Where, when and what do tolerogenic dendritic cells do to T cells?

Dahlstrom, Jennifer Elizabeth (2021) Where, when and what do tolerogenic dendritic cells do to T cells? PhD thesis, University of Glasgow.

Abstract

Rheumatoid arthritis (RA) is the most common autoimmune disease which affects up to 1% of the population. During RA there is a systemic loss of immunological tolerance which results in inflammation in the joints. This leads to progressive and irreversible cartilage and bone erosion. The current treatments for RA involve broad immunosuppression which leave patients at risk of developing infections and cancer. There is a need for more targeted treatments which suppress the pathological immune response while leaving protective immunity intact. Tolerogenic dendritic cells (tol-DCs) have gained interest in recent years as a potential treatment of autoimmunity as they allow a targeted antigen (Ag) specific suppression of the immune response. Tol-DCs have been investigated in multiple clinical trials for the treatment of RA, multiple sclerosis, diabetes type 1, Crohn’s disease and transplantation. Tol-DCs are thought to mainly mediate their effects through CD4+ T cells.

The main barriers in advancing this treatment are; tol-DCs exact mechanisms of action on CD4+ T cells still needs to be elucidated, quality control (QC) markers which inform tol-DCs potency as a treatment need to be identified, as well as biomarkers of successful tol-DC therapy in CD4+ T cells which would confirm tolDC therapy had been successful and the injection route which maximises this treatment is unknown. Intradermal, intravenous, intra-articular, intraperitoneal and intranodal injection routes of tol-DCs have been tested in clinical trials. Subcutaneous injection of tol-DCs has not been tested in human clinical trials. It is thought tol-DCs need to migrate to the draining LN (dLN) to induce tolerance. Choosing an injection route which maximises migration to the dLN could therefore enhance the effects of tol-DC treatment.

In this thesis, I investigated potential mechanisms of action of tol-DCs, QC markers of tol-DCs and markers of tolerogenicity in CD4+ T cells in human Dexamethasone + Vitamin D3 tol-DCs. In a murine study, Dex+VitD3 tol-DCs were shown to migrate to the dLN after subcutaneous footpad injection. This tol-DC type’s ability to modulate Ag-specific CD4+ T cell activation in vivo was measured and finally subcutaneous footpad injection of tol-DCs was tested in an acute model of inflammatory arthritis. This work will help inform and improve future clinical trials with tol-DCs.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from Versus Arthritis.
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Brewer, Prof. James
• Date of Award: 2021
• Depositing User: Theses Team
• Unique ID: glathesis:2021-82733
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 07 Mar 2022 14:28
• Last Modified: 08 Apr 2022 16:46
• Thesis DOI: 10.5525/gla.thesis.82733
• URI: https://theses.gla.ac.uk/id/eprint/82733