Further investigation of the biological properties of streptococcal cells and their components has produced a model of erosive synovitis in rats. A single intraperitoneal injection of an aqueous suspension of whole cell sonicate of group A streptococci into Sprague-Dawley rats induced an acute arthritis which evolved into a prolonged inflammatory process characterized by several complete or partial remissions, joint deformity, and ankylosis. The toxic moiety is a peptidoglycan-polysaccharide fragment of the cell wall which persists in tissue. Histologic features of the arthritis include an acute exudative phase followed by an erosive synovitis that leads to destruction of cartilage and subchondral bone and fibrous ankylosis of the joints. The arthropathic properties of whole cell sonicates of several species of streptococci are compared along with studies of the ability of heat-killed, whole cells of groups A, B, and C streptococci to induce arthritis in rats. Whole cells induce arthritis after a latent period of 57-120 days when group A cells are injected and 7-10 days when group B cells are tested.

Restoration of the impaired balance between pro-and antiinflammatory cytokines should provide effective treatment of rheumatoid arthritis. Gene therapy has been proposed as an approach for delivery of therapeutic proteins to arthritic joints. Here, we examined the efficacy of antiinflammatory gene therapy in bacterial cell wall-induced arthritis in rats. Human secreted interleukin 1 receptor antagonist (sIL-1ra) was expressed in joints of rats with recurrent bacterial cell wall-induced arthritis by using ex vivo gene transfer. To achieve this, primary synoviocytes were transduced in culture with a retroviral vector carrying the sIL-lra cDNA. Transduced cells were engrafted in ankle joints of animals prior to reactivation of arthritis. Animals in control groups were engrafted with synoviocytes transduced with lacZ and neo marker genes. Cells continued to express transferred genes for at least 9 days after engraftment. We found that gene transfer of sIL-lra significantly suppressed the severity of recurrence of arthritis, as assessed by measuring joint swelling and by the gross-observation score, and attenuated but did not abolish erosion of cartilage and bone. The effect of intraarticularly expressed sIL-lra was essentially local, as there was no significant difference in severity of recurrence between unengrafted contralateral joints in control and experimental groups. We estimate that locally expressed sIL-lra was about four orders of magnitude more therapeutically efficient than systemically administered recombinant sIL-lra protein. These findings provide experimental evidence for the feasibility of antiinflammatory gene therapy for arthritis.

The covalently bound polymers of peptidoglycan and group-specific polysaccharide (PG-APS) were isolated from the cell walls of group A streptococci. Arthritis was induced in rats with a single intraperitoneal injection of an aqueous suspension of PG-APS fragments derived by sonication. The joint lesions induced with this polydisperse suspension followed a bimodal pattern consisting of an acute phase, which reached a peak 5 days after injection and then receded, followed by a chronic, remittent, erosive arthritis lasting several months. The relative severities of the acute and chronic phases could be manipulated by selection of the size of PG-APS fragments. The fragments of PG-APS obtained by sonic treatment were resolved on the basis of size into three major populations by sucrose gradient or differential centrifugation. Based upon light scattering and gel filtration, the average molecular weight of the largest family of fragments was estimated to be about 500 x 106, the intermediate fragments were 50 x 106 daltons, and the predominant size in the smallest population was 5.3 x 106 daltons. The larger fragments induced negligible acute inflammation, but chronic disease became apparent 5 to 9 weeks after injection. The smallest fragments induced the most severe acute inflammation, with relatively little late, chronic joint disease. The particles of intermediate size induced moderate acute inflammation and the most severe chronic, erosive joint lesions. A single injection of fragments of the isolated peptidoglycan moiety of the PG-APS induced only a moderate acute inflammation ofjoints, with no apparent capacity to maintain the injury and induce chronic disease.

The intraperitoneal injection of an aqueous suspension of cell wall fragments from group A streptococci induces a chronic intermittent arthritis in rats that is associated with the persistence of cell wall material in joint tissues. The radiographic techniques utilized to study this experimental model are described and the radiologic findings encountered during the natural history of the disease are presented. The progressive erosive synovitis of this model is similar to that seen in rheumatoid arthritis.