TRANSMEMBRANE TNF IS SUFFICIENT TO INDUCE LOCALIZED TISSUE TOXICITY AND CHRONIC INFLAMMATORY ARTHRITIS IN TRANSGENIC MICE

TNF plays a pivotal role in the pathogenesis of a broad spectrum of in fectious, inflammatory, and autoimmune diseases. In addition to the se creted mature 17 kD form, TNF exists as a bioactive precursor 26 kD tr ansmembrane protein. Transmembrane TNF signaling has been directly ass ociated with specific immune mechanisms, including the contact-depende nt lymphocyte and monocyte-mediated cell killing and the CD40 ligand-i ndependent, T cell-mediated polyclonal B cell activation. In previous studies, we have reported that mice expressing 3'-UTR modified human T NF transgenes develop chronic inflammatory polyarthritis with a 100% p henotypic penetrance and timed disease onset. In additional experiment s, we have also shown that high-level expression of human TNF in lymph oid cells of transgenic mice results in both local (thymic hypoplasia) and systemic (ischaemia, tissue necrosis, and wasting) TNF-mediated p athology. In this study we show that transgenic mice expressing a T ce ll-targeted membrane-associated mutant human TNF alpha protein are dis playing only local TNF-mediated pathologies, ranging from lymphoid tis sue derangements to proliferative synovitis and chronic inflammatory a rthritis. These results demonstrate that in vivo, at least part of the pathogenic activities of TNF alpha may be assigned to the functioning of its uncleaved membrane-associated form. (C) 1996 Wiley-Liss, Inc.