Antigen-specific immunotherapy: identification of T cell epitopes in autoimmune hepatitis type 2 and characterisation of bystander suppression mechanisms

Richardson, Naomi ORCID: 0000-0001-9682-9857 (2021). Antigen-specific immunotherapy: identification of T cell epitopes in autoimmune hepatitis type 2 and characterisation of bystander suppression mechanisms. University of Birmingham. Ph.D.

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Abstract

A diverse and effective T cell repertoire is critical for protection against pathogens and prevention of self-reactivity. Central and peripheral tolerance mechanisms delete and actively suppress self-reactive T cells with autoimmune potential. However, these regulatory processes are not perfect, hence, individuals can develop autoimmune, allergic and chronic inflammatory diseases potentiated by poorly regulated effector T cells.

Current treatments for autoimmune diseases are rarely curative and rely heavily on broad-range immunosuppressive drugs. Antigen-specific immunotherapies (ASI) induce protective immunity targeted towards pathogenic T cells and require identification of disease-relevant antigen(s) and a tolerogenic delivery system. In complex, multi-antigen diseases, it may be sufficient to induce tolerance to immunodominant antigen(s) only, due to the process of bystander suppression. We first studied the cellular and molecular mechanisms involved in peptide immunotherapy using transgenic mice with T cell receptor specificity to one of two myelin antigenic peptides. We then expanded upon these findings using wild-type mice to study bystander suppression in the context of a complete T cell repertoire.

Despite the tolerogenic propensity of the liver, autoreactive T cells can orchestrate chronic immune damage and eventual loss of organ function without medical intervention. We targeted Autoimmune Hepatitis Type 2 which has a clearly defined autoantigen, CYP2D6. We characterised two T cell epitopes from CYP2D6. These T cell epitope peptides have the potential to form the basis of a novel peptide-based immunotherapy to treat Autoimmune Hepatitis Type 2.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):