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

Severe combined immunodeficiency (SCID) mice were engrafted with rheumatoid arthritis (RA) synovium and evaluated to determine whether RA synovial morphology and function were maintained in the RA-SCID grafts. The four major components of RA synovitis, inflammation, immune reactivity, angiogenesis, and synovial hyperplasia persisted in RASCID grafts for 12 weeks. Retention of chronic inflammatory infiltrates was demonstrated by histological evaluation and by immunohistology for CD3, CD20, and CD68. Staining for CD68 also revealed that the grafts had undergone reorganization of the tissue, possibly as a result of fibroblast hyperplasia. Immune and inflammatory components were confirmed by the detection of human immunoglobulins and human interleukin-6 in serum samples obtained from grafted animals. Human blood vessels were detected by dense expression of CD31. Small vessels persistently expressed the vitronectin receptor, v 3, a marker of angiogenesis. All vessels expressed VAP-1, a marker of activated endothelial cells. Finally, the grafts retained the ability to support immigration by human leukocytes, as demonstrated by the functional capacity to recruit adoptively transferred 5(and -6)-carboxyfluorescein diacetate succinimidyl ester-labeled T cells. T cells entering the RA-SCID grafts became activated and produced interferon, as detected by reverse transcriptase-polymerase chain reaction analysis. These studies demonstrate that the RA-SCID model maintains many of the phenotypic and functional features of the inflamed RA synovium. (Am J Pathol 2002, 160:357–367) Rheumatoid arthritis (RA) is a chronic progressive disease involving both local and systemic inflammation. RA is characterized by persistent inflammation of synovial tissue and eventually the destruction of cartilage and adjacent bone. RA synovitis involves local activation of lymphocytes, inflammation, and synovial hyperplasia as well as angiogenesis. The etiology of RA remains unknown and much is left to be elucidated about the progression of the pathological processes. The mechanism of the immune component in RA has not been resolved, although large numbers of CD3 ,CD4 T cells are found in perivascular areas and CD3 ,CD8 T cells are distributed diffusely throughout the synovium. Recent evidence including the polyclonal nature of the CD4 T-cell infiltrate and the nearly uniform expression of activation molecules by these cells suggest they play a role in perpetuating chronic inflammation. CD8 cells in the synovium seem to be both proinflammatory and regulatory, whereas CD20 B cells secreting immunoglobulins (Igs) are found in defined aggregates throughout the synovial tissue along with CD4 T cells and interdigitating dendritic cells. The local generation of immune complexes and activation of complement have been proposed as mechanisms contributing to tissue damage and propagation of inflammation. Inflammatory cells in the RA joint consist primarily of polymorphonuclear leukocytes, monocytes, and macrophages. Few polymorphonuclear leukocytes are localized in the RA synovium, although large numbers characteristically accumulate in the synovial fluid, presumably because of limited chemokine receptor expression. Numerous monocytes and macrophages are found within the RA synovial tissue and fluid. Activated monocytes produce cytokines such as interleukin (IL)-1 , IL-6, and