Pathogenic and protective functions of TNF, produced by T lymphocytes, in autoimmune diseases

• Applicant: Professor Dr. Sergei A. Nedospasov
• Subject Area: Immunology
• Term: from 2011 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 194474834

Tumor necrosis factor (TNF, TNF-a) is a potent immunomodulatory and pro-inflammatory cytokine produced by many types of immunocytes and targeting a wide spectrum of cells and tissues. Its local or systemic overproduction may lead to disease development, such as polyarthritis in TNF overexpressing transgenic mice. Not surprisingly, genetic or pharmacological TNF ablation may ameliorate several autoimmune diseases in mice and anti-TNF therapy is efficient in at least some rheumatoid arthritis (RA) patients. During the first phase of this project completed in 2014 we have documented the contrasting and opposite contributions of TNF produced by myeloid cells and T cells in disease development. Remarkably, TNF produced by T cells in its transmembrane form provides protection in experimental arthritis through distinct immune modulatory mechanism that needs to be further explored. Our findings suggest that optimal TNF blockers should neutralize TNF produced by myeloid cells, and not neutralize TNF produced by T cells. We have recently developed the first prototype of a novel TNF blocker, based on bi-specific antibodies that according to our in vitro data should prevent systemic dissemination of TNF produced by macrophages - the main source of pathogenic TNF in several disease models, including CIA. We are also proposing to dissect the molecular mechanisms of TNF pathogenicity in diseases, such as antibody-mediated experimental arthritis and colitis, with special focus on the function of TNF-TNFR2 axis in immune regulation.

• DFG Programme: Research Grants