Prof Mark Exley

Mark Exley – Research summary

Mark Exley

Mark Exley

We functionally defined 2 distinct human ‘NKT’ cell populations (bearing both NK cell and T cell characteristics) from blood and tissues. NKT produce high levels of various immune controlling factors as well as being able to kill cells expressing their target molecule. NKT have physiological roles in anti-tumour and anti-pathogen responses and can positively or negatively regulate immunity via NK and other cells. In mice, we found that interactions between NKT and their target cells augment anti-viral and anti-tumour immunity, promising for therapy both directly and with various vaccines. NKT from tumour-bearing mice had reversible defects, similar to those we first identified of cancer patients.

In humans, NKT cells also appear to contribute to protective responses against cancers and infections. Reversible defects of NKT from cancer and hepatitis patients have led to promising translational observations. Cancer patient survival is associated with NKT cell activity. Our NKT cell monoclonal antibody has begun both cell therapy and direct use clinical trials, as well as being widely used in research. A clinical trial for melanoma using the antibody to expand NKT in the Lab. before infusion has completed, producing only minimal toxicity. NKT activity assayed in the Lab. was restored, suggesting potential for improved anti-tumour activity, and systemic immune cell activation was seen. Half of these highly-selected patients remained with no evidence of disease long-term, half had (mostly slow) treatment-responsive progression.

Finally, we are monitoring contrasting NKT populations in adipose and liver, where they can respectively suppress or contribute to inflammation (including Type 2 Diabetes) and eventual fibrosis. NKT cells represent a unique potentially therapeutic population.

The Exley lab is a member of the Manchester Immunology Group and the Manchester Collaborative Centre for Inflammation Research.

Email: mark.exley@manchester.ac.uk Tel: 0161 306 6052

Publications

  • Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, Balk SP, O'Shea D, O'Farrelly C, Exley MA. (2012). Unique Adipose Tissue Invariant Natural Killer T Cells Protect Against Diet-Induced Obesity and Metabolic Disorder Through Regulatory Cytokine Production. Immunity. 37:574-87.
  • Li S, Vriend LE, Nasser IA, Popov Y, Afdhal NH, Koziel MJ, Schuppan D, Exley MA, Alatrakchi N (2012). Hepatitis C virus-specific T cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis. Hepatology. 56(6):2094-105.
  • Rout N, Greene J, Yue S, O’Connor D, Johnson RP, Else, JG, Exley MA, Kaur A. (2012) Loss of Effector and Anti-Inflammatory Natural Killer T Lymphocyte Function in Pathogenic Simian Immunodeficiency Virus Infection. PLoS Pathog 8(9): e1002928.
  • Exley MA, Lynch, L, Varghese B, Nowak M, Alatrakchi N, Balk S. (2011) Developing Understanding of the Roles of CD1d-restricted T cell Subsets in Cancer: Reversing Tumor-induced Defects. Clin. Immunol. Special Edition. Review. 140:184-95.
  • Exley MA, SB Wilson, SP Balk (New edition 2010). Chap: Isolation and functional use of human NKT cells. Current Protocols Immunol. Wiley & Sons. Eds. J. Coligan, et al. Unit 14.11.
  • Yue SC, Shaulov A, Wang R, Balk SP, Exley MA (2005). CD1d ligation on human monocytes directly signals rapid NF-kappaB activation and production of bioactive IL-12. Proc Natl Acad Sci U S A. 102(33):11811-6.