, including inflammation and cancer. LCN2 synthesis has been described in epithelia, bone and cells of the immune system. Despite its wide expression the role of LCN2 remains to be fully elucidated. To better understand the role of this lipocalin in the bone/bone marrow system we generated transgenic mice over-expressing LCN2 specifically in bone under the control of a type I collagen promoter. In the bone marrow of these transgenic mice we observed an increased expression of SDF-1 that correlated with an increased number of CD34+/CXCR4+ (SDF-1 receptor) cells. To some extent, this appeared due to an enhanced cell proliferation rate. The higher level of the factor synthesis and the increased number of cells expressing its receptor was maintained during animal aging. Our results show that LCN2 could play a role in determining the number of CD34+/CXCR4+ precursor cells in the bone marrow thus contributing to the control of the bone marrow microenvironment.
Sujet(s)
Protéine de la phase aigüe/métabolisme , Os et tissu osseux/cytologie , Os et tissu osseux/métabolisme , Chimiokine CXCL12/métabolisme , Lipocalines/métabolisme , Protéines oncogènes/métabolisme , Protéine de la phase aigüe/génétique , Animaux , Antigènes CD34/métabolisme , Cellules de la moelle osseuse/cytologie , Cellules de la moelle osseuse/métabolisme , Broxuridine/métabolisme , Séparation cellulaire , Chimiokine CXCL12/génétique , Cellules souches hématopoïétiques/cytologie , Cellules souches hématopoïétiques/métabolisme , Fer/métabolisme , Lipocaline-2 , Lipocalines/sang , Lipocalines/génétique , Souris , Souris transgéniques , Protéines oncogènes/sang , Protéines oncogènes/génétique , Liaison aux protéinesRÉSUMÉ
Due to the aging of the populations of developed countries and a common occurrence of risk factors, it is increasingly probable that a patient may have both cancer and cardiovascular disease. In addition, cytotoxic agents and targeted therapies used to treat cancer, including classic chemotherapeutic agents, monoclonal antibodies that target tyrosine kinase receptors, small molecule tyrosine kinase inhibitors, and even antiangiogenic drugs and chemoprevention agents such as cyclooxygenase-2 inhibitors, all affect the cardiovascular system. One of the reasons is that many agents reach targets in the microenvironment and do not affect only the tumor. Combination therapy often amplifies cardiotoxicity, and radiotherapy can also cause heart problems, particularly when combined with chemotherapy. In the past, cardiotoxic risk was less evident, but it is increasingly an issue, particularly with combination therapy and adjuvant therapy. Today's oncologists must be fully aware of cardiovascular risks to avoid or prevent adverse cardiovascular effects, and cardiologists must now be ready to assist oncologists by performing evaluations relevant to the choice of therapy. There is a need for cooperation between these two areas and for the development of a novel discipline, which could be termed cardio-oncology or onco-cardiology. Here, we summarize the potential cardiovascular toxicities for a range of cancer chemotherapeutic and chemopreventive agents and emphasize the importance of evaluating cardiovascular risk when patients enter into trials and the need to develop guidelines that include collateral effects on the cardiovascular system. We also discuss mechanistic pathways and describe several potential protective agents that could be administered to patients with occult or overt risk for cardiovascular complications.
