1,721,339 research outputs found
Development of a stable autologous regulatory T cell-based cell therapy for multiple sclerosis
No full textIn autoimmune diseases, FOXP3 + regulatory T cells (Tregs) skew towards a pro-inflammatory, non-suppressive phenotype and are unable to control the exaggerated autoimmune responses. This may largely impact the success of autologous Treg therapy which is currently under investigation for treatment of autoimmune diseases, including multiple sclerosis (MS). Our recent findings provide for the first time evidence that the inflamed blood-brain barrier (BBB) affects human Treg stability. Using functional in vitro assays, we found that the suppressive capacity of migrated Tregs was affected. Transcriptome analysis indicated that migrated human Tregs of healthy donors and MS patients are less suppressive, have a pro-inflammatory Th1/17 signature and upregulate the mTOR signaling pathway. In vitro treatment of migrated Tregs with the clinically-approved mTOR inhibitor rapamycin restored the loss of suppressive function. In MS-derived Tregs specifically, Th17-related pathways were increased while amphiregulin was downregulated. This suggests a pre-existing susceptibility towards inflammation and lost regenerative capacity in MS-derived migrated Tregs. These insights and specific target identification can help in significantly improving the efficacy of autologous Treg therapy of MS. The aim is to target this BBB-induced Treg instability in patient-derived Tregs by genetic manipulation. By this, we restore and stabilize their immunosuppressive and regenerative function and use these designer Tregs as a powerful, autologous cell therapy for MS
Development of a stable autologous regulatory T cell-based cell therapy for multiple sclerosis
No full textIn autoimmune diseases, FOXP3 + regulatory T cells (Tregs) skew towards a pro-inflammatory, non-suppressive phenotype and are unable to control the exaggerated autoimmune responses. This may largely impact the success of autologous Treg therapy which is currently under investigation for treatment of autoimmune diseases, including multiple sclerosis (MS). Our recent findings provide for the first time evidence that the inflamed blood-brain barrier (BBB) affects human Treg stability. Using functional in vitro assays, we found that the suppressive capacity of migrated Tregs was affected. Transcriptome analysis indicated that migrated human Tregs of healthy donors and MS patients are less suppressive, have a pro-inflammatory Th1/17 signature and upregulate the mTOR signaling pathway. In vitro treatment of migrated Tregs with the clinically-approved mTOR inhibitor rapamycin restored the loss of suppressive function. In MS-derived Tregs specifically, Th17-related pathways were increased while amphiregulin was downregulated. This suggests a pre-existing susceptibility towards inflammation and lost regenerative capacity in MS-derived migrated Tregs. These insights and specific target identification can help in significantly improving the efficacy of autologous Treg therapy of MS. The aim is to target this BBB-induced Treg instability in patient-derived Tregs by genetic manipulation. By this, we restore and stabilize their immunosuppressive and regenerative function and use these designer Tregs as a powerful, autologous cell therapy for MS
Oncostatin M: a love-hate relationship in neuroinflammation
No full textOncostatin M and multiple sclerosis: Every 5 minutes, someone in the world is diagnosed with multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS appears in unpredictable episodes of symptoms, which are highly patient-dependent, but often include visual impairment, muscle weakness/spasms, fatigue, cognitive difficulties, and bladder, bowel, or sexual dysfunction. In severe cases, MS patients become wheelchairbound due to paralysis. These symptoms are the result of a dysfunctional signal transduction from one neuron to another after the immune system has attacked the neuron's insulating myelin sheath. Therefore, hyperactivation of immune cells and the presence of demyelinating plaques in the CNS are the main pathological hallmarks of MS.This work was supported by Fonds voor Wetenschappelijk Onderzoek (FWO), Charcot Foundation, Hasselt University (to BB)
When Helpers Go Above and Beyond: Development and Characterization of Cytotoxic CD4(+) T Cells
No full textOnce regarded as an experimental artefact, cytotoxic CD4(+) T cells (CD4 CTL) are presently recognized as a biologically relevant T cell subset with important functions in anti-viral, anti-tumor, and autoimmune responses. Despite the potentially large impact on their micro-environment, the absolute cell counts of CD4 CTL within the peripheral circulation are relatively low. With the rise of single cell analysis techniques, detection of these cells is greatly facilitated. This led to a renewed appraisal of CD4 CTL and an increased insight into their heterogeneous nature and ontogeny. In this review, we summarize the developmental path from naïve CD4(+) T cells to terminally differentiated CD4 CTL, and present markers that can be used to detect or isolate CD4 CTL and their precursors. Subsets of CD4 CTL and their divergent functionalities are discussed. Finally, the importance of local cues as triggers for CD4 CTL differentiation is debated, posing the question whether CD4 CTL develop in the periphery and migrate to site of inflammation when called for, or that circulating CD4 CTL reflect cells that returned to the circulation following differentiation at the local inflammatory site they previously migrated to. Even though much remains to be learned about this intriguing T cell subset, it is clear that CD4 CTL represent interesting therapeutic targets for several pathologies
Train your T cells: How skeletal muscles and T cells keep each other fit during aging
