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

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

Measles IgG Antibody Index Correlates with T2 Lesion Load on MRI in Patients with Early Multiple Sclerosis

Background: B cells and humoral immune responses play an important role in the pathogenesis and diagnosis of multiple sclerosis (MS). A characteristic finding in patients with MS is a polyspecific intrathecal B cell response against neurotropic viruses, specifically against measles virus, rubella virus, and varicella zoster virus, also known as an MRZ reaction (MRZR). Here, we correlated from the routine clinical diagnostics individual IgG antibody indices (AIs) of MRZR with magnetic resonance imaging (MRI) findings in patients with first MS diagnosis. Methods/Results: MRZR was determined in 68 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting MS (RRMS). Absolute AI values for measles virus, rubella virus, and varicella zoster virus were correlated with T2 lesion load and gadolinium enhancing lesions on cerebral MRI (cMRI) and cMRI combined with spinal MRI (sMRI). Measles virus AI correlated significantly with T2 lesion load on cMRI (p = 0.0312, Mann-Whitney U test) and the sum of lesions on cMRI and sMRI (p = 0.0413). Varicella zoster virus AI also showed a correlation with T2 lesion load on cMRI but did not reach statistical significance (p = 0.2893). Conclusion: The results confirm MRZR as part of the polyspecific immune reaction in MS with possible prognostic impact on MRI and clinical parameters. Furthermore, the data indicate that intrathecal measles virus IgG production correlates wit

Environmental factors in early childhood are associated with multiple sclerosis: a case-control study

<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with increasing incidence mainly in high-income countries. One explanation of this phenomenon may be a higher prevalence of allergic and autoimmune diseases in industrialized countries as a consequence of otherwise beneficial advances in sanitation (hygiene hypothesis). We investigated environmental factors in early childhood associated with MS.</p> <p>Methods</p> <p>A case-control study was performed of 245 MS patients and 296 population-based controls in Berlin. The study participants completed a standardized questionnaire on environmental factors in childhood and youth, including aspects of personal and community hygiene. Multivariable logistic regression analysis was performed to investigate factors in childhood and youth associated with the occurrence of MS.</p> <p>Results</p> <p>Mean age was 46 years (range, 20-80) in the MS group and 42 years (range 18-80) in the control group, of which 73.9% in the MS and 61.5% in the control group were female. The multivariable analysis showed that having at least two older siblings (OR 0.54; p = 0.05, for individuals with two older siblings compared to individuals without older siblings), attending a day-care center (OR 0.5; p = 0.004) and growing up in an urban center with more than 100, 000 inhabitants (OR 0.43; p = 0.009) were factors independently associated with a lower chance for MS.</p> <p>Conclusions</p> <p>The hygiene hypothesis may play a role in the occurrence of MS and could explain disease distribution and increasing incidence.</p

Serum levels of brain-derived neurotrophic factor (BNDF) in multiple sclerosis patients with

We previously analysed clinical and immunological parameters under Trichuris suis ova (TSO) therapy in four patients with secondary progressive multiple sclerosis. The serum Brain-derived neurotrophic factor (BDNF) levels of these four patients were assessed before, during and after therapy with TSO and showed significant decrease of BDNF during TSO therapy (p < 0.05)

Proresolution lipid mediators in multiple sclerosis - differential, disease severity-dependent synthesis - a clinical pilot trial.

The severity and longevity of inflammation is controlled by endogenous counter-regulatory signals. Among them are long-chain polyunsaturated fatty acid (PUFA)-derived lipid mediators, which promote the resolution of inflammation, an active process for returning to tissue homeostasis.To determine whether endogenous production of lipid-derived resolution agonists is regulated differentially in patients with highly active and less active multiple sclerosis (MS).Matched-pairs study in University hospital Neurology department.Based on clinical (relapse frequency) and paraclinical (MRI lesions, contrast enhancement) criteria, 10 pairs of age- and sex-matched patients with relapsing-remitting MS were assigned either to a group with highly active or less active MS. Lipid mediators were quantified in serum and cerebrospinal fluid using LC-MS/MS-based lipidomics.Levels of the key arachidonic (ω-6) and docosahexaenoic acid (ω-6)-derived mediators prostaglandins (PG), leukotrienes, hydroxyeicosatetraenoic acids (HETE) and resolution agonists lipoxin A(4) (LXA(4)), resolvin D1 (RvD1) and neuroprotectin D1 (NPD1) were quantified. In the patient group with highly active MS, 15-HETE and PGE(2) were increased, which are products of the 15-lipoxygenase and cyclooxygenase pathways. The proresolution mediator RvD1 was significantly upregulated and NPD1 was detected in the highly active group only. LXA(4) levels were not increased in patients with highly active MS.Lipid mediator pathways are regulated differentially in the cerebrospinal fluid of MS patients, depending on disease severity. Non-exhaustive or possibly 'delayed' resolution pathways may suggest a defective resolution program in patients with highly active MS. Longitudinal analyses are required to hetero-typify this differential resolution capacity, which may be associated with disease progression, longevity and eventual termination

Demographic data of all 68 patients. MRZR+ = AI for measles virus, rubella virus, varicella zoster virus, two or more AI≥1.5.

<p>Demographic data of all 68 patients. MRZR+ = AI for measles virus, rubella virus, varicella zoster virus, two or more AI≥1.5.</p

IgG antibody index of MRZR and MRI activity.

<p>IgG antibody index (AI) results for measles virus (A), rubella virus (B) and varicella zoster virus (C) for patients with <6 lesions, ≥6 lesions, no Gd-enhancing lesions and Gd-enhancing lesions on cMRI are shown as box plot graphs. The boxes include values between the 25^th and 75^th percentile of the distribution, while the line within the box represents the median value. The whiskers above and below the box indicate the 90^th and 10^th percentile, respectively, and the black dots indicate the outliers, while the dotted line at AI 1.5 indicates the upper limit of the reference range. The number of patients in each group is shown in brackets above boxes.</p

LC/MS/MS Lipid Mediator Profiling.

<p>A) MRM profile of 12 eicosanoid and docosanoid synthetic standards (NPD1, 4-HDHA, 17-HDHA, RVD1, PGE₂, PGD₂, LTB₄, 6-trans LTB₄ (C1), 6-trans-12-epi-LTB₄ (C2), 12-HETE, 15-HETE, 5-HETE). B) Representative MRM chromatogram of 15-HETE, PGE₂ and RvD1 from patients with less active MS (black line) and with highly active MS (red line). MRM signals (CPS) were corrected for recovery and cerebrospinal fluid sample size. Calibration curves (1–1000 pg) and specific LC retention times for each compound were established with synthetic standards (Cayman Chemical, Ann Arbor, MI). Structures were confirmed for selected samples by MS/MS analyses using enhanced product ion mode with appropriate selection of the parent ion in quadrupole 1.</p