scholarly journals Differential Expression of the T cell Inhibitor TIGIT in Glioblastoma and Multiple Sclerosis

2019 ◽  
Author(s):  
Liliana E. Lucca ◽  
Benjamin A. Lerner ◽  
Danielle DeBartolo ◽  
Calvin Park ◽  
Gerald Ponath ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Differential Expression ◽  
Peripheral Lymphocytes ◽  
Immune Pathways ◽  
Novel Targets ◽  
The Brain

AbstractTo identify co-inhibitory immune pathways important in the brain, we hypothesized that comparison of T cells in lesions from patients with MS with tumor infiltrating T cells (TILs) from patients with GBM may reveal novel targets for immunotherapy. Focusing on PD-1 and TIGIT, we found that TIGIT and its ligand CD155 were highly expressed on GBM TILs but were near-absent in MS lesions, while lymphocytic expression of PD-1/PDL-1 was comparable. TIGIT was also upregulated in peripheral lymphocytes in GBM, suggesting recirculation of TILs. These data raise the possibility that anti-TIGIT therapy may be beneficial for patients with glioblastoma.

T cell vaccination in multiple sclerosis

1996 ◽  
Vol 1 (6) ◽  
pp. 353-356 ◽  
Author(s):  
Jingwu Zhang ◽  
Jef Raus
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Brain Lesions ◽  
Brain Inflammation ◽  
Central Position ◽  
Host Immune System ◽  
Autoreactive T Cells ◽  
T Cell Vaccination ◽  
The Brain

T cell responses to myelin bask protein (MBP) are implicated to play an important role in the pathogenesis of multiple sclerosis (MS). These MBP autoreactive T cells are found to undergo in vivo activation and clonal expansion in patients with MS. They accumulate in the brain compartment and may reside in the brain lesions of patients with MS. As MBP-reactive T cells potentially hold a central position in initiation and perpetuation of the brain inflammation, specific immune therapies designed to deplete them may improve the clinical course of the disease. In this paper, the therapeutic potential of T cell vaccination in the treatment of MS is discussed in context of its immunological and clinical effect The results of our phase one clinical vial indicate that T cell vaccination with inactivated MBP autoreactive T cells induces specific regulatory T cell network of the host immune system to deplete circulating MBP-reactive T cells in a clonotype-specific fashion. The immunity induced by T cell vaccination is clonotype-specific and long-lasting. Our longitudinal clinical evaluation further suggests a moderate reduction of rate of clinical exacerbation, disability score and the brain lesions (measured by magnetic resonance imaging) in vaccinated patients, as compared to matched controls. Our study should encourage further investigation on the treatment efficacy of T cell vaccination and further improvement for its clinical application.

scholarly journals Differential expression of the T-cell inhibitor TIGIT in glioblastoma and MS

2020 ◽  
Vol 7 (3) ◽  
pp. e712 ◽  
Author(s):  
Liliana E. Lucca ◽  
Benjamin A. Lerner ◽  
Calvin Park ◽  
Danielle DeBartolo ◽  
Brian Harnett ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
T Cells ◽  
Healthy Controls ◽  
Costimulatory Receptor ◽  
Healthy Donors ◽  
Circulating Lymphocytes ◽  
Immune Pathways ◽  
Novel Targets ◽  
The Brain

ObjectiveTo identify coinhibitory immune pathways important in the brain, we hypothesized that comparison of T cells in lesions from patients with MS with tumor-infiltrating T cells (TILs) from patients with glioblastoma multiforme may reveal novel targets for immunotherapy.MethodsWe collected fresh surgical resections and matched blood from patients with glioblastoma, blood and unmatched postmortem CNS tissue from patients with MS, and blood from healthy donors. The expression of TIGIT, CD226, and their shared ligand CD155 as well as PD-1 and PDL1 was assessed by both immunohistochemistry and flow cytometry.ResultsWe found that TIGIT was highly expressed on glioblastoma-infiltrating T cells, but was near-absent from MS lesions. Conversely, lymphocytic expression of PD-1/PD-L1 was comparable between the 2 diseases. Moreover, TIGIT was significantly upregulated in circulating lymphocytes of patients with glioblastoma compared with healthy controls, suggesting recirculation of TILs. Expression of CD226 was also increased in glioblastoma, but this costimulatory receptor was expressed alongside TIGIT in the majority of tumor-infiltrating T cells, suggesting functional counteraction.ConclusionsThe opposite patterns of TIGIT expression in the CNS between MS and glioblastoma reflects the divergent features of the immune response in these 2 CNS diseases. These data raise the possibility that anti-TIGIT therapy may be beneficial for patients with glioblastoma.

