IL-12-Induced Immune Suppressive Deficit During CD8+ T-Cell Differentiation.

Autoimmune diseases are characterized by regulatory deficit in both the CD4+ and CD8+ T-cell compartments. We have shown that CD8+ T-cells associated with acute relapse of multiple sclerosis are significantly deficient in their immune suppressive ability. We hypothesized that distinct CD8+ cytotoxic T-cell (Tc) lineages, determined by cytokine milieu during naïve T-cell differentiation, may harbor differential ability to suppress effector CD4+ T-cells.

Altered expression of SIRPγ on the T-cells of relapsing remitting multiple sclerosis and type 1 diabetes patients could potentiate effector responses from T-cells.

Factors regulating self-antigen directed immune-responses in autoimmunity are poorly understood. Signal regulatory protein gamma (SIRPγ) is a human T-cell specific protein with genetic variants associated with type 1 diabetes (T1D). SIRPγ's function in the immune system remains unclear.

CD4 T cell-intrinsic role for the T helper 17 signature cytokine IL-17: Effector resistance to immune suppression.

Untoward effector CD4+ T cell responses are kept in check by immune regulatory mechanisms mediated by CD4+ and CD8+ T cells. CD4+ T helper 17 (Th17) cells, characterized by IL-17 production, play important roles in the pathogenesis of autoimmune diseases (such as arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, among others) and in the host response to infection and cancer. Here, we demonstrate that human CD4+ T cells cells exposed to a Th17-differentiating milieu are significantly more resistant to immune suppression by CD8+ T cells compared to control Th0 cells.

Cigarette and Cannabis Smoking Effects on GPR15+ Helper T Cell Levels in Peripheral Blood: Relationships with Epigenetic Biomarkers.

: Smoking causes widespread epigenetic changes that have been linked with an increased risk of smoking-associated diseases and elevated mortality. Of particular interest are changes in the level of T cells expressing G-protein-coupled receptor 15 (GPR15), a chemokine receptor linked with multiple autoimmune diseases, including inflammatory bowel disease, multiple sclerosis and psoriasis. Accordingly, a better understanding of the mechanisms by which smoking influences variation in the GPR15 helper T cell subpopulation is of potential interest.

Autoimmunity-associated intronic SNP (rs2281808) detected by a simple phenotypic assay: Unique case or broader opportunity?

Multiple genome-wide association studies have shown that the single-nucleotide polymorphism (SNP) rs2281808 TT variant, present within the signal regulatory protein gamma (SIRPG) gene, is associated with autoimmune diseases, such as type 1 diabetes. SIRPγ is the only SIRP expressed on T cells. The role of SIRPγ in human T-cells or the effect of the TT variant are poorly understood.

An autoimmune disease risk SNP, rs2281808, in SIRPG is associated with reduced expression of SIRPγ and heightened effector state in human CD8 T-cells.

Multiple GWAS studies have shown that the SNP rs2281808 TT variant, present within the SIRPG gene, is associated with autoimmune diseases, such as type 1 diabetes. However, the role of SIRPγ in human T-cells is not known, neither is the functional significance of TT variant. Here we investigated SIRPG genotypes and their effects on the fate and function of human T-cells.

Suppression of autoimmune demyelinating disease by preferential stimulation of CNS-specific CD8 T cells using Listeria-encoded neuroantigen.

CD8 T-cells predominate in CNS lesions of MS patients and display oligoclonal expansion. However, the role of myelin-specific CD8 T-cells in disease remains unclear, with studies showing protective and pathogenic roles in EAE. We demonstrated a disease-suppressive function for CNS-specific CD8 T-cells in a model where the antigen is exogenously administered in vivo and used for in vitro activation.

Induction of regulatory T-cells from memory T-cells is perturbed during acute exacerbation of multiple sclerosis.

Regulatory T-cells (Tregs) are vital for maintaining immunological self-tolerance, and the transcription factor FOXP3 is considered critical for their development and function. Peripheral Treg induction may significantly contribute to the total Treg pool in healthy adults, and this pathway may be enhanced in thymic-deficient conditions like multiple sclerosis (MS). Here, we evaluated iTreg formation from memory versus naïve CD4(+)CD25(-) T-cell precursors.

CD8(+) T-Cells as Immune Regulators of Multiple Sclerosis.

The vast majority of studies regarding the immune basis of MS (and its animal model, EAE) have largely focused on CD4(+) T-cells as mediators and regulators of disease. Interestingly, CD8(+) T-cells represent the predominant T-cell population in human MS lesions and are oligoclonally expanded at the site of pathology. However, their role in the autoimmune pathologic process has been both understudied and controversial.

