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 RA-SCID 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, alpha v beta 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-gamma, 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.
Davis
Laurie S
LS
Department of Internal Medicine and the Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8884, USA. laurie.davis@utsouthwestern.edu
Sackler
Marian
M
Brezinschek
Ruth I
RI
Lightfoot
Ellis
E
Bailey
Jennifer L
JL
Oppenheimer-Marks
Nancy
N
Lipsky
Peter E
PE
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology* / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007107:Immune System / Q000503:physiopathology*; D007136:Immunoglobulins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID / Q000502:physiology*; D009000:Monocytes / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology*; D013583:Synovial Membrane / Q000637:transplantation; D013601:T-Lymphocytes / Q000502:physiology; D014183:Transplantation, Heterologous
D016207:Cytokines; D007136:Immunoglobulins; D018836:Inflammation Mediators