Autoreactive CD4+ and CD8+ T cells play a critical role in the pathophysiology of autoimmune diseases such as Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA) by sustaining a chronic inflammatory process that takes place in the central nervous system and in the joints, respectively.
Bacterial infections provoked by Staphylococcus aureus have been brought up as critical environmental factors that may trigger and/or exacerbate MS and RA. Interestingly, this pathogen shares the ability to produce or induce the production of toxin superantigens (SAgs), which can trigger an inflammatory cytokine storm thanks to their unique ability to bind MHC class II molecules on antigen presenting cells and specific elements within the variable domain of the T-cell receptor (TCR) ß-chain (Vß) on T cells, thus inducing the polyclonal activation of T cells. Therefore, S. aureus SAgs can play a dual role in the pathogenesis of autoimmune diseases either by initiating the autoimmune process or by inducing a relapse in patients in clinical remission phases.
CD28 is a critical costimulatory receptor that ensures a full T cell activation and an optimal response to microbes. Recent studies, have identified CD28 as an additional SAg ligand able to elicit an inflammatory cytokine storm. Importantly, short mimetic peptides targeting the CD28 homodimer interface and inhibiting the CD28/B7 interaction, were effective in dampening inflammatory cytokine production induced by S aureus SAgs without affecting the immune response to pathogens. Therefore, selective targeting of the CD28/B7 costimulatory axis through mimetic peptides may provide a novel strategy for preventing the activation of inflammatory T cells mediated by SAg in MS and RA.
The aim of this project will be to analyse the contribution of CD28 and SAgs in regulating the expansion of specific T cells in MS and RA patients and to assess the inhibitory effects of CD28 homodimer interface mimetic peptides.
Several studies evidenced microbial infections as critical environmental factors that may trigger and/or exacerbate several autoimmune diseases, including MS and RA. Therefore, a better characterization of the molecules and mechanisms regulating SAg-mediated inflammatory responses in MS and RA patients may help in clarifying the contribution of microbial infections to MS and RA and may help to develop new therapeutic strategies for preventing relapses. The major goal of this project is to provide biological bases for immunotherapeutic approaches targeting CD28 to dampen microbial SAg-inflammatory response in MS and RA. The role of CD28 in the regulation of T cell activation has been evidenced in several autoimmune diseases. However, the biological functions of CD28 in MS and RA remain still unknown. The data obtained from our analyses on CD28 functions in amplifying pro-inflammatory cytokine production in peripheral T lymphocytes from stable RRMS as well as recent data identifying CD28 as a target of microbial SAgs strongly support that abnormalities resulting in hyperactivity of the CD28 costimulatory axis may lead to the development and/or exacerbation of autoimmunity. The experiments presented in this project will highlight this issue, thus contributing to a better insight into the pathophysiological contribution of microbial SAgs and CD28 in triggering and/or exacerbating MS and RA.
The present project predicts that intercellular CD28/B7 engagement could contribute in exacerbating microbial SAg-induced inflammatory response in MS and RA by favouring the expansion and pro-inflammatory functions of pathogenic T cell subsets. Moreover, this project will provide the ex vivo data required for the potential use of CD28 dimer interface mimetic peptides for further translation to clinical research in MS and RA. For instance, CD28 dimer interface mimetic peptides completed phase 2 (ClinicalTrials.gov Identifier: NCT01417780) and phase 3 clinical trials (ClinicalTrials.gov Identifier: NCT02469857) of patients with necrotizing soft-tissue infections.