Introduction to the Session “Mechanisms of Pathological and Therapeutic Effects of the TNF Family”
The prototype family member of the TNF family is TNF itself. Very early after its discovery and cloning, about 25 years ago, it became clear that TNF has very powerful and dramatic toxic activities when injected in experimental animals, such as mice and rats, and in humans. Also, in experimental animals, tumor regression was observed in many tumors, but the therapy was associated with very dangerous toxicity. The toxic response to TNF could best be compared with endotoxemia and septic shock, and hence TNF was considered as an essential mediator of these acute inflammatory conditions. TNF also proved to be a very strong inducer of gene expression programs through activation of signaling cascades, and because circulating TNF could be measured in several diseases, many research groups have embarked in studies to establish clearly in which inflammatory disease cytokines such as TNF should be considered a toxic mediator and hence a therapeutic target. A major breakthrough in this research were the studies which proved that TNF-neutralizing antibodies and soluble receptors protect arthritic patients. These data provided the community not only with very valuable research tools, but also with the belief that TNF is really to be considered as a drug target and that the market for anti-TNF strategies is huge indeed. In the mean time, more and more diseases are approached with anti-TNF therapies, but the search to increase the market is still ongoing, both in clinical trials and in fundamental research. Very instrumental in this search are the mouse models and tools which are available.