Sujet(s)
Antinéoplasiques/effets indésirables , Cardiotoniques/usage thérapeutique , Maladies cardiovasculaires/induit chimiquement , Maladies cardiovasculaires/prévention et contrôle , Système cardiovasculaire/effets des médicaments et des substances chimiques , Système cardiovasculaire/physiopathologie , Coeur/effets des médicaments et des substances chimiques , Débit systolique/effets des médicaments et des substances chimiques , Acétylcystéine/usage thérapeutique , Antagonistes bêta-adrénergiques/usage thérapeutique , Inhibiteurs de l'enzyme de conversion de l'angiotensine/usage thérapeutique , Animaux , Anti-inflammatoires non stéroïdiens/usage thérapeutique , Anticoagulants/usage thérapeutique , Fibrillation auriculaire/induit chimiquement , Fibrillation auriculaire/physiopathologie , Fibrillation auriculaire/prévention et contrôle , Coagulation sanguine/effets des médicaments et des substances chimiques , Maladies cardiovasculaires/diagnostic , Maladies cardiovasculaires/microbiologie , Maladies cardiovasculaires/physiopathologie , Flavonoïdes/usage thérapeutique , Piégeurs de radicaux libres/usage thérapeutique , Coeur/physiopathologie , Humains , Hypertension artérielle/induit chimiquement , Hypertension artérielle/physiopathologie , Hypertension artérielle/prévention et contrôle , Équipe soignante , Phénols/usage thérapeutique , Antiagrégants plaquettaires/usage thérapeutique , Polyphénols , Thromboembolisme veineux/induit chimiquement , Thromboembolisme veineux/physiopathologie , Thromboembolisme veineux/prévention et contrôle , Dysfonction ventriculaire gauche/induit chimiquement , Dysfonction ventriculaire gauche/physiopathologie , Dysfonction ventriculaire gauche/prévention et contrôleRÉSUMÉ
The clinical use of stem cells to prevent tissue injury or reconstruct damaged organs is constrained by different ethical and biological issues. Whereas the use of adult stem cells isolated from differentiated tissues is advantageous from the ethical point of view, the immune response of a host to implants of either embryonic or adult stem cells remains a critical problem. Embryonic stem cells can be rejected by an immunocompetent recipient as well as some types of adult stem cells. There is, however, a population of adult stem cells able to differentiate into the three mesenchymal lineages, osteocytes, chondrocytes, adipocytes that have the additional capacity of modulating the immune response by the activation of disparate mechanisms, among which the generation of antigen-specific CD4(+)CD25(+)FoxP3(+) regulatory T lymphocytes. This short review will focus on the immunological properties of embryonic and adult stem cells are, with particular emphasis on the immunomodulatory function of mesenchymal stem cells and their interactions with regulatory T lymphocytes.
Sujet(s)
Cellules souches adultes/immunologie , Cellules souches embryonnaires/immunologie , Immunomodulation , Cellules souches mésenchymateuses/immunologie , Lymphocytes T régulateurs/immunologie , Adipocytes/cytologie , Adipocytes/physiologie , Animaux , Antigènes CD4 , Différenciation cellulaire , Chondrocytes/cytologie , Chondrocytes/physiologie , Cellules souches embryonnaires/cytologie , Facteurs de transcription Forkhead , Humains , Sous-unité alpha du récepteur à l'interleukine-2 , Activation des lymphocytes , Cellules souches mésenchymateuses/cytologie , Ostéocytes/cytologie , Ostéocytes/physiologieRÉSUMÉ
The contribution of the host's circulating progenitor cells after implantation of mesenchymal stem cells (MSC)/bioscaffold combinations for repairing bone defects has not been elucidated, although this issue affects the clinical application of the tissue engineering approach. We implanted blocks of hydroxyapatite loaded with murine MSCs into syngenic, allogenic, and immunocompromised recipients. After 8 weeks, we found that bone tissue was formed in syngenic and immunocompromised animals. The implanted cells appeared pivotal in the early stages of tissue development, but cells of the recipient's origin finally made bone. In this system, osteoprogenitors migrated from the recipient to the implant, whereas the implanted cells left the scaffold and entered the circulatory flow. We observed rapid destruction of implanted cells when allogenic MSC/bioscaffold combinations were grafted onto immunocompetent recipients without immunosuppressant therapy. This destruction blocked the recruitment process and did not allow the formation of new bone tissue. The possibility that the implanted exogenous MSCs could engage the host's osteoprogenitor cells to form new bone tissue could open new perspectives for the tissue engineering approach to bone repair, including the opportunity of using allogenic cells combined with a temporary immunosuppressant therapy, stimulating the replacement of the exogenous cells with autologous cells.
