IngentaConnect Tumour necrosis factor-alpha (TNF-) enhances lymphocyte migration...

Authors: Wahid, S.¹; Blades, M. C.¹; De Lord, D.¹; Brown, I.¹; Blake, G.¹; Yanni, G.¹; Haskard, D. O.²; Panayi, G. S.¹; Pitzalis, C.¹

Source: Clinical & Experimental Immunology, Volume 122, Number 1, October 2000 , pp. 133-142(10)

Publisher: Blackwell Publishing

Abstract:

Adhesion mechanisms play a major role in the recruitment of peripheral blood lymphocytes (PBL) which characteristically infiltrate rheumatoid arthritis (RA) synovium and other chronically inflamed tissues. Through a sequential series of complex integrated adhesion and signalling events, `multistep model of migration', specific subsets of PBL are recruited into inflamed tissues. In this process both leucocyte receptors and microvascular endothelial (MVE) counter-receptors play a critical role. The MVE in particular, during an inflammatory state, is the target of various inflammatory mediators that cause the up-regulation of several cell adhesion molecules (CAM). One of the most important factors known to be a powerful inducer of MVE CAM is TNF-α. Conversely, blocking TNF-α causes a down-modulation of CAM expression. To test directly the capacity of TNF-α to induce cell migration into RA synovium we adapted a model in which synovial grafts were implanted into SCID mice subcutaneously. Using this model we demonstrate that: (i) transplants remain viable and become vascularized and fed by mouse subdermal vessels; (ii) the mouse vasculature connects to the transplant vasculature which maintains the ability to express human CAM; (iii) intragraft injections of TNF-α up-regulate the expression of human CAM, following the down-regulation which occurred 4 weeks post-transplantation; and (iv) the up-regulation of graft CAM is associated with increased human PBL migration into the transplants. This study provides direct evidence in vivo of the capacity of TNF-α to induce cell migration. In addition, it provides the experimental background for the optimal use of this model.

Keywords: adhesion molecules; in vivo SCID model; lymphocyte migration; tumour necrosis factor-alpha; rheumatoid arthritis

Document Type: Research article

DOI: 10.1046/j.1365-2249.2000.01342.x

Affiliations: 1: Rheumatology Unit, Guy's, St Thomas and King's College (GKT) School of Medicine and Dentistry, and 2: British Heart Foundation, Cardiovascular Medicine Unit, Imperial College School of Medicine, Hammersmith Hospital, London, UK

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