Plasma IL-2 and Symptoms Response after Acute Gluten Exposure in Subjects With Celiac Disease or Nonceliac Gluten Sensitivity.

Introduction: Treated patients with celiac disease (CeD) and nonceliac gluten sensitivity (NCGS) report acute, transient, incompletely understood symptoms after suspected gluten exposure. To determine whether (i) blinded gluten exposure induces symptoms, (ii) subjects accurately identify gluten exposure, and (iii) serum interleukin-2 (IL-2) levels distinguish CeD from NCGS subjects after gluten exposure.

Methods: Sixty subjects (n = 20 treated, healed CeD; n = 20 treated NCGS; n = 20 controls) were block randomized to a single, double-blind sham (rice flour) or 3-g gluten challenge with 72-hours follow-up.

A Sensitive Whole Blood Assay Detects Antigen-Stimulated Cytokine Release From CD4+ T Cells and Facilitates Immunomonitoring in a Phase 2 Clinical Trial of Nexvax2 in Coeliac Disease.

Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial ("RESET CeD") of Nexvax2, a peptide-based immunotherapy for CD.

Cytokine release after gluten ingestion differentiates coeliac disease from self-reported gluten sensitivity.

Background: Diagnosing coeliac disease (CD) in patients on a gluten-free diet (GFD) is difficult. Ingesting gluten elevates circulating interleukin (IL)-2, IL-8 and IL-10 in CD patients on a GFD.

Objective: We tested whether cytokine release after gluten ingestion differentiates patients with CD from those with self-reported gluten sensitivity (SR-GS).

Elevated serum interleukin-2 after gluten correlates with symptoms and is a potential diagnostic biomarker for coeliac disease.

Background: Coeliac disease patients on a gluten-free diet experience reactions to gluten, but these are not well characterised or understood. Systemic cytokine release was recently linked to reactivation of gluten immunity in coeliac disease.

Aim: To define the nature and time-course of symptoms and interleukin-2 changes specific for coeliac disease patients.

Cytokine release and gastrointestinal symptoms after gluten challenge in celiac disease.

Celiac disease (CeD), caused by immune reactions to cereal gluten, is treated with gluten -elimination diets. Within hours of gluten exposure, either perorally or extraorally by intradermal injection, treated patients experience gastrointestinal symptoms. To test whether gluten exposure leads to systemic cytokine production time -related to symptoms, series of multiplex cytokine measurements were obtained in CeD patients after gluten challenge.

Epitope-Specific Immunotherapy Targeting CD4-Positive T Cells in Celiac Disease: Safety, Pharmacokinetics, and Effects on Intestinal Histology and Plasma Cytokines with Escalating Dose Regimens of Nexvax2 in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study.

Background: Nexvax2® is a novel, peptide-based, epitope-specific immunotherapy intended to be administered by regular injections at dose levels that increase the threshold for clinical reactivity to natural exposure to gluten and ultimately restore tolerance to gluten in patients with celiac disease. Celiac disease patients administered fixed intradermal doses of Nexvax2 become unresponsive to the HLA-DQ2·5-restricted gluten epitopes in Nexvax2, but gastrointestinal symptoms and cytokine release mimicking gluten exposure, that accompany the first dose, limit the maximum tolerated dose to 150μg. Our aim was to test whether stepwise dose escalation attenuated the first dose effect of Nexvax2 in celiac disease patients.

Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies.

Background: A gluten-free diet is the only means to manage coeliac disease, a permanent immune intolerance to gluten. We developed a therapeutic vaccine, Nexvax2, designed to treat coeliac disease. Nexvax2 is an adjuvant-free mix of three peptides that include immunodominant epitopes for gluten-specific CD4-positive T cells.

Immunosuppressive activity of a novel peptide analog of α-melanocyte stimulating hormone (α-MSH) in experimental autoimmune uveitis.

Autoimmune uveitis is an inflammatory disorder of the eye that can lead to pain and vision loss. Steroids and immunosuppressive drugs are currently the only therapeutics for uveitis and have serious ocular and systemic toxicities. Therefore, safer alternative therapeutics are desired.

A retro-inverso α-melanocyte stimulating hormone analog with MC1R-binding selectivity.

α-melanocyte stimulating hormone (α-MSH) is a tridecapeptide fragment of pro-opiomelanocortin (POMC) with broad effects on appetite, skin pigmentation, hormonal regulation, and potential roles in both inflammation and autoimmunity. The use of this peptide as an anti-inflammatory agent is limited by its low selectivity between the melanocortin receptors, susceptibility to proteolytic degradation, and rapid clearance from circulation. A retro-inverso (RI) sequence of α-MSH was characterized for receptor activity and resistance to protease.

Polyclonal rabbit antithymocyte globulin exhibits consistent immunosuppressive capabilities beyond cell depletion.

Background: Polyclonal antithymocyte globulins (ATGs) are used clinically to prevent and treat acute allograft rejection and are believed to modulate the immune response primarily by depleting T cells. However, nondepleting mechanisms may also be important mediators of graft survival. In the present study, 14 lots of thymoglobulin (rabbit ATG) were analyzed and compared for nondepletive immunomodulatory activities in vitro.

Characterization of in vitro antimurine thymocyte globulin-induced regulatory T cells that inhibit graft-versus-host disease in vivo.

Antithymocyte/antilymphocyte globulins are polyclonal antihuman T-cell antibodies used clinically to treat acute transplant rejection. These reagents deplete T cells, but a rabbit antihuman thymocyte globulin has also been shown to induce regulatory T cells in vitro. To examine whether antithymocyte globulin-induced regulatory cells might be functional in vivo, we generated a corresponding rabbit antimurine thymocyte globulin (mATG) and tested its ability to induce regulatory cells in vitro and whether those cells can inhibit acute graft-versus-host disease (GVHD) in vivo upon adoptive transfer.

Class I molecules with similar peptide-binding specificities are the result of both common ancestry and convergent evolution.

HLA class I molecules can be classified into supertypes associated with overlapping peptide-binding motifs and repertoires. Herein, overlaps in peptide-binding and T-cell recognition repertoires were demonstrated between mouse and human molecules. Since rodent and primate lineages separated before the current allelic variation of mouse and human class I molecules, these data demonstrate that supertypic specificities originated by convergent evolution.

Multiple Chlamydia pneumoniae antigens prime CD8+ Tc1 responses that inhibit intracellular growth of this vacuolar pathogen.

CD8(+) T cells play an essential role in immunity to Chlamydia pneumoniae (Cpn). However, the target Ags recognized by Cpn-specific CD8(+) T cells have not been identified, and the mechanisms by which this T cell subset contributes to protection remain unknown. In this work we demonstrate that Cpn infection primes a pathogen-specific CD8(+) T cell response in mice.

Characterization of the peptide-binding specificity of Mamu-B*17 and identification of Mamu-B*17-restricted epitopes derived from simian immunodeficiency virus proteins.

The SIV-infected rhesus macaque is an excellent model to examine candidate AIDS virus vaccines. These vaccines should elicit strong CD8(+) responses. Previous definition of the peptide-binding motif and optimal peptides for Mamu-A*01 has created a demand for Mamu-A*01-positive animals.