Sujet(s)
Céramiques/pharmacologie , Transplantation de cellules souches mésenchymateuses , Cellules souches mésenchymateuses/cytologie , Cellules souches mésenchymateuses/effets des médicaments et des substances chimiques , Animaux , Rejet du greffon , Immunocompétence , Immunophénotypage , Implants expérimentaux , Souris , Souris de lignée C57BL , Néovascularisation physiologique/effets des médicaments et des substances chimiques , Ostéogenèse/effets des médicaments et des substances chimiques , Porosité/effets des médicaments et des substances chimiques , Structures d'échafaudage tissulaires , Transplantation homologueRÉSUMÉ
Spatiotemporal organized patterns of cell surface-associated and extracellular matrix (ECM)-embedded molecules play important roles in the development and functioning of tissues. ECM proteins interact with the surface of bioscaffold polymers and influence material-driven control of cell differentiation., Using X-ray phase-contrast micro computed tomography (microCT), we visualized the three-dimensional (3D) image of ECM organization after in vitro seeding of bone marrow-derived human and murine mesenchymal stem cells (MSCs) induced to myogenic differentiation, labelled with iron oxide nanoparticles, and seeded onto polyglycolic acid-polylactic acid scaffolds. X-ray microCT enabled us to detect with high spatial resolution the 3D structural organization of ECM within the bioscaffold and how the presence of cells modified the construct arrangement. Species-specific differences between the matrix produced by human and murine cells were observed. In conclusion, X-ray synchrotron radiation microCT analysis appeared to be a useful tool to identify the spatiotemporal pattern of organization of ECM fibers within a bioscaffold.
Sujet(s)
Matériaux biocompatibles/composition chimique , Protéines de la matrice extracellulaire/métabolisme , Protéines de la matrice extracellulaire/ultrastructure , Cellules souches mésenchymateuses/ultrastructure , Acide polyglycolique/composition chimique , Ingénierie tissulaire/méthodes , Animaux , Techniques de culture cellulaire/méthodes , Cellules cultivées , Cristallisation/méthodes , Matrice extracellulaire/composition chimique , Humains , Test de matériaux , Souris , Conformation moléculaire , Taille de particule , Propriétés de surface , Synchrotrons , TomodensitométrieRÉSUMÉ
Bone marrow-derived mesenchymal stem cells (MSCs) are precursors of bone, cartilage and fat tissue. MSC can also regulate the immune response. For these properties, they are tested in clinical trials for tissue repair in combination with bioscaffolds or injected as cell suspension for immunosuppressant therapy. Experimental data, however, indicate that MSC can undergo or induce a tumorigenic process in determined circumstances. We used a modified model of ectopic bone formation in mice by subcutaneously implanting porous ceramic seeded with murine MSC. In this new model, host-derived sarcomas developed when we implanted MSC/bioscaffold constructs into syngeneic and immunodeficient recipients, but not in allogeneic hosts or when MSCs were injected as cell suspensions. The bioscaffold provided a tridimensional support for MSC to aggregate, thus producing the stimulus for triggering the process eventually leading to the transformation of surrounding cells and creating a surrogate tumor stroma. The chemical and physical characteristics of the bioscaffold did not affect tumor formation; sarcomas developed either when a stiff porous ceramic was used or when the scaffold was a smooth collagen sponge. The immunoregulatory function of MSC contributed to tumor development. Implanted MSC expanded clones of CD4+CD25+ T regulatory lymphocytes that suppressed host's antitumor immune response.
Sujet(s)
Transplantation cellulaire , Cellules souches mésenchymateuses/cytologie , Sarcome expérimental/anatomopathologie , Animaux , Prolifération cellulaire , Protéines à fluorescence verte/génétique , Immunohistochimie , Hybridation fluorescente in situ , Souris , Souris de lignée BALB C , Souris de lignée C57BL , Souris nude , Souris transgéniques , Sarcome expérimental/immunologieRÉSUMÉ
The mouse model of experimental autoimmune uveitis, induced by immunization of mice with the retinal protein IRBP, was developed in our laboratory 20 years ago and published in 1988. Since that time it has been adopted by many investigators and has given rise to many studies that helped elucidate genetic influences, dissect the basic mechanisms of pathogenesis and test novel immunotherapeutic paradigms. The current overview will summarize the salient features of the experimental autoimmune uveitis model and discuss its mechanisms.
