Tumour necrosis factor-alpha (TNP-alpha) enhances lymphocyte migration into rheumatoid synovial tissue transplanted into severe combined immunodeficient (SCID) mice

Adhesion mechanisms play a major role in the recruitment of peripheral bloo d lymphocytes (PBL) which characteristically infiltrate rheumatoid arthriti s (RA) synovium and other chronically inflamed tissues. Through a sequentia l series of complex integrated adhesion and signalling events, 'multistep m odel of migration', specific subsets of PBL are recruited into inflamed tis sues. In this process both leucocyte receptors and microvascular endothelia l (MVE) counter-receptors play a critical role. The MVE in particular, duri ng an inflammatory state, is the target of various inflammatory mediators t hat cause the up-regulation of several cell adhesion molecules (CAM). One o f the most important factors known to be a powerful inducer of MVE CAM is T NF-alpha. Conversely, blocking TNF-alpha causes a downmodulation of CAM exp ression. To test directly the capacity of TNF-alpha to induce cell migratio n into RA synovium we adapted a model in which synovial grafts were implant ed into SCID mice subcutaneously. Using this model we demonstrate that: (1) transplants remain viable and become vascularized and fed by mouse subderm al vessels; (ii) the mouse vasculature connects to the transplant vasculatu re which maintains the ability to express human CAM; (iii) intragraft injec tions of TNF-alpha up-regulate the expression of human CAM, following the d own-regulation which occurred 4 weeks post-transplantation; and (iv) the up -regulation of graft CAM is associated with increased human PBL migration i nto the transplants. This study provides direct evidence in vivo of the cap acity of TNF-alpha to induce cell migration. In addition, it provides the e xperimental background for the optimal use of this model.