The aim of this programme is to explore whether delivery of autoantigens as short epitopes by injection can induce tolerance and slow disease. We have previously conducted an early phase study in patients with long-standing type 1 diabetes to examine the safety of administration of a peptide from proinsulin, C19-A3. This peptide is naturally processed and presented by HLA-DR4 and in our first-in-human study we showed that when given to patients, C19-A3 induces a transient CD4 T cell IL-10+ response in some (Thrower et al, Clin Exp Immunol, 2009). With our collaborators from Cardiff University we have recently completed a multi-centre Phase Ib study of C19-A3 peptide immunotherapy in new-onset disease, at which stage residual β-cell function remains, and these data are currently being analysed. A recent Translation Award from the Wellcome Trust has enabled us to progress from this prototype drug to a second-stage peptide therapeutic (MultiPepT1De) which has recently started recruitment for a Phase I study. Our programme in peptide immunotherapy development is currently being developed under a licence agreement ( http://www.kcl.ac.uk/lsm/newsevents/newsrecords/2015/jan/Kings-College-London-signs-licence-agreement-with-UCB-in-immunology-and-type-1-diabetes.aspx ).
Characterizing the inflammatory response of autoreactive T cells
Our laboratory has been interested in studying CD4 and CD8 T cells involved in type 1 diabetes pathogenesis for some years. We approached studying these rare cells by identifying naturally processed and presented epitope targets from major diabetes-related autoantigens using a cell/biochemical/chromatographic/mass spectrometric technology (Peakman et al, J Clin Invest 1999; Arif et al, J Clin Invest 2004; Skowera et al, J Clin Invest 2009) and developing sensitive immunoassays (ELISPOT, peptide-HLA multimer in caollaboration with Cardiff University). We have used the peptide epitope panels to examine the quality of the response of autoreactive T cells after encounter with specific autoantigens. Our findings suggest that a pro-inflammatory, IFN-γ/IL-17 pathway drives disease from the CD4 compartment, recruiting autoreactive CD8s that have the capacity to kill β-cells. The processing of targets such as preproinsulin by β-cells is of great interest as it appears to follow non-canonical pathways, and this is a current focus of our work. Likewise we are beginning to explore the autoreactive CD8 T cell response using more sophisticated multi-dimensional flow cytometry to reveal the antigen-driven nature of this response. We are also currently addressing questions about disease initiation by examining virus-specific CD8 T cell responses. Finally, we have uncovered a cell population of interest that is autoreactive and has IL-10 as its signature cytokine, and in collaboration with Tim Tree’s group in the Department, we are characterizing the transcriptome and function of these cells. We continue to exploit new technologies for understanding autoreactivity, including single-cell resolution transcriptomics and T cell receptor analysis as well as using deep sequencing to characterise the global T cell receptor repertoire in different functional compartments. We are increasingly adept at using different patient populations (pre-disease, peri-disease, post-immunotherapy trials) to gain a deeper perspective on the immune correlates of disease and protection in this disease.
All of the above work has been achieved through generous funding from Diabetes UK, Wellcome Trust, Juvenile Diabetes Research Foundation, Diabetes Vaccine Development Centre, EU, NIH and collaboration with Type 1 Diabetes TrialNet. In addition to the collaborations mentioned, we have benefited from close interactions with colleagues at Leiden University Medical Centre, NL; Technische Universität Dresden; Monash University; Turku University.