Immune checkpoint molecules: signifance in rheumatoid arthritis and iatrogenic inflammatory arthritis

The aim of the project is to study the role of immune checkpoint (ICP) molecules on T cells and their receptors on joint fibroblast-like synoviocytes (FLS) in the pathogenesis and prediction to therapy in early rheumatoid arthritis (RA), and in inflammatory arthritis disease that appears as adverse event to treatment of cancer with ICP inhibitors, including anti-PD1/PD-L1.

My group has a track record of translational research in RA, and has built up infrastructure for research in rheumatologic adverse events to ICP inhibitors in recent years.

We will use data from a clinical trial in early RA, from a prospective study of inflammatory adverse events after ICPi, as well as cells from joints.The project specifically aims to test the following hypotheses: 1)  Baseline proportions of PD1-expressing CD4 T cells or levels of soluble ICP molecules in blood predict sustained treatment response at 24 and 48 weeks in untreated early RA.2) Increased levels of soluble PD1 or soluble PD-L1 in early RA block PD1-receptors and cause uncontrolled PD-1 expressing T cells in the joint.

Alternatively, FLS from RA express for PD-1 receptors at lower levels than FLS from non-inflammatory controls.3) Specific T cell subsets and chemokine levels in blood predict who will develop inflammatory arthritis after ICPi treatment or are markers for such arthritis. 4) The chronicity of ICPi-induced inflammatory arthritis can be explained by transformation of FLS to a pathogenic phenotype like in RA.