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.

scholarly journals IMMU-28. INDUCTION OF TERTIARY LYMPHOID STRUCTURE-LIKE T-CELL CLUSTERS BY DELIVERY OF A NOVEL GENE COMBINATION INTO AN IMMUNOCOMPETENT MOUSE MODEL OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii110-ii111
Author(s):  
Kira Downey ◽  
Bindu Hegde ◽  
Zinal Chheda ◽  
Jason Zhang ◽  
Hideho Okada
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphatic Drainage ◽  
Lymphoid Follicle ◽  
Brain Parenchyma ◽  
Cell Therapies ◽  
Gene Combination ◽  
Cell Clustering ◽  
The Brain

Abstract The lack of conventional lymphatic drainage to and from the brain parenchyma restricts the capacity of the peripheral immune system to recognize and respond to glioma antigens. In some peripheral solid tumor types and central nervous system autoimmunity, the spontaneous development of tertiary lymphoid structures (TLS) with varying degrees of organization have been observed in human patients and mice following chronic inflammation. In the cancer setting, presence of TLS are generally associated with improved prognosis, especially when they are characterized by intratumoral infiltration of CD8+ T-cells. We aimed to induce the development of TLS in vivo, utilizing our SB28 glioblastoma model which is sparsely infiltrated by lymphocytes. As a proof-of-concept study, we stably transduced SB28 with a combination of several TLS-stimulating factors that we’ve identified and injected these cells into the brain parenchyma of syngeneic C57BL/6J mice. A combination of the chemoattractant and lymphoid follicle-stimulating cytokines LIGHT, CCL21, IL-7, and IL-17 produced substantial infiltration of CD8+CD3+ T-cells into the tumor and nearby parenchyma. However, this combination was also associated with accelerated tumor growth. A modified gene combination including LIGHT, CCL21, and IL-7 promoted CD8+CD3+ T-cell infiltration by flow cytometry, T-cell clustering by immunofluorescence analysis, and inhibited tumor burden compared with the control as measured by bioluminescent imaging. There was also evidence of increased lymphatic vasculature around the margins of T-cell clustering as demonstrated by LYVE-1 staining. Together, these analyses highlight a role for these factors in stimulating the recruitment and clustering of T-cell to the glioblastoma microenvironment in a TLS-like phenomenon. Future studies will evaluate whether the recruitment of other lymphocytes and stromal cells to these TLS-like clusters can promote T-cell memory and persistence. Ultimately, we aim to provide these factors utilizing a gene delivery method that will prove translatable to the clinic and complementary to existing T-cell therapies.

EXTH-82. T CELL HITCHHIKING AS A MECHANISM OF DRUG DELIVERY TO THE BRAIN

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi182-vi182
Author(s):  
Kirit Singh ◽  
Patrick Gedeon ◽  
Teilo Schaller ◽  
David Snyder ◽  
Mustafa Khasraw ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Survival ◽  
Mass Spectroscopy ◽  
Ct Imaging ◽  
Spectroscopy Analysis ◽  
Activated T Cells ◽  
Pet Ct ◽  
The Brain ◽  
Mass Spectroscopy Analysis

Abstract INTRODUCTION The blood-brain barrier (BBB) restricts access to the central nervous system (CNS). Our brain bispecific T cell engager (hEGFRvIII:CD3 BRiTE) treats subcutaneous syngeneic tumor (CT2AvIII) but not intracranial CT2AvIII. CD3 engaging molecules such as nanoparticles can be carried into the brain by binding to activated T cells. We therefore sought to determine if co-administration of larger molecules (BRiTE, approx. 55kDa) with activated T cells could cross the BBB, enhancing survival. METHODS We implanted 8–10-week-old transgenic hCD3 mice (n=7-8 per group) with 30,000 CT2AvIII cells. Tumors were established for 6 days. Mice were administered either (1) autologous lymphocyte transfer (ALT) alone (single intravenous (IV) injection, 1 x 107 activated T cells), (2) serial IV BRiTE doses (50ug, 10 days) (3) BRiTE and ALT or (4) no treatment. Mice were followed for survival using Kaplan-Meier curves and compared via log rank test. Targeted mass spectroscopy analysis as well as PET/CT imaging of mice administered Iodine-124 radiolabelled BRiTE was performed to assess for intracranial accumulation. RESULTS Mice who received BRiTE and ALT demonstrated significantly enhanced survival compared to controls (median survival 29 vs 21 days, p=0.0135). Mice who received only BRiTE or ALT exhibited median survival comparable to controls (p=0.192, p=0.944 respectively). Mass spectroscopy analysis revealed that mice had a 7-fold increased peak area ratio of BRiTE in the CNS when co-treated with activated T cells compared to BRiTE alone (0.14, 0.02 respectively) while PET/CT imaging demonstrated increased radioactive signal over background localized to coordinates within the brain where tumors were injected. CONCLUSIONS Giving activated T cells alongside BRiTE allows better access to the intracranial compartment and is required to achieve efficacy in mice with syngeneic orthotopic glioma. Future work will determine the optimal dose and schedule for this approach, as well as defining the precise mechanism by which this occurs.

