Antigen-based immunotherapy (AIT) for autoimmune and allergic disease

MacLeod, Megan K. L.; Anderton, Stephen M.

doi:10.1016/j.coph.2015.05.003

Cited by 22 publications

(28 citation statements)

References 39 publications

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“…15 For these reasons, CeD is exceptionally well positioned for the development and testing of epitope-specific immunotherapy, complimenting the limited clinical experience of this novel class of antigen-specific immunotherapy in allergy and autoimmunity, and translating insights from preclinical models. 25 …”

Section: Discussionmentioning

confidence: 99%

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

Goel

King

Daveson

et al. 2017

The Lancet Gastroenterology & Hepatology

125

117

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SUMMARY Background Gluten-free diet (GFD) is the only management available for celiac disease (CeD), a permanent immune intolerance to gluten. Nexvax2® is the first therapeutic vaccine designed to treat CeD. The adjuvant-free formulation of peptides is intended to engage and render gluten-specific CD4+ T cells unresponsive to further antigenic stimulation. We have assessed safety and pharmacodynamics of Nexvax2® in patients with CeD on GFD. Methods In two randomized, double-blind, placebo-controlled, phase 1 studies at 12 community sites in Australia, New Zealand and the United States, we screened for HLA-DQ2·5+ CeD patients (aged 18–70 years) on GFD. The screening and post-treatment periods included either a crossover, placebo-controlled, oral gluten challenge (OGC) to mobilize and assess T cells responsive to Nexvax2 or, for the final cohort in each study, endoscopy and duodenal histology without OGC. Participants and study staff were masked to the gluten content of food provided for each interval of the OGCs. One of two sequences of active and placebo challenges was assigned (1:1) by central randomization using a simple block method. The sequence of challenges was active/placebo then active/placebo, or placebo/active then active/placebo for the OGCs in the screening and post-treatment periods, respectively. Participants with a negative interferon (IFN)-γ release assay (IGRA) to Nexvax2 peptides after the screening OGC, or Marsh score >1 were discontinued before dosing. There was temporal allocation of participants to sequential cohorts assessing multiple fixed intradermal doses of Nexvax2 (60µg, 90µg, or 150µg weekly in the 3-dose study; or 150µg, or 300µg two-times weekly in the 16-dose study) in 0.1 mL 0.9% sodium chloride. A maximum tolerated dose (MTD) was administered in the final biopsy cohort in each study. Participants within each cohort were assigned to receive Nexvax2 or placebo by central randomization (2:1, respectively) using simple block method in SAS software Version 9·2. Participants, investigators, and study staff were masked to the treatment assignment, except for the study pharmacist. The primary endpoint was the number and percentage of adverse events in the treatment period. Other safety outcomes included duodenal histology, gastrointestinal symptoms, plasma cytokines, and immune cell frequencies. The main pharmacodynamic endpoint was IGRA to Nexvax2 peptides. All participants who received Nexvax2 or placebo, the safety population, were included in an intention to treat analysis for the primary endpoint. Additional post hoc analyses were also performed. Both trials were completed and closed before data analysis. Trials were registered with Australian New Zealand Clinical Trials Registry, numbers ACTRN12612000355875 and ACTRN12613001331729. Findings Participants were screened from November 28, 2012 to August 14, 2014, and August 3, 2012 to September 10, 2013, for the 3-dose and 16-dose studies respectively. Across both studies, 136 (80%) of 169 volunteers met initial eligibility crite...

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Section: Discussionmentioning

confidence: 99%

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

Goel

King

Daveson

et al. 2017

The Lancet Gastroenterology & Hepatology

125

117

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“…While much is known about tolerizing naïve CD4 T cells, memory CD4 T cells present more of a challenge ( 132 ). Classically, tolerance in naïve CD4 T cells involves presentation of antigen in the absence of accompanying costimulatory signals ( 133 ).…”

Section: Why We Might Need To Restrain or Retrain Memory Cellsmentioning

confidence: 99%

Development and Function of Protective and Pathologic Memory CD4 T Cells

Jaigirdar

MacLeod

2015

Front. Immunol.

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Immunological memory is one of the defining features of the adaptive immune system. As key orchestrators and mediators of immunity, CD4 T cells are central to the vast majority of adaptive immune responses. Generated following an immune response, memory CD4 T cells retain pertinent information about their activation environment enabling them to make rapid effector responses upon reactivation. These responses can either benefit the host by hastening the control of pathogens or cause damaging immunopathology. Here, we will discuss the diversity of the memory CD4 T cell pool, the signals that influence the transition of activated T cells into that pool, and highlight how activation requirements differ between naïve and memory CD4 T cells. A greater understanding of these factors has the potential to aid the design of more effective vaccines and to improve regulation of pathologic CD4 T cells, such as in the context of autoimmunity and allergy.

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“…Memory CD4 T cells can respond more quickly to a secondary challenge because, in part, they are less reliant on heightened level of costimulatory signals (Holzer et al, 2003, London et al, 2000, MacLeod et al, 2006. While this contributes to rapid pathogen control, this presents significant hurdles for treatments that aim to induce antigen-specific tolerance in autoimmunity, allergy or transplantation (Hartigan et al, 2019, MacLeod andAnderton, 2015).…”

Section: Introductionmentioning

confidence: 99%

Tolerance induction in memory CD4 T cells is partial and reversible

Gray

Al‐Khabouri

Morton

et al. 2020

Preprint

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19Memory T cells respond rapidly in part because they are less reliant on heightened levels of 20 costimulatory molecules. This presents challenges to silencing memory T cells in tolerance 21 strategies for autoimmunity or allergy. We find that memory CD4 T cells generated by infection 22 or immunisation survive secondary activation with antigen delivered without adjuvant, 23 regardless of their location in secondary lymphoid organs or peripheral tissues. These cells 24 were, however, functionally altered following a tertiary immunisation with antigen and 25 adjuvant, proliferating poorly but maintaining their ability to produce inflammatory cytokines.

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Antigen-based immunotherapy (AIT) for autoimmune and allergic disease

Cited by 22 publications

References 39 publications

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

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

Development and Function of Protective and Pathologic Memory CD4 T Cells

Tolerance induction in memory CD4 T cells is partial and reversible

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