scholarly journals The Worm-Specific Immune Response in Multiple Sclerosis Patients Receiving Controlled Trichuris suis Ova Immunotherapy

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 101
Author(s):  
Ivet A. Yordanova ◽  
Friederike Ebner ◽  
Axel Ronald Schulz ◽  
Svenja Steinfelder ◽  
Berit Rosche ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Clinical Efficacy ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Th2 Cells ◽  
Continuous Increase ◽  
Trichuris Suis ◽  
Multiple Sclerosis Patients

Considering their potent immunomodulatory properties, therapeutic applications of Trichuris suis ova (TSO) are studied as potential alternative treatment of autoimmune disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), or inflammatory bowel disease (IBD). Clinical phase 1 and 2 studies have demonstrated TSO treatment to be safe and well tolerated in MS patients, however, they reported only modest clinical efficacy. We therefore addressed the cellular and humoral immune responses directed against parasite antigens in individual MS patients receiving controlled TSO treatment (2500 TSO p.o. every 2 weeks for 12 month). Peripheral blood mononuclear cells (PBMC) of MS patients treated with TSO (n = 5) or placebo (n = 6) were analyzed. A continuous increase of serum IgG and IgE antibodies specific for T. suis excretory/secretory antigens was observed up to 12 months post-treatment. This was consistent with mass cytometry analysis identifying an increase of activated HLA-DRhigh plasmablast frequencies in TSO-treated patients. While stable and comparable frequencies of total CD4+ and CD8+ T cells were detected in placebo and TSO-treated patients over time, we observed an increase of activated HLA-DR+CD4+ T cells in TSO-treated patients only. Frequencies of Gata3+ Th2 cells and Th1/Th2 ratios remained stable during TSO treatment, while Foxp3+ Treg frequencies varied greatly between individuals. Using a T. suis antigen-specific T cell expansion assay, we also detected patient-to-patient variation of antigen-specific T cell recall responses and cytokine production. In summary, MS patients receiving TSO treatment established a T. suis-specific T- and B-cell response, however, with varying degrees of T cell responses and cellular functionality across individuals, which might account for the overall miscellaneous clinical efficacy in the studied patients.

T cells from multiple sclerosis patients recognize immunoglobulin G from cerebrospinal fluid

2003 ◽  
Vol 9 (3) ◽  
pp. 228-234 ◽  
Author(s):  
T Holmøy ◽  
B Vandvik ◽  
F Vartdal
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Cerebrospinal Fluid ◽  
T Cell ◽  
Mononuclear Cells ◽  
Neurological Diseases ◽  
Affinity Maturation ◽  
Peripheral Blood Mononuclear ◽  
Number Of Patients ◽  
Multiple Sclerosis Patients

Idiotopic sequences are created after V, D and J recombinations and by somatic mutations during affinity maturation of immuglobulin (Ig) molecules, and may therefore be potential immunogenic epitopes. Idiotope-specific T cells are able to activate and sustain the B cells producing such idiotopes. It is therefore possible that idiotope-specific intrathecal T cells could help maintain the persisting intrathecal synthesis of oligoclonal IgG observed in patients with multiple sclerosis (MS). This study was undertaken to examine T-cell responses to cerebrospinal fluid (CSF) IgG. Peripheral blood mononuclear cells (PBMC) from 14 of 21 MS patients and four of 17 control patients with other neurological diseases proliferated upon stimulation with autologous C SF IgG, while five and three, respectively, responded to serum IgG. By comparison, responses to myelin basic protein were recorded in only four MS and three control patients. Data from a limited number of patients indicate that the C SF IgG responsive cells were CD4+ and human leucocyte antigen DR restricted, that PBMC also respond to C SF IgG from other MS patients and that the C SF may contain T cells responding to autologous C SF IgG. This suggests that C SF IgG, or substances bound to this IgG, may represent T-cell immunogens, which could contribute to the intrathecal immune response in MS.

Immunoglobulin-like transcript 3, an inhibitor of T cell activation, is reduced on blood monocytes during multiple sclerosis relapses and is induced by interferon β-1b

2009 ◽  
Vol 16 (1) ◽  
pp. 30-38 ◽  
Author(s):  
Mark A Jensen ◽  
Rachel N Yanowitch ◽  
Anthony T Reder ◽  
David M White ◽  
Barry GW Arnason
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Mononuclear Cells ◽  
Interferon Β ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis

Immunoglobulin-like transcripts (ILTs) are immunoregulatory proteins that either activate or inhibit immune responses. ILT3 is inhibitory and is expressed preferentially by antigen-presenting cells. When its extracellular domain binds to an unidentified ligand of activated T cells, the T cell is silenced. Our objective was to study the expression of ILT3 on circulating monocytes in RRMS. Freshly isolated peripheral blood mononuclear cells were analyzed by multicolored flow cytometry. The proportion of ILT3+CD14+ monocytes in blood, and ILT3 levels expressed by them, is lower in untreated multiple sclerosis in relapse than in: (1) untreated multiple sclerosis in remission (p < 0.009); (2) stable interferon β-treated relapsing—remitting multiple sclerosis (p < 0.001) and; (3) healthy controls (p < 0.009). Glatiramer acetate-stimulated CD4 + T cells, co-cultured with freshly isolated monocytes, proliferate significantly better (p = 0.0017 for multiple sclerosis; p = 0.0015 for controls) when T cell interaction with monocyte-expressed ILT3 is blocked by anti-ILT3 antibody. Interferon β is beneficial in multiple sclerosis; why so remains unclear. Interferon β-1b markedly increases ILT3 expression in vitro by monocytes from multiple sclerosis patients and controls. These findings identify a putative novel mechanism for the therapeutic benefit bestowed by Interferon β and a new target for therapeutic intervention in relapsing—remitting multiple sclerosis.

