George Kollias Research Group

The Kollias lab focuses on understanding the molecular and cellular mechanisms orchestrating complex phenotypes in chronic inflammation, immunity and cancer. The lab has pioneered genetic approaches in mice to model human diseases and has a long-standing expertise in gene targeting and transgenic technologies, cellular and molecular biology and immunology. It is internationally credited for providing fundamental in vivo tools and knowledge of the biological mechanisms underlying the development of chronic inflammation and autoimmunity and, even more notably, for the imminent and successful translation of these findings into innovative treatments.

Major achievements

In 1991, the lab was the first to provide in vivo, proof-of-principle studies confirming that deregulated TNF production is causal to the development of chronic polyarthritis in a transgenic animal model, and the original finding that anti-TNF antibody treatment is efficacious for treating the modeled disease (Keffer et al., EMBO 1991). These studies were instrumental in mobilizing the interest of the anti-TNF industry and drove the development of the first successful clinical trials performed initially in RA (1994), followed by other diseases such as Crohn’s disease, psoriasis, psoriatic arthritis, juvenile idiopathic arthritis, spondylarthritis and Behçet's disease, which collectively affect 2-3% of the population.

Further work performed in the Kollias lab provided the first description of physiological functions of TNF in host defense and the structure and function of secondary lymphoid organs (Pasparakis et al., JEM 1996), which was later expanded to confirm that establishment of TNFRI and NF-κB signals specifically in follicular dendritic cells (FDCs) and is of pivotal significance in the regulation of humoral B cell responses and autoimmunity (Victoratos et al., Immunity 2006; Immunity 2009). Importantly, pharmacological interference in the maintenance of FDCs ameliorated disease development, suggesting the FDCs as a potential target for dampening autoimmunity. These studies offered a deeper understanding of the associated side-effects of anti-TNF therapy, such as patient susceptibility to infection, and introduced new concepts for treatment of autoimmune disorders, for example by suppressing autoantibody production mechanisms.

Kollias and colleagues also provided further mechanistic insights into the differential functions of transmembrane and soluble TNF in pathophysiology. By blocking the shedding of endogenous murine TNF through deletion of its cleavage site, they demonstrated for the first time that transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity (Alexopoulou et al., Eur. J. Immunol. 2006). These data supported the hypothesis that selective targeting of soluble TNF may offer several advantages over complete blockade of TNF in the treatment of chronic inflammation and autoimmunity, thus rationalizing potential complications or optimizations of anti-TNF therapies in TNF-driven diseases.

Moreover, the lab provided the first mechanistic evidence of the multi-layered roles of TNF and its receptors, and were the first to hypothesize that anti-TNFRI therapies will be advantageous and safer than current anti-TNF treatments, particularly for organ-specific autoimmune diseases such as multiple sclerosis (Kassiotis et al., JEM 2001). Using knock-in mice expressing a mutated non-sheddable TNF receptor I, they subsequently showed that TNF receptor shedding controls thresholds of innate immune activation, which balance opposing TNF functions in infectious and inflammatory diseases (Xanthoulea et al., JEM 2004).

The group provided the first genetic evidence of the physiology and post-transcriptional role of AU-rich elements (AREs) in the regulation of TNF expression, and introduced new animal models that develop combined joint and gut pathologies (Kontoyiannis et al., Immunity 1999; EMBO 2001; JEM 2002). Based on these models, the Kollias lab introduced a novel pathogenic principle to explain the cellular basis of TNF function in gut/joint axis diseases by showing that the mesenchymal cell compartment, namely synovial fibroblasts and intestinal subepithelial myofibroblasts, are common pathogenic targets of TNF, sufficient to drive the chronic inflammatory pathologies. These studies offered a novel mechanistic perspective for TNF function in gut and joint pathologies, established the sufficiency of synovial and intestinal subepithelial fibroblasts in mediating TNF signals and driving the complete arthritic and intestinal pathologies, and indicated early common cellular pathways that explain the often observed synovial–gut axis diseases in humans (Armaka et al., JEM 2008). These findings not only provided a more complete understanding of the cellular function of TNF, but also introduced new therapeutic innovations, such as mesenchymal stem cell transplantation in combination with impaired TNF receptor function in these cells, which could also lead to a new generation of more effective disease treatments for chronic inflammatory bowel disease.

In extent of these studies, the lab has explored the role of intestinal epithelial cells (IEC) as a potential source of TNF in a mouse model of IBD and showed that TNF overexpression specifically by IEC leads to early activation of the underlying mesenchymal cells and is sufficient for complete induction of Crohn's-like pathology in the mouse. These findings provided insight into the mechanisms of Crohn's disease pathogenesis by showing that IEC are potential TNF producers and that IEC and mesenchymal cells can form a cellular axis of TNF function in the gut sufficient to cause the full spectrum of pathology seen in relevant human diseases, including spondyloarthropathies (Roulis et al., PNAS 2011). Furthermore, the lab has recently demonstrated that intestinal myofibroblast (IMF)-specific signals play an important physiological role in colitis-associated cancer and more generally in intestinal tumorigenesis, in line with a novel hypothesis that dysregulations in the mesenchymal compartment (MC) may be causal to chronic inflammatory and tumorigenic pathologies (Κoliaraki et al., JCI 2012; JEM 2015; Cell Rep 2019; Henriques et al., PNAS 2018).