Sujet(s)
Maladies auto-immunes/immunologie , Modèles animaux de maladie humaine , Uvéite/immunologie , Animaux , Autoantigènes/immunologie , Maladies auto-immunes/génétique , Auto-immunité/génétique , Épitopes/immunologie , Prédisposition génétique à une maladie , Haplotypes , Complexe majeur d'histocompatibilité/génétique , Complexe majeur d'histocompatibilité/immunologie , Souris , Lignées consanguines de souris , Rétine/immunologie , Lymphocytes T/immunologie , Uvéite/génétiqueRÉSUMÉ
PURPOSE: Experimental autoimmune uveitis (EAU) is an established model for immune-mediated human uveitis. Although several genes from major histocompatibility complex (MHC) loci have been shown to play a role in uveitis, little is known about the role of non-MHC genes in the pathogenesis of EAU. Several non-MHC genes have been implicated in the pathogenesis of various autoimmune diseases. The primary objective of this study was to identify the non-MHC genes involved in the pathogenesis of EAU, to identify potential drug targets and possibly to target their protein products for immunotherapy. METHODS: EAU was induced in the susceptible (Lewis; LEW) or resistant (Fischer 344; F344) rats that have identical MHC class II haplotype. Draining lymph node cells were obtained during the innate and adaptive phase of the immune response, and the pattern of gene expression was evaluated using microarray technology. Differentially expressed genes were validated at mRNA and protein levels using various methods. RESULTS: Susceptibility to EAU was associated with an increased expression of numerous non-MHC genes such as Th1-type cytokines and chemokines, antiapoptotic factors, hormones, and neurotransmitters and a downregulation of selected adhesion molecules. In this study a combined genetic-genomic approach was used to identify different patterns of gene expression associated with the sensitization and effector phase of EAU pathogenesis. CONCLUSIONS: The data demonstrate that the differential expression of several non-MHC genes is associated with the mechanism of uveitis.
Sujet(s)
Maladies auto-immunes/génétique , Modèles animaux de maladie humaine , Régulation de l'expression des gènes/physiologie , Gènes MHC de classe II/physiologie , Uvéite/génétique , Animaux , Antigènes de surface/génétique , Antigènes de surface/métabolisme , Maladies auto-immunes/immunologie , Prédisposition aux maladies , Protéines de l'oeil/génétique , Femelle , Cytométrie en flux , Analyse de profil d'expression de gènes , Activation des lymphocytes , Séquençage par oligonucléotides en batterie , Fragments peptidiques , Locus de caractère quantitatif , ARN messager/métabolisme , Rats , Rats de lignée F344 , Rats de lignée LEW , Protéines de liaison au rétinol , RT-PCR , Lymphocytes T/immunologie , Uvéite/immunologieRÉSUMÉ
OBJECTIVE: Mesenchymal stem cells (MSCs) are precursors of tissue of mesenchymal origin, but they also have the capacity to regulate the immune response by suppressing T and B lymphocyte proliferation in a non-major histocompatibility complex-restricted manner. Use of MSCs as immunosuppressant agents in autoimmune diseases has been proposed and successfully tested in animal models. We explored the feasibility of using allogeneic MSCs as therapy for collagen-induced arthritis, a mouse model for human rheumatoid arthritis. METHODS: DBA/1 mice were immunized with type II collagen in Freund's complete adjuvant, and some of the animals received an intraperitoneal injection of allogeneic MSCs. RESULTS: A single injection of MSCs prevented the occurrence of severe, irreversible damage to bone and cartilage. MSCs induced hyporesponsiveness of T lymphocytes as evidenced by a reduction in active proliferation, and modulated the expression of inflammatory cytokines. In particular, the serum concentration of tumor necrosis factor alpha was significantly decreased. MSCs exerted their immunomodulatory function by educating antigen-specific Tregs. CONCLUSION: Our results suggest an effective new therapeutic approach to target the pathogenic mechanism of autoimmune arthritis using allogeneic MSCs. However, further studies are required before these results can be translated to clinical settings.
Sujet(s)
Arthrite expérimentale/thérapie , Os et tissu osseux/effets des médicaments et des substances chimiques , Cartilage articulaire/effets des médicaments et des substances chimiques , Articulations/effets des médicaments et des substances chimiques , Transplantation de cellules souches mésenchymateuses , Animaux , Arthrite expérimentale/anatomopathologie , Arthrite expérimentale/physiopathologie , Cellules de la moelle osseuse , Os et tissu osseux/anatomopathologie , Cartilage articulaire/anatomopathologie , Prolifération cellulaire/effets des médicaments et des substances chimiques , Cytokines/sang , Femelle , Articulations/anatomopathologie , Mâle , Cellules souches mésenchymateuses/immunologie , Souris , Souris de lignée C57BL , Souris de lignée DBA , Souris transgéniques , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Lymphocytes T régulateurs/métabolisme , Lymphocytes T régulateurs/anatomopathologie , Transplantation homologueRÉSUMÉ
Multipotent mesenchymal stromal cells isolated from bone marrow and other sites are currently being studied to determine their potential role in the pathogenesis and/or management of autoimmune diseases. In vitro studies have shown that they exhibit a dose-dependent antiproliferative effect on T and B lymphocytes, dendritic cells, natural killer cells and various B cell tumour lines--an effect that is both cell contact and soluble factor dependent. Animal models of autoimmune disease treated with multipotent mesenchymal stromal cells have mostly exhibited a positive clinical response, as have a limited number of patients suffering from acute graft versus host disease. This review summarizes the findings of a 1-day meeting devoted to the subject with the aim of coordinating efforts.
