Tumour necrosis factor (TNF) ligand-receptor family members are important regulators of the immune system and are intimately connected with the development of diseases such as cancer and autoimmune diseases. Our group is working for about 10 years on members of the TNF Family and their implication in tumorigenesis. Since the integration of Professors Combe and Morel from the department of Immuno-Rheumatology of the University Hospital (CHU) of Montpellier in our group our research is also focusing on rheumatoid disease. At present we have two main lines of research by studying the role of the TNF ligands APRIL and TRAIL in tumour formation and autoimmune diseases.
The TNF-like ligand APRIL (A PRoliferation-Inducing Ligand) and the first evidence of its tumor-supporting role have been first described by Hahne et al. in 1998. We have previously reported that old APRIL transgenic mice develop lymphoid tumors that originate from an expansion of the peritoneal B-1 cell population. These tumors are highly reminiscent of human B cell chronic lymphoid leukemia (CLL) and in a retrospective study we could demonstrate that APRIL serum levels are elevated in the majority of CLL patients and correlate with the progression of disease and prognosis of patients. It is established by now that APRIL is involved in tumor formation and/or maintenance of certain cancers, notably in colon carcinoma. Moreover, reports are accumulating that APRIL can also act as a pro-inflammatory cytokine and that inflammatory cells as well as intestinal epithelial cells that have been exposed to bacterial antigens can produce APRIL. As APRIL appears to act as both, a tumor supporter, as well as a proinflammatory cytokine we are presently analyzing its contribution to inflammation-associated colon carcinoma formation in established mouse models and human tumor tissues. Evidence is accumulating that APRIL is also a player in several autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis and Sjoegren’s syndrome. We are presently characterizing the implication of APRIL in these autoimmune diseases by comparing APRIL levels in sera and tissues of patients and controls and by employing established mouse models for the respective autoimmune disease.
A hallmark of RA is the pseudo-tumoral expansion of fibroblast-like synoviocytes (FLS), as these cells invade and finally destroy the joint structure. The TNF-related apoptosis-inducing ligand (TRAIL) has gained much attention as a possible therapeutic reagent for the treatment of tumors, as TRAIL was originally described to induce apoptosis specifically in cancer cells but not in normal cells. As RA FLS exhibit tumor like features, led us to investigate the effect of TRAIL on ex-vivo RA FLS. We have previously described that TRAIL induces apoptosis only in a subset of RA FLS, but an induction of proliferation in the surviving cells. The pseudo-tumoral expansion of RA FLS can be easily mimicked in vitro and we will therefore take advantage of this cellular model to analyze the pleiotropic effects triggered by TRAIL using biochemical approaches as well as micorarray experimentation. By identifying TRAIL-induced signaling pathways it will be possible to propose molecular targets that, upon blocking, shift TRAIL-induced signaling from proliferation towards apoptosis. Combinatorial TRAIL treatments are first tested in vitro and subsequently evaluated in vivo in human synovium-mouse chimeras.