Protection against streptococcal cell wall-induced arthritis by pretreatment with the 65-kD mycobacterial heat shock protein.

Abstract

Arguments for an involvement of bacteria in the pathogenesis ofchronicjoint inflammation (arthritis) are several (1-12). To study the pathogenetic mechanism ofbacteriuminduced sterile arthritis, different animal models are used, among which, Mycobacterium tuberculosis-induced or adjuvant arthritis (AA)t (2) and streptococcal cell wall (SCW)-induced arthritis (1) are the best known. In both models, bacterium-specific T lymphocytes have been demonstrated to play a crucial role (13-24, and van den Broek, M. F, M. C. J. van Bruggen, A. J. Severijnen, and W B. van den Berg, manuscript submitted for publication), and one aspect ofthis role might be the crossreactive nature of these T lymphocytes to cartilage-associated components (22, 25).In AA it is a well known fact that rats that have recovered from arthritis are resistant to a subsequent induction of AA (17,18), and it has been demonstrated recently that pretreatment of rats with the mycobacterial 65-kD protein resulted in the same resistance to AA when tested 35 d later (13) . Since the 65-kD protein is an ubiquitous bacterial common antigen (26), with a homologous molecule present also in streptococci, and probably even associated with cell walls (27), we tested the effects ofpretreatment with the mycobacteria165-kD protein on the development of SCW arthritis.Here we show that intraperitoneal administration of 50 lAg 65-kD protein to rats 35, 25, 15, or even as short as 5 d before induction of SCW arthritis completely protected the rats against the chronic erosive polyarthritis. The resistance against SCW arthritis is transferrable by spleen T cells to naive recipients . The protection coincides with a suppression of SCW-specific T cell responses, thus displaying features much alike suppression or tolerance leading to resistance in other models for autoimmune diseases (28-31).

Autoreactivity to human heat‐shock protein 60 predicts disease remission in oligoarticular juvenile rheumatoid arthritis

“…On days 3,6, and 9, medium was replaced with medium containing 10% autologous serum, 10 units/ml of recombinant interleukin-2 (rIL-2), and 10 units …”

Prevention of adjuvant arthritis in rats by a nonapeptide from the 65-kD mycobacterial heat-shock protein

“…In addition, in SNP-pretreated groups, rats that did develop AA were found to have lower clinical as well as radiographical scores compared with rats ofthe FIA-pretreated control groups (Tables 1 and 2). Interestingly, SOP, an A'-acetylated octapeptide lacking the N-terminal threonine of 11,14,17,19,19,21,23 SNP, did not have any protective capacity