Systemic Characteristics of Chronic Arthritis Induced by Transfer of Human Rheumatoid Synovial Membrane into SCID Mice (Human/Murine SCID Arthritis)

Sack, Ulrich; Günther, Albrecht; Robert, Paul; Genest, Michael; Kinne, Jörg; Biskop, M; Kämpfer, I; Krenn, Veit; Emmrich, Frank; Lehmann, Jörg

doi:10.1006/jaut.1999.0328

Cited by 15 publications

(21 citation statements)

References 19 publications

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“…Several reports suggest that T cells in RA synovium might not be so active, less amounts of both cell surface activation Ags and cytokine production (29,30). In SCID mouse model of RA, depletion of T cells rather amplifies synovial cell proliferation, the growth of pannus, and subsequent degradation of bones (31). Furthermore, a minority of patients have to date benefited from the therapy using anti-CD4 mAb, which failed to control growth of synovium in vivo (32,33).…”

Section: Discussionmentioning

confidence: 99%

CD44 Is the Physiological Trigger of Fas Up-Regulation on Rheumatoid Synovial Cells

Fujii

Hübscher

et al. 2001

The Journal of Immunology

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CD44 is a ubiquitous molecule known as a hyaluronan receptor. However, the relevance of CD44 to inflammatory processes, for example, rheumatoid synovitis, remains unclear. In this study, we propose a novel function for CD44 using synovial cells from rheumatoid arthritis (RA) patients and demonstrated that CD44 cross-linking augmented Fas expression and subsequent Fas-mediated apoptosis of the cells: 1) cross-linking of CD44 on RA synovial cells markedly augmented Fas expression and its mRNA transcription; 2) engagement of CD44 up-regulated Fas on the cells within 3 h, much more than IL-1β and TNF-α did; 3) the Fas-mediated early apoptotic change of the cells was amplified by CD44 cross-linking; and 4) hyaluronan, especially when fragmented, also augmented Fas-mediated early apoptosis of the cells. Based on these findings, we postulate a new concept: that interaction of CD44 on RA synovial cells with hyaluronan fragments present in the surrounding extracellular matrix augments Fas expression as well as Fas-mediated apoptosis of synovial cells. This may lead to spontaneous growth arrest through Fas-Fas ligand pathway observed in synovial cells of RA synovitis in vivo.

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Section: Discussionmentioning

confidence: 99%

CD44 Is the Physiological Trigger of Fas Up-Regulation on Rheumatoid Synovial Cells

Fujii

Hübscher

et al. 2001

The Journal of Immunology

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“…24 This effect was also induced in RAGÀ/À mice suggesting no involvement of T and B cells. 24 Finally, extra-articular engraftment of human RA synovial tissue under the skin also induced an oligoarticular pattern of arthritis, suggesting no direct neurological transmission of disease. 24 Large numbers of murine DC were found in the arthritic joint with murine macrophages near the front of cartilage destruction, suggesting a role for APC in both the polyarticular dispersal and destructive nature of the disease.…”

Section: Discussionmentioning

confidence: 90%

“…24 Finally, extra-articular engraftment of human RA synovial tissue under the skin also induced an oligoarticular pattern of arthritis, suggesting no direct neurological transmission of disease. 24 Large numbers of murine DC were found in the arthritic joint with murine macrophages near the front of cartilage destruction, suggesting a role for APC in both the polyarticular dispersal and destructive nature of the disease. 24 Consistent with these results is our observation that intraarticular adenoviral-mediated gene transfer of TNF was able to initiate disease pathology in not only the treated joint, but also to a low level in distal joints (Lechman et al, manuscript in preparation).…”

Section: Discussionmentioning

confidence: 98%

“…Unilateral implantation was found to develop into a bilateral knee joint disorder, often involving homo-and contralateral hips. 24 No migration of the human cells was observed in secondarily affected joints suggesting that bilateral joint disease was not due to the spreading of human cells. 24 This effect was also induced in RAGÀ/À mice suggesting no involvement of T and B cells.…”