Regulation of IL-17 in chronic inflammation in the human lung

2011 ◽  
Vol 120 (12) ◽  
pp. 515-524 ◽  
Author(s):  
Carol Pridgeon ◽  
Laurence Bugeon ◽  
Louise Donnelly ◽  
Ursula Straschil ◽  
Susan J. Tudhope ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Tissue ◽  
Mononuclear Cells ◽  
Human Lung ◽  
Treg Cells ◽  
Orphan Receptor ◽  
Th2 Cells ◽  
Chronic Obstructive ◽  
Interleukin 17

The regulation of human Th17 cell effector function by Treg cells (regulatory T-cells) is poorly understood. In the present study, we report that human Treg (CD4+CD25+) cells inhibit the proliferative response of Th17 cells but not their capacity to secrete IL (interleukin)-17. However, they could inhibit proliferation and cytokine production by Th1 and Th2 cells as determined by IFN-γ (interferon-γ) and IL-5 biosynthesis. Currently, as there is interest in the role of IL-17-producing cells and Treg cells in chronic inflammatory diseases in humans, we investigated the presence of CD4+CD25+ T-cells and IL-17 in inflammation in the human lung. Transcripts for IL-17 were expressed in mononuclear cells and purified T-cells from lung tissue of patients with chronic pulmonary inflammation and, when activated, these cells secrete soluble protein. The T-cell-specific transcription factors RORCv2 (retinoic acid-related orphan receptor Cv2; for Th17) and FOXP3 (forkhead box P3; for Treg cells) were enriched in the T-cell fraction of lung mononuclear cells. Retrospective stratification of the patient cohort into those with COPD (chronic obstructive pulmonary disease) and non-COPD lung disease revealed no difference in the expression of IL-17 and IL-23 receptor between the groups. We observed that CD4+CD25+ T-cells were present in comparable numbers in COPD and non-COPD lung tissue and with no correlation between the presence of CD4+CD25+ T-cells and IL-17-producing cells. These results suggest that IL-17-expressing cells are present in chronically inflamed lung tissue, but there is no evidence to support this is due to the recruitment or expansion of Treg cells.

Modulation of the central memory and Tr1-like regulatory T cells in multiple sclerosis patients responsive to interferon-beta therapy

2011 ◽  
Vol 18 (6) ◽  
pp. 788-798 ◽  
Author(s):  
M Chiarini ◽  
F Serana ◽  
C Zanotti ◽  
R Capra ◽  
S Rasia ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Interferon Beta ◽  
Central Memory ◽  
T Cell Subsets ◽  
Individual Treatment ◽  
Cell Phenotype ◽  
Multiple Sclerosis Patients

Background: Interferon-beta is used to reduce disease activity in multiple sclerosis, but its action is incompletely understood, individual treatment response varies among patients, and biological markers predicting clinical benefits have yet to be identified. Since it is known that multiple sclerosis patients have a deficit of the regulatory T-cell subsets, we investigated whether interferon-beta therapy induced modifications of the two main categories of regulatory T cells (Tregs), natural and IL-10-secreting inducible Tr1 subset, in patients who are biologically responsive to the therapy. Methods: T-cell phenotype was determined by flow cytometry, while real-time PCR was used to evaluate interferon-beta bioactivity through MxA determination, and to measure the RNA for IL-10 and CD46 molecule in peripheral blood mononuclear cells stimulated with anti-CD46 and anti-CD3 monoclonal antibodies, which are known to expand a Tr1-like population. Results: Interferon-beta induced a redistribution of natural Treg subsets with a shift of naive Tregs towards the ‘central memory-like’ Treg population that expresses the CCR7 molecule required for the in vivo suppressive activity. Furthermore, in a subgroup of treated patients, the CD46/CD3 co-stimulation, probably through the Tr1-like subset modulation, increased the production of RNA for IL-10 and CD46. The same group showed a lower median EDSS score after two years of therapy. Conclusions: The selective increase of ‘central memory-like’ subset and the involvement of the Tr1-like population may be two of the mechanisms by which interferon-beta achieves its beneficial effects. The quantification of RNA for IL-10 and CD46 could be used to identify patients with a different response to interferon-beta therapy.