Sujet(s)
Congrès comme sujet , Facteurs immunologiques/usage thérapeutique , Cellules souches mésenchymateuses/immunologie , Rhumatologie/méthodes , Animaux , Polyarthrite rhumatoïde/immunologie , Polyarthrite rhumatoïde/chirurgie , Congrès comme sujet/tendances , Humains , Facteurs immunologiques/immunologie , Londres , Transplantation de cellules souches mésenchymateuses/méthodes , Transplantation de cellules souches mésenchymateuses/tendances , Rhumatologie/tendancesRÉSUMÉ
Bone marrow mesenchymal progenitor cells (BMSC) are used for regenerating tissues of mesodermal origin, as well as tissues of different embryological derivation. Experimental evidence shows that BMSC are able to suppress the activation of the immune response by mechanisms that are still not completely understood. Thus far, in vitro studies carried using human or mouse cells indicate that autologous or allogeneic BMSC strongly suppress proliferation of T lymphocytes, triggered by cellular stimuli, nonspecific mitogenic stimuli, or antigenic peptides. Using cell proliferation and blocking assays, we demonstrated that BMSC inhibited the activation of murine splenocytes, T, and B lymphocytes. Direct contact of BMSC and target cells in a cognate fashion determined the inhibition of cell proliferation via engagement of the inhibitory molecule programmed death 1 (PD-1) to its ligands PD-L1 and PD-L2, leading the target cells to modulate the expression of different cytokine receptors and transduction molecules for cytokine signaling. Soluble factors present on supernatants of BMSC cultures were effective in suppressing proliferation of B cells to a mitogenic stimulus. Taken together, these results highlight the complexity of the role of BMSC in regulating the immune response, asserting the possibility of their therapeutic application in transplantation and autoimmune diseases.
Sujet(s)
Antigènes de surface/immunologie , Lymphocytes B/immunologie , Moelle osseuse/immunologie , Activation des lymphocytes/immunologie , Cellules souches mésenchymateuses/immunologie , Lymphocytes T/immunologie , Animaux , Antigènes CD , Protéines régulatrices de l'apoptose , Communication cellulaire/immunologie , Différenciation cellulaire/immunologie , Prolifération cellulaire , Souris , Récepteur-1 de mort cellulaire programmée , ARN messager/analyse , RT-PCRRÉSUMÉ
Experimental autoimmune uveitis (EAU) is a disease of the neural retina induced by immunization with retinal antigens, such as interphotoreceptor retinoid-binding protein (IRBP) and arrestin (retinal soluble antigen, S-Ag). EAU serves as a model for human autoimmune uveitic diseases associated with major histocompatibility complex (HLA) genes, in which patients exhibit immunological responses to retinal antigens. Here we report the development of a humanized EAU model in HLA transgenic (TG) mice. HLA-DR3, -DR4, -DQ6, and -DQ8 TG mice were susceptible to IRBP-induced EAU. Importantly, HLA-DR3 TG mice developed severe EAU with S-Ag, to which wild-type mice are highly resistant. Lymphocyte proliferation was blocked by anti-HLA antibodies, confirming that antigen is functionally presented by the human MHC molecules. Disease could be transferred by immune cells with a Th1-like cytokine profile. Antigen-specific T cell repertoire, as manifested by responses to overlapping peptides derived from S-Ag or IRBP, differed from that of wild-type mice. Interestingly, DR3 TG mice, but not wild-type mice, recognized an immunodominant S-Ag epitope between residues 291 and 310 that overlaps with a region of S-Ag recognized by uveitis patients. Thus, EAU in HLA TG mice offers a new model of uveitis that should represent human disease more faithfully than currently existing models.