Multiparameter Flow Cytometric Assays to Quantify Effector and Regulatory T-Cell Function in Multiple Sclerosis.

The immune system plays a major pathological and regulatory role in multiple sclerosis (MS) and, therefore, is a focus of extensive research. Animal models of MS have been crucial in understanding the pathological processes in MS and developing certain treatments, however, all crucial aspects of the human disease may not be appropriately modeled. With the exception of detecting oligoclonal bands and IgG synthesis in cerebrospinal fluids of MS patients, there has not been major progress in the development of immunologic tests that can be used for diagnosis of MS.

Immune regulation of multiple sclerosis by CD8+ T cells.

The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) with underlying T cell-mediated immunopathology. CD8+ T cells are the predominant T cells in human MS lesions, showing oligoclonal expansion at the site of pathology.

Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Although its etiology remains unknown, pathogenic T cells are thought to underlie MS immune pathology. We recently showed that MS patients harbor CNS-specific CD8+ Tregs that are deficient during disease relapse.

Modulation of immune function occurs within hours of therapy initiation for multiple sclerosis.

Daily administration of FDA-approved glatiramer acetate (GA) has beneficial effects on clinical course of relapsing remitting multiple sclerosis (RRMS). Although mechanisms of GA-action have been widely investigated and partially understood, immediate immune dynamics following GA-therapy are unknown. In the present study, we characterized the immediate effects of GA on phenotype, quantity and function of immune cells in MS patients.

Gilt required for RTL550-CYS-MOG to treat experimental autoimmune encephalomyelitis.

MHC class II-derived recombinant T cell receptor ligands (RTLs) modulate the behavior of pathogenic T cells and can reverse clinical and histological signs of autoimmune disease in experimental autoimmune encephalomyelitis (EAE), experimental autoimmune uveitis (EAU) and collagen-induced arthritis (CIA), and are currently in clinical trials for treatment of multiple sclerosis (MS). To expand the utility of these rationally-designed biologics and explore their mechanism(s) of activity in vivo, we have engineered RTL constructs bearing cysteine-tethered antigenic peptides and demonstrate that the appropriate cysteine-tethered RTLs effectively treat EAE. The data presented here suggests that the mechanism by which antigen-specific tolerance induction by RTLs bearing cysteine-tethered antigenic peptides in vivo involves delivery of RTL/antigen to endosomal compartments for processing and re-presentation by full-length MHC class II, with RTLs bearing cysteine-tethered antigenic peptides requiring gamma-interferon-inducible lysosomal thiol-reductase (GILT) for therapeutic activity.

RTL551 treatment of EAE reduces CD226 and T-bet+ CD4 T cells in periphery and prevents infiltration of T-bet+ IL-17, IFN-γ producing T cells into CNS.

Recombinant T cell receptor ligands (RTLs) that target encephalitogenic T-cells can reverse clinical and histological signs of EAE, and are currently in clinical trials for treatment of multiple sclerosis. To evaluate possible regulatory mechanisms, we tested effects of RTL therapy on expression of pathogenic and effector T-cell maturation markers, CD226, T-bet and CD44, by CD4+ Th1 cells early after treatment of MOG-35-55 peptide-induced EAE in C57BL/6 mice. We showed that 1-5 daily injections of RTL551 (two-domain I-A(b) covalently linked to MOG-35-55 peptide), but not the control RTL550 ("empty" two-domain I-A(b) without a bound peptide) or Vehicle, reduced clinical signs of EAE, prevented trafficking of cells outside the spleen, significantly reduced the frequency of CD226 and T-bet expressing CD4+ T-cells in blood and inhibited expansion of CD44 expressing CD4+ T-cells in blood and spleen.

Characterization of human platelet binding of recombinant T cell receptor ligand.

Background: Recombinant T cell receptor ligands (RTLs) are bio-engineered molecules that may serve as novel therapeutic agents for the treatment of neuroinflammatory conditions such as multiple sclerosis (MS). RTLs contain membrane distal α1 plus β1 domains of class II major histocompatibility complex linked covalently to specific peptides that can be used to regulate T cell responses and inhibit experimental autoimmune encephalomyelitis (EAE). The mechanisms by which RTLs impede local recruitment and retention of inflammatory cells in the CNS, however, are not completely understood.

RTL therapy for multiple sclerosis: a Phase I clinical study.