scholarly journals Vitamin D/CD46 Crosstalk in Human T Cells in Multiple Sclerosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Justin Killick ◽  
Joanne Hay ◽  
Elena Morandi ◽  
Sonja Vermeren ◽  
Saniya Kari ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
T Cells ◽  
T Cell ◽  
Chronic Inflammatory Disease ◽  
Vitamin D Supplementation ◽  
Type I ◽  
T Cell Migration ◽  
The Impact

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which T-cell migration into the CNS is key for pathogenesis. Patients with MS exhibit impaired regulatory T cell populations, and both Foxp3+ Tregs and type I regulatory T cells (Tr1) are dysfunctional. MS is a multifactorial disease and vitamin D deficiency is associated with disease. Herein, we examined the impact of 1,25(OH)2D3 on CD4+ T cells coactivated by either CD28 to induce polyclonal activation or by the complement regulator CD46 to promote Tr1 differentiation. Addition of 1,25(OH)2D3 led to a differential expression of adhesion molecules on CD28- and CD46-costimulated T cells isolated from both healthy donors or from patients with MS. 1,25(OH)2D3 favored Tr1 motility though a Vitamin D-CD46 crosstalk highlighted by increased VDR expression as well as increased CYP24A1 and miR-9 in CD46-costimulated T cells. Furthermore, analysis of CD46 expression on T cells from a cohort of patients with MS supplemented by vitamin D showed a negative correlation with the levels of circulating vitamin D. Moreover, t-Distributed Stochastic Neighbor Embedding (t-SNE) analysis allowed the visualization and identification of clusters increased by vitamin D supplementation, but not by placebo, that exhibited similar adhesion phenotype to what was observed in vitro. Overall, our data show a crosstalk between vitamin D and CD46 that allows a preferential effect of Vitamin D on Tr1 cells, providing novel key insights into the role of an important modifiable environmental factor in MS.

scholarly journals Anti-CD20 therapy depletes activated myelin-specific CD8+T cells in multiple sclerosis

2019 ◽  
Vol 116 (51) ◽  
pp. 25800-25807 ◽  
Author(s):  
Joseph J. Sabatino ◽  
Michael R. Wilson ◽  
Peter A. Calabresi ◽  
Stephen L. Hauser ◽  
Jonathan P. Schneck ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Antibody Therapy ◽  
Myelin Proteins ◽  
T Cell Epitopes ◽  
Control Subjects ◽  
Anti Cd20

CD8+T cells are believed to play an important role in multiple sclerosis (MS), yet their role in MS pathogenesis remains poorly defined. Although myelin proteins are considered potential autoantigenic targets, prior studies of myelin-reactive CD8+T cells in MS have relied on in vitro stimulation, thereby limiting accurate measurement of their ex vivo precursor frequencies and phenotypes. Peptide:MHC I tetramers were used to identify and validate 5 myelin CD8+T cell epitopes, including 2 newly described determinants in humans. The validated tetramers were used to measure the ex vivo precursor frequencies and phenotypes of myelin-specific CD8+T cells in the peripheral blood of untreated MS patients and HLA allele-matched healthy controls. In parallel, CD8+T cell responses against immunodominant influenza epitopes were also measured. There were no differences in ex vivo frequencies of tetramer-positive myelin-specific CD8+T cells between MS patients and control subjects. An increased proportion of myelin-specific CD8+T cells in MS patients exhibited a memory phenotype and expressed CD20 compared to control subjects, while there were no phenotypic differences observed among influenza-specific CD8+T cells. Longitudinal assessments were also measured in a subset of MS patients subsequently treated with anti-CD20 monoclonal antibody therapy. The proportion of memory and CD20+CD8+T cells specific for certain myelin but not influenza epitopes was significantly reduced following anti-CD20 treatment. This study, representing a characterization of unmanipulated myelin-reactive CD8+T cells in MS, indicates these cells may be attractive targets in MS therapy.

Sign in / Sign up

Export Citation Format

Share Document