γδ T cell responses to activated T cells in multiple sclerosis patients induced by T cell vaccination

1998 ◽  
Vol 87 (1-2) ◽  
pp. 94-104 ◽  
Author(s):  
Piet Stinissen ◽  
Jingwu Zhang ◽  
Caroline Vandevyver ◽  
Guy Hermans ◽  
Jef Raus
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Γδ T Cell ◽  
Activated T Cells ◽  
Cell Responses ◽  
T Cell Vaccination ◽  
Multiple Sclerosis Patients

scholarly journals Preserved T-cell Response in anti-CD20 Treated Multiple Sclerosis Patients Following SARS-CoV-2 Vaccination

2021 ◽  
Author(s):  
Simon Faissner ◽  
Neele Heitmann ◽  
Ricarda Rohling ◽  
Ulas Ceylan ◽  
Marielena Bongert ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
T Cell ◽  
B Cell ◽  
T Cell Response ◽  
Th2 Cells ◽  
Multiple Sclerosis Patients ◽  
Cellular Immune ◽  
Cell Repopulation

Abstract The SARS-CoV-2 pandemic has tremendous implications for the management of patients with autoimmune conditions such as multiple sclerosis (MS) under immune therapies targeting CD20+ B cells (aCD20). We here investigated humoral and cellular immune responses, including neutralization against SARS-CoV-2 WT and delta variant and T cell responses of aCD20-treated MS patients following SARS-CoV-2 vaccination compared to healthy controls. aCD20-treated MS patients had lower anti-SARS-CoV-2-Spike titers, which correlated with B-cell repopulation. Sera of aCD20 treated patients had reduced capacity to neutralize WT and delta pseudoviruses in vitro. On the contrary, aCD20 treated patients elicited higher frequencies of CD3+ T cells, Th1 cells, Th2 cells, Tc1 cells and CD8+IFN-γ+IL-2+ cells. In summary, aCD20 treated patients have a reduced humoral immune response, depending on B cell repopulation, in accordance with a shift of cellular immune response to a stronger Th1, Th2 and Tc1 phenotype, suggesting strong cellular protection against SARS-CoV-2.

scholarly journals Quantitative Proteomics Reveals Protein Dysregulation During T Cell Activation in Multiple Sclerosis Patients Compared to Healthy Controls

2021 ◽  
Author(s):  
Chiara Cappelletti ◽  
Anna Maria Eriksson ◽  
Ina Skaara Brorson ◽  
Ingvild S. Leikfoss ◽  
Oda Glomstad Kråbøl ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Susceptibility Genes ◽  
Healthy Controls ◽  
Activated T Cells ◽  
Multiple Sclerosis Patients

Abstract Background: Multiple sclerosis (MS) is an autoimmune, neurodegenerative disorder with a strong genetic component that acts in a complex interaction with environmental factors for disease development. CD4 + T cells are pivotal players in MS pathogenesis, where peripherally activated T cells migrate to the central nervous system leading to demyelination and axonal degeneration. Through a proteomic approach, we aim at identifying dysregulated pathways in activated T cells from MS patients as compared to healthy controls. Methods: CD4 + T cells were purified from peripheral blood from MS patients and healthy controls by magnetic separation. Cells were left unstimulated or stimulated in vitro through the TCR and costimulatory CD28 receptor for 24 hours prior to sampling. Electrospray liquid chromatographytandem mass spectrometry was used to measure protein abundances. Results: Upon T cell activation the abundance of 1,801 proteins was changed. Among these proteins, we observed an enrichment of proteins expressed by MS-susceptibility genes. When comparing protein abundances in T cell samples from healthy controls and MS patients, 18 and 33 proteins were differentially expressed in unstimulated and stimulated CD4 + T cells, respectively. Moreover, 353 and 304 proteins were identified as proteins exclusively induced upon T cell activation in healthy controls and MS patients, respectively and dysregulation of the Nur77 pathway was observed only in samples from MS patients. Conclusions: Our study highlights the importance of CD4 + T cell activation for MS, as proteins that change in abundance upon T cell activation are enriched for proteins encoded by MS susceptibility genes. The results provide evidence for proteomic disturbances in T cell activation in MS, and pinpoint to dysregulation of the Nur77 pathway, a biological pathway known to limit aberrant effector T cell responses.

scholarly journals Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients

2005 ◽  
Vol 201 (5) ◽  
pp. 805-816 ◽  
Author(s):  
Paolo A. Muraro ◽  
Daniel C. Douek ◽  
Amy Packer ◽  
Katherine Chung ◽  
Francisco J. Guenaga ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Multiple Sclerosis Patients

Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease are mediated by lympho-depletive effects alone or are sustained by a regeneration of the immune repertoire, we examined the long-term immune reconstitution in patients with MS who received HSCT. After numeric recovery of leukocytes, at 2-yr follow-up there was on average a doubling of the frequency of naive CD4+ T cells at the expense of memory T cells. Phenotypic and T cell receptor excision circle (TREC) analysis confirmed a recent thymic origin of the expanded naive T cell subset. Analysis of the T cell receptor repertoire showed the reconstitution of an overall broader clonal diversity and an extensive renewal of clonal specificities compared with pretherapy. These data are the first to demonstrate that long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment.

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