A human recombinant T cell receptor ligand (RTL1000) consisting of DR2 α1 and β1 domains linked covalently to MOG-35-55 peptide can reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE), and was evaluated for safety in a Phase 1 randomized, placebo-controlled, escalating dose study in 34 subjects with multiple sclerosis (MS). RTL1000 was safe and well tolerated at a dose of ≤60 mg that is well within the effective dose range for EAE and did not cause worsening of MS disease at doses ≤200 mg. RTL1000 represents a novel approach for the treatment of MS that promises potent immunoregulation and CNS repair without global immunosuppression.

Binding of recombinant T cell receptor ligands (RTL) to antigen presenting cells prevents upregulation of CD11b and inhibits T cell activation and transfer of experimental autoimmune encephalomyelitis.

Recombinant T cell ligands (RTLs) ameliorate experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner. We evaluated effects of RTL401 (I-A(s) alpha1beta1+PLP-139-151) on splenocytes from SJL/J mice with EAE to study RTL-T cell tolerance-inducing mechanisms. RTLs bound to B, macrophages and DCs, through RTL-MHC-alpha1beta1 moiety.

Association of TLR4 Asp299Gly and Thr399Ile polymorphisms with Guillain-Barré syndrome in Northern Indian population.

Molecular mimicry between Campylobacter jejuni lipopolysaccharide and host gangliosides induces an immune response leading to axonal damage and Guillain-Barré syndrome (GBS). TLR polymorphisms are associated with many autoimmune diseases. The role of the TLR4 gene in GBS susceptibility largely remains unknown.

Recombinant TCR ligand reverses clinical signs and CNS damage of EAE induced by recombinant human MOG.

Increasing evidence suggests that in addition to T cell-dependent effector mechanisms, autoantibodies are also involved in the pathogenesis of MS, including demyelinating antibodies specific for myelin oligodendrocyte glycoprotein (MOG). Our previous studies have demonstrated that recombinant T cell receptor ligands (RTLs) are very effective for treating T cell-mediated experimental autoimmune encephalomyelitis (EAE). In order to expand the scope of RTL therapy in MS patients, it was of interest to study RTL treatment of EAE involving a demyelinating antibody component.

Cell cycle arrest & apoptosis of epithelial cell line by cytolethal distending toxin positive Campylobacter jejuni.

Background & Objective: Campylobacter jejuni is the leading cause of gastroenteritis worldwide; cytolethal distending toxin (CDT) being an important virulence determinant. As its role in pathogenesis remains unclear, this study aims to investigate cell cycle arrest and apoptosis by CDT (+ve) and CDT (-ve) C. jejuni isolates on HeLa cells.

Cytokine switch and bystander suppression of autoimmune responses to multiple antigens in experimental autoimmune encephalomyelitis by a single recombinant T-cell receptor ligand.

Recombinant T-cell receptor ligands (RTLs) can reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner, and are currently in clinical trials for treatment of subjects with multiple sclerosis (MS). Antigen specificity of RTL raises the question as to whether this treatment would be successful in MS patients where target antigens are unknown. Using spinal cord homogenate or combinations of two different peptides to induce disease, we found that treatment with single RTL could reverse EAE as long as targeted T-cells were present.

Recombinant T cell receptor ligands: immunomodulatory, neuroprotective and neuroregenerative effects suggest application as therapy for multiple sclerosis.

Recombinant T cell receptor (TCR) ligands (RTL) represent the minimal interactive surface with antigen-specific T cell receptors. These novel constructs fold similarly to native four-domain MHC/peptide complexes but deliver suboptimal and qualitatively different signals that cause a 'cytokine switch' to anti-inflammatory factors in targeted encephalitogenic T cells. RTL treatment can reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) and most dramatically can promote myelin and axonal recoveiy in the CNS of mice with chronic disease.

Differences in virulence attributes between cytolethal distending toxin positive and negative Campylobacter jejuni strains.

Campylobacter jejuni is a common gastrointestinal bacterial pathogen. Although cytolethal distending toxin (CDT) is proposed to be an important virulence determinant of this pathogen, how CDT(+) and CDT(-) strains differ in their biological properties remains largely unknown. The virulence properties of CDT(+) and CDT(-) strains were studied on HeLa cells and in the suckling mouse model.

IL-13-mediated gender difference in susceptibility to autoimmune encephalomyelitis.

Females tend to have stronger Th1-mediated immune responses and are more prone to develop autoimmune diseases, including multiple sclerosis. Macrophages are major effector cells capable of mediating or modulating immune responses in experimental autoimmune encephalomyelitis (EAE). IL-13 and estrogen have opposing roles on macrophages (the former enhancing and the latter inhibiting) in terms of MHC class II (MHC II) up-regulation and, thus, these factors might influence susceptibility to EAE differently in females vs males.