No full textFrailty and a failing immune system lead to significant morbidities in the final years of life and bring along a significant burden on healthcare systems. The good news is that regular exercise provides an effective countermeasure for losing muscle tissue when we age while supporting proper immune system functioning. For a long time, it was assumed that exercise-induced immune responses are predominantly mediated by myeloid cells, but it has become evident that they receive important help from T lymphocytes. Skeletal muscles and T cells interact, not only in muscle pathology but also during exercise. In this review article, we provide an overview of the most important aspects of T cell senescence and discuss how these are modulated by exercise. In addition, we describe how T cells are involved in muscle regeneration and growth. A better understanding of the complex interactions between myocytes and T cells throughout all stages of life provides important insights needed to design strategies that effectively combat the wave of age-related diseases the world is currently faced with.N.H. and B.O.E. received a grant (G040321FWO) from the Flemish Fund for Scientific Research (FWO Vlaanderen). N.H. and H.S. were also supported by the Interreg Euregio Meuse-Rine Healthy Aging project grant (EMR51), funded by the European Fund for Regional Development of the EU, supporting innovation in this regio
Inhibitors of Bruton's tyrosine kinase as emerging therapeutic strategy in autoimmune diseases
No full textBruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor signal transducer, initially identified as an essential signaling molecule for B cells, with genetic mutations resulting in a disorder characterized by disturbed B cell and antibody development. Subsequent research revealed the critical role of BTK in the functionality of monocytes, macrophages and neutrophils. Various immune cells, among which B cells and neutrophils, rely on BTK activity for diverse signaling pathways downstream of multiple receptors, which makes this kinase an ideal target to treat hematological malignancies and autoimmune diseases. First-generation BTK inhibitors are already on the market to treat hematological disorders. It has been demonstrated that B cells and myeloid cells play a significant role in the pathogenesis of different autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and primary Sjogren's syndrome. Consequently, second-generation BTK inhibitors are currently being developed to treat these disorders. Despite the acknowledged involvement of BTK in various cell types, the focus on B cells often overshadows its impact on innate immune cells. Among these cell types, neutrophils are often underestimated in the pathogenesis of autoimmune diseases. In this narrative review, the function of BTK in different immune cell subsets is discussed, after which an overview is provided of different upcoming BTK inhibitors tested for treatment of autoimmune diseases. Special attention is paid to BTK inhibition and its effect on neutrophil biology.This work was supported by grants from the Research Foundation of Flanders (FWO Vlaanderen), Bijzonder Onderzoeksfonds (BOF), UHasselt, KU Leuven and the Charcot Foundation. Mirre De Bondt holds a personal PhD fellowship from FWO Vlaanderen (1192221N)
Oncostatin M, an Underestimated Player in the Central Nervous System
Full text linkFor a long time, the central nervous system (CNS) was believed to be an immune privileged organ. In the last decades, it became apparent that the immune system interacts with the CNS not only in pathological, but also in homeostatic situations. It is now clear that immune cells infiltrate the healthy CNS as part of immune surveillance and that immune cells communicate through cytokines with CNS resident cells. In pathological conditions, an enhanced infiltration of immune cells takes place to fight the pathogen. A well-known family of cytokines is the interleukin (IL)-6 cytokine family. All members are important in cell communication and cell signaling in the immune system. One of these members is oncostatin M (OSM), for which the receptor is expressed on several cells of the CNS. However, the biological function of OSM in the CNS is not studied in detail. Here, we briefly describe the general aspects related to OSM biology, including signaling and receptor binding. Thereafter, the current understanding of OSM during CNS homeostasis and pathology is summarized
T-cell-based immunotherapy in multiple sclerosis: induction of regulatory immune networks by T-cell vaccination
No full textMultiple sclerosis (MS) is a chronic inflammatory disease of the CNS with presumed autoimmune origin. Pathogenic autoimmune responses in MS are thought to be the result of a breakdown of self tolerance. Several mechanisms account for the natural state of immunological tolerance to self antigens, including clonal deletion of self-reactive T cells in the thymus. However, autoimmune T cells are also part of the normal T-cell repertoire, supporting the existence of peripheral regulatory mechanisms that keep these potentially pathogenic T cells under control. One such mechanism involves active suppression by regulatory T cells. It has been indicated that regulatory T cells do not function properly in autoimmune disease. Immunization with attenuated autoreactive T cells, T-cell vaccination, may enhance or restore the regulatory immune networks to specifically suppress autoreactive T cells, as shown in experimental autoimmune encephalomyelitis, an animal model for MS. In the past decade, T-cell vaccination has been tested for MS in several clinical trials. This review summarizes these clinical trials and updates our current knowledge on the induction of regulatory immune networks by T cell vaccination.We thank J Zhang, R Medaer, A Van der Aa and G Hermans for their contribution to the above-reviewed results of our laboratory. This work was funded by grants from the Belgian Instituut voor de bevordering van het Wetenschappelijk Technologisch Onderzoek in de Industrie, the Belgian Charcot Foundation, the Belgian WOMS Foundation and Hasselt University (UHasselt)
The EBV-MS connection: the enigma remains
No full textThe author(s) declare financial support was received for the research, authorship, and/or publication of this article. Our research on EBV and MS is funded by the Belgian Charcot Foundation, the Flemish Research Foundation (FWO), and the National Fund of Scientific Research (FNRS)
Natural naive regulatory T cell development and function are disturbed in multiple sclerosis patients
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