Background:Recent studies suggest dysregulation in T cell activation in systemic sclerosis (SSc). Co-inhibitory-receptors (Co-IRs) such as TIM-3, PD-1 and LAG-3 play a crucial role in controlling excessive T cell activation and in maintaining immune homeostasis. Engagement of these receptors by their ligand’s limits cytokine production in response to TCR or activating NK receptor stimulation and hence limit tissue damage from excessive immune activation. However, chronically increased expression of multiple Co-IRs is a hallmark of immune exhaustion. We evaluate the role of these soluble Co-IRs in diffuse SSc (dcSSc).Objectives:Establish the role of CiR and their ligands in diffuse systemic sclerosis.Understand how immune regulatory mechanisms influence the development of fibrosis.Provide a better understanding of the disease and fibrosis in general.Methods:PBMC’s(Peripheral blood mononuclear cells) and dermal fibroblasts from SSc patients were isolated and investigated for markers of T cell inhibition. These cells were analysed using flow cytometry in a 10 colour panel. Cells were stained for PD1, TIM3, TIGIT, LAG3, CD3, CD8, CD4 and CD19 along with a Live/dead marker. Co-cultures of fibroblasts and PBMCs will be setup, and treated with various drugs that act on the Co-IRs.Results:The proportion of CD4+ T cells expressing PD1 were markedly increased in SSc patients compared to healthy volunteers and Rheumatoid Arthritis patients.There was increased expression of both TIGIT and TIM3 in the CD4+ T cells. (Figure 1)Similarly, the co-expression of these receptors on the CD4+ T cell population was elevated compared to healthy volunteers. (figure 2)Conclusion:Soluble co-inhibitors are differentially expressed in early dcSSc compared to healthy volunteers and other autoimmune diseases. Our preliminary data indicates that these co inhibitors could play an important role in unravelling the pathogenesis of systemic sclerosis. Inhibition or activation of these receptors through different treatment modalities can be utilized as a novel patient centric treatment strategy.References:[1]Fukasawa, T., Yoshizaki, A., Ebata, S., Nakamura, K., Saigusa, R., Miura, S., … Sato, S. (2017). Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis.Arthritis & Rheumatology,69(9), 1879–1890.[2]Greisen S, Rasmussen T, Stengaard-Pedersen K, Hetland M, Hørslev-Petersen K, Hvid M, et al. Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis. Scand J Rheumatol 2014; 43:101-8.[3]de Paoli, F., Nielsen, B., Rasmussen, F., Deleuran, B., & Søndergaard, K. (2014). Abatacept induces clinical improvement in patients with severe systemic sclerosis.Scandinavian Journal of Rheumatology,43(4), 342–345.[4]Kwon, B. (2010). Intervention with costimulatory pathways as a therapeutic approach for graft-versus-host disease.Experimental and Molecular Medicine. Nature Publishing Group.Acknowledgments:FOREUM: Foundation of Research in RheumatologyDisclosure of Interests:None declared
Blockade of Programmed Death-1 Ligands on Dendritic Cells Enhances T Cell Activation and Cytokine Production
