1,721,376 research outputs found
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)
CNS delivery of anti-CD52 antibodies modestly reduces disease severity in an animal model for multiple sclerosis
No full textBackground and aims: Alemtuzumab is a humanized monoclonal antibody that depletes CD52-bearing B and T lymphocytes. Clinical trials defined that systemic administration of alemtuzumab reduces disease severity in the relapsing-remitting phase of multiple sclerosis (MS). However, its efficacy in progressive MS patients is limited, which may reflect the inability of alemtuzumab to cross the reconstituted BBB in these patients. Objective: to study whether central nervous system (CNS) delivery of anti-CD52 antibodies reduces disease severity and the neuroinflammatory burden in the experimental autoimmune encephalomyelitis (EAE) model. Methods: Anti-CD52 antibodies were administered intrathecally during the acute and chronic phases of EAE. Flow cytometry and immunohistochemistry were utilized to define immunological and pathological parameters. Results: We show that subcutaneously administrated anti-CD52 antibodies completely abolish EAE disease severity. CNS delivery of anti-CD52 antibodies during both the acute and chronic phases of EAE moderately reduces disease severity and the neuroinflammatory burden. Our findings further suggest that CNS delivery of anti-CD52 antibodies impacts both the peripheral and CNS immune cell compartments in the EAE model but not in healthy mice. Conclusion: Collectively, our findings highlight the therapeutic potential of CNS delivery of alemtuzumab for the treatment of progressive as well as early MS.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by Sanofi Genzyme, and grants of the Belgian Charcot Foundation, Research Foundation Flanders (FWO), and European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).Hendriks, JJA (corresponding author), Hasselt Univ, Biomed Res Inst, Dept Immunol & Infect, Agoralaan Bldg C, B-3590 Diepenbeek, Belgium.
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Natural naive CD4(+)CD25(+)CD127(low) regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: Recovery of memory treg homeostasis during disease progression
No full textPatients with relapsing-remitting multiple sclerosis (RR-MS) show a suboptimal CD4(+)CD25(+) regulatory T cell (Treg) function, whereas no Treg alterations are observed in secondary progressive MS (SP-MS) patients. To clarify the difference in Treg activity between early and chronic disease stages in MS, we analyzed the functional capacity and homeostatic parameters of naive CD4(+)CD25(+)CD127(low)CD45RA(+) Tregs (nTregs) and their memory counterparts CD4(+)CD25(+)CD127(low) CD45RO(+) Tregs (mTregs) in untreated MS patients and healthy controls. Interestingly, whereas the suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, only the latter group showed a restored mTreg function. Consistent with this observation, chronic MS patients had increased numbers of mTregs as compared with age-matched early MS patients, whereas nTreg frequencies did not differ significantly. TCR excision circle numbers were reduced in nTregs of early MS patients, suggestive of a diminished nTreg thymic output. Moreover, a decreased number of CD31(+) mTregs were observed in early vs chronic MS patients, indicating that inflammatory processes drive the homeostatic turnover of mTregs during the early disease stage. Additionally, early MS patients showed a more restricted nTreg and mTreg TCR BV gene profile as compared with healthy controls and chronic MS patients. Finally, analysis of IFN-beta and glatiramer acetate-treated MS patients showed that these immunomodulatory drugs modify nTreg homeostasis. Taken together, this study provides strong evidence for a disturbed thymic nTreg development and function in MS patients. Moreover, memory Treg but not naive Treg homeostasis recovers during disease progression
Natural naive regulatory T cell development and function are disturbed in multiple sclerosis patients
No full textType I alfa 1 collagen gene polymorphism is associated with bone density, muscle strength and susceptibility for fractures in elderly women.
No full textA CFSE based assay for measuring CD4+CD25+ regulatory T cell mediated suppression of auto-antigen specific and polyclonal T cell responses
No full textCD4(+)CD25(+) regulatory T cells (Tregs) are considered to play a key role as suppressors of immune inediated reactions. The analysis of Treg function in patients with autoimmune, allergic or oncogenic diseases has emerged over the past years. In the present study we describe a CFSE based protocol to measure Treg mediated suppression of CD4(+) T cells. Measuring Treg suppressive capacity towards proliferation of anti-CD3 Ab stimulated CD4(+)CD25(-) T cells in coculture experiments by means of a CFSE based and a classical [H-3]thymidine incorporation assay gave similar results, provided that CD4(+)CD25(+) T cells were anergic. However, when CD4(+)CD25(+) T cells proliferated upon mitogenic stimulation, data obtained by the CFSE assay allowed the detection of a significant Treg suppression whereas this was clearly underestimated using the [H-3]thymidine assay. In addition, an indirect CFSE based method was developed to analyze antigen specific responses of total CD4(+) T cells and Treg depleted CD4(+) T cells (i.e. CD4(+)CD25(-) T cells). Our results indicate that, in healthy individuals, CD4(+) T cell responses against the multiple sclerosis (MS) auto-antigens, myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG), were increased in Treg depleted CD4(+) T cells as compared to total CD4(+) T cells. Our initial data suggest that Tregs in MS patients show an impaired suppression of myelin reactive T cells when compared to healthy controls. Moreover, this experimental setup permits the measurement of cytokine production of the antigen proliferated CFSElow T cells by additional flow cytometric analyses. In conclusion, the described CFSE based Treg suppression assay is a valuable tool to study suppressor T cells in (auto)immune disorders. (C) 2007 Elsevier B.V. All rights reserved
Natural naive regulatory T cell development and function are disturbed in multiple sclerosis patients
No full textBackground: Myelin-reactive T cells may play a pathogenic role in
multiple sclerosis (MS). We and others have shown that regulatory
CD4+CD25+FOXP3+CD127low T cells (Tregs) are functionally disturbed
in relapsing-remitting (RR) MS patients but not in secondary
progressive (SP) MS patients. Objective: To clarify this difference in
Treg activity between early and chronic disease stages in MS.
Methods: We analyzed the functional capacity and homeostatic
parameters of (precursor) naive Tregs (nTregs) and memory Tregs
(mTregs). We also measured myelin basic protein (MBP) and myelin
oligodendrocyte glycoprotein (MOG) proliferative responses of
CD4total T cells (including Tregs), naive (CD45RAhigh) and memory
(CD45RA-) CD4+CD25-CD127high T cells (no Tregs included) of
RRMS and SPMS patients and healthy controls (HC) by means of a
CFSE dilution assay and measured cytokine production of the myelinreactive
T cells. Results: The suppressive capacity of FACS-sorted
nTregs was impaired in both early and chronic MS patients, whereas
only the latter group showed a restored mTreg function. Chronic MS
patients had increased numbers of mTregs as compared with agematched
early MS patients, whereas nTreg frequencies did not differ
Type I alfa 1 collagen gene polymorphism is associated with bone density, muscle strength and susceptibility for fractures in elderly women.
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