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

Abstract

SUMMARYAdhesion 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-a . Conversely, blocking TNF-a causes a downmodulation of CAM expression. To test directly the capacity of TNF-a 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-a 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-a to induce cell migration. In addition, it provides the experimental background for the optimal use of this model.

Inflammation, Immune Reactivity, and Angiogenesis in a Severe Combined Immunodeficiency Model of Rheumatoid Arthritis

“…Lymphodepletion has been reported in several similar models. 15,38,39 Likewise, Wahid and colleagues 39 concluded that in the absence of T cells producing the Figure 11. CFSE-labeled human T cells traffic specifically into RA synovial grafts.…”

“…For example, in previous models in which cell suspensions or small pieces of synovium were implanted, lymphodepletion was routinely observed. 15,21,38,39 In some of these models the synovial tissue was implanted under the kidney capsule or in an ear pouch. It is possible that the location of the graft played a role in the lymphodepletion.…”

“…Others have noted similar results by dual staining for human and murine vessels indicating ongoing angiogenesis. 39 The establishment of an anastomosis between murine and human vessels suggests that complex recognition and organization of structural elements might have allowed continuity of vessels. However, it was evident that murine vessels were primarily excluded from the human grafts, whereas human vessels did not infiltrate the surrounding murine tissue.…”

“…39 These cellular adhesion molecules, indicative of an inflammatory state, could be up-regulated once again by intragraft injection of tumor necrosis factor-␣. Several important differences were observed between this report and the current studies in tissue preparation and engraftment.…”

T cell lessons from the rheumatoid arthritis synovium SCID mouse model: CD3‐rich synovium lacks response to CTLA‐4ig but is successfully treated by interleukin‐17 neutralization

“…In this model, standardized pieces of synovial tissue from RA patients are transplanted subcutaneously on the back or under the renal capsule of immunodeficient mice (9,10 (14,15). Adoptive T cell transfer into the RA synovium SCID mouse model augmented this cytokine production (14).…”