Valerie Corrigall

.  For many years we have investigated inflammation and inflammatory systems in rheumatoid arthritis (RA) focussed on the role of the T cell and fibroblast-like synoviocyte (FLS).  This laboratory was the first to describe the pivotal importance of the T cell in the pathogenesis of RA.  Since then additional projects have highlighted FLS induced anergy in T cells, the association between IL-2 and IL-10 production that correlates with poor recall antigen T cell response in RA and the abnormal expression of early and late activation molecules by synovial fluid T cells indicative of a recirculating population of T cells.

Using proteomics, in a search for the initiating autoantigen in RA, we discovered, isolated and identified a powerful immunomodulatory protein, BiP.  Human in vitro studies have investigated the effect of BiP on the activation of human peripheral blood monocytes and differentiation of dendritic cells (DC) and regulatory T cells (CD4+/CD8+). In parallel, BiP has been shown to have prophylactic and therapeutic action in the murine collagen–induced arthritis (CIA) disease model.  The therapeutic effect of BiP in CIA appears to be long-lived suggesting a re-education of the immune system to produce regulatory cells which have been used to resolve CIA in adoptive transfer experiments.  Thus BiP is the first human protein to be described that will induce functional regulatory cells by intravenous administration and in vitro in human mononuclear cell cultures.

Our present laboratory projects focussed on BiP include the following:

• Search for the cell surface expressed receptor(s) for BiP
• Gene therapy using lentiviral vectors containing the BiP gene in the murine collagen induced arthritis model
• Investigation of the mechanism by which BiP directly affects T cells and DC inducing regulatory T cells and tolerogenic DC respectively.
• Future work will incorporate projects looking at the efficacy of BiP in osteoporosis and transplantation where preliminary in vitro data shows that BiP has therapeutic potential

As a translational project BiP has preliminary approval by the MHRA for a PhaseI/IIa clinical trial.

Complementing the Taams laboratory we have an interest in CD8+ T regulatory cells. Two aspects are currently under investigation: the preferential activation, by BiP, of CD8+CD122+ regulatory cells, described in mice, and an ongoing study of human CD8+CD28- regulatory T cells.  When isolated from RA patients CD8+CD28- T cells are unable to suppress autologous T cell activation. This correlates with altered expression of negative costimulatory molecules. 

• Functional studies aimed at understanding the specific effect BiP has on CD8+ T cells.
• Detect the mechanism by which RA CD8+ regulatory T cells are compromised and which makes them ineffective.

These studies will continue to provide the scientific basis and rationale for novel therapies which counter chronic inflammation in a range of diseases.