Section: Discussionmentioning

confidence: 99%

“…24 No migration of the human cells was observed in secondarily affected joints suggesting that bilateral joint disease was not due to the spreading of human cells. 24 This effect was also induced in RAGÀ/À mice suggesting no involvement of T and B cells. 24 Finally, extra-articular engraftment of human RA synovial tissue under the skin also induced an oligoarticular pattern of arthritis, suggesting no direct neurological transmission of disease.…”

Section: Discussionmentioning

confidence: 99%

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The contralateral effect conferred by intra-articular adenovirus-mediated gene transfer of viral IL-10 is specific to the immunizing antigen

et al. 2003

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We have demonstrated previously that local, adenoviralmediated gene transfer of vIL-10 to a single joint of rabbits and mice with experimental arthritis can suppress disease in both the treated and untreated contralateral joints. These therapeutic effects observed in distant untreated joints following local intra-articular gene delivery have been termed the 'contralateral effect'. To begin to understand the underlying immunologic mechanism that confers this effect, a dualantigen model of antigen-induced arthritis (AIA) in rabbit knee joints was utilized. Rabbits were immunized against two antigens, ovalbumin and keyhole limpet hemocyanin, and AIA generated by intra-articular injection of each antigen into contralateral knees. Intra-articular adenovirus-mediated gene transfer of vIL-10 significantly reduced intra-articular leukocytosis and cartilage matrix degradation, while preserving near normal levels of cartilage matrix synthesis within treated joints. However, no antiarthritic effect was conferred in the contralateral control joints that received only a marker gene, in contrast to the results seen in a single-antigen AIA model. These results suggest that the distant antiarthritic effects associated with local gene delivery to joints are antigen-specific, and not due to vIL-10-induced generalized immunosuppression of the animal.

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Tumor necrosis factor α‐mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin

Redlich¹,

Hayer²,

Maier³

et al. 2002

Arthritis & Rheumatism

274

185

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Objective. To study the effects of osteoclasttargeted therapies, such as osteoprotegerin (OPG) and pamidronate, on joint inflammation and bone destruction using a tumor necrosis factor ␣ (TNF␣)-transgenic mouse model.Methods. Mice were placed into 5 groups that received either OPG, pamidronate, a combination of both agents, infliximab as a positive control, or phosphate buffered saline as a negative control. Treatment was initiated at the onset of arthritis, continued over 6 weeks, and thereafter, the clinical, radiologic, and histologic outcomes were assessed.Results. A significant improvement in clinical symptoms, as assessed by the reduction of paw swelling, was only found in the infliximab group, whereas all other treatment groups failed to show significant improvement. However, when assessing structural damage with radiographic analysis, a significant retardation of joint damage was evident in animals treated with OPG (55% reduction of erosions), pamidronate (50% reduction of erosions) the combination therapy of OPG and pamidronate (64% reduction of erosions), and with infliximab (66% reduction of erosions). Confirming these data, quantitative histologic analysis revealed a significant reduction in the size of bone erosions in all treatment groups (OPG 56%, pamidronate 53%, OPG and pamidronate 81%, and infliximab 46%) compared with the control group. Furthermore, a significant reduction of osteoclast numbers was seen in animals treated with OPG alone or in combination with pamidronate as well as in animals treated with infliximab.Conclusion. These data suggest that OPG alone or in combination with bisphosphonates is an effective therapeutic tool for the prevention of TNF␣-mediated destruction of bone by reducing the number of boneresorbing cells in the inflammatory tissue.

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Systemic Characteristics of Chronic Arthritis Induced by Transfer of Human Rheumatoid Synovial Membrane into SCID Mice (Human/Murine SCID Arthritis)

Cited by 15 publications

References 19 publications

CD44 Is the Physiological Trigger of Fas Up-Regulation on Rheumatoid Synovial Cells

CD44 Is the Physiological Trigger of Fas Up-Regulation on Rheumatoid Synovial Cells

The contralateral effect conferred by intra-articular adenovirus-mediated gene transfer of viral IL-10 is specific to the immunizing antigen

Tumor necrosis factor α‐mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin

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