Supervisor Database Search
Search for supervisors below. You can filter your search using the options and select
multiple fields by holding CTRL (Cmd on Mac) + clicking multiple options in a list.
Full NameProfessor Derek Doherty
Organisation:Trinity College Dublin
- infectious disease and the immune system
- Geriatric Medicine
- Infectious diseases
- Respiratory Medicine
Our research is focused on the mechanisms by which the immune system can protect against or cause disease in humans and how it can be manipulated for the development of novel therapies. We are particularly interested in populations of innate T lymphocytes, including natural killer T (NKT) cells, gamma/delta (γδ) T cells and mucosa-associated invariant T (MAIT) cells, which appear to be “master regulators” of the immune system, being able to determine the type and strength of an immune response, and which are defective in many infectious and immune-mediated diseases and cancers.
We have demonstrated that human innate T cells can influence the activation and subsequent responses of other immune cells, including natural killer cells, dendritic cells, B cells and conventional T cells and have provided in vitro evidence to support their utility for immunotherapy.
We have published roles for innate T cell populations in immunity against hepatitis B and C viruses, HIV, Candida albicans and in protection against oesophageal and lung cancer, chronic lymphocytic leukaemia, sepsis, coeliac disease, antibody deficiencies and granulomatosus with polyangiitis.
We are currently optimizing a number of therapeutic strategies involving innate T cells for future testing in clinical trials.
Innate T cells play central roles in immunity against infection and tumours and in the prevention of autoimmune and metabolic disease. Therefore, a project could be designed for a clinician PhD in almost any clinical discipline to investigate the roles and treatment potential of innate T cell subset(s) in disease. The following is one such project that would continue our recent research in the area of lung cancer (Dockry et al. Epigenetic induction of CD1d expression primes lung cancer cells for killing by invariant natural killer T cells. Oncoimmunology 7: e1428156, 2018).
Invariant natural killer T (iNKT) cells are depleted from blood and bronchial lavage samples from patients with non-small cell lung cancer (NSCLC). Furthermore, pulmonary CD1d expression, which is required to activate iNKT cells, is reduced in patients with NSCLC and low CD1d expression is associated with poor patient survival. We hypothesized that CD1d expression in NSCLC is epigenetically regulated and can be modulated using epigenetic targeting therapies. Treatment of the CD1d-negative NSCLC cell lines with DNA methyltransferase inhibitors and histone deacetylase inhibitors resulted in a dose-dependent induction of CD1d mRNA and protein expression by a mechanism that directly involved chromatin remodelling. Induction of CD1d expression using therapeutic low doses of these epigenetic targeting drugs made them targets for iNKT cell-mediated cytolytic degranulation. Thus, epigenetic manipulation of CD1d expression may augment the efficacy of iNKT cell-based immunotherapies for NSCLC.
The aims of the present proposed research are (1) to test the effects of these epigenetic targeting drugs on CD1d expression by NSCLC cells taken directly from patients, (2) to generate lines of iNKT cells and to test their ability to kill NSCLC cells, treated as above, (3) to optimise the numbers, functions and lung homing capacities of iNKT cells in patients to promote their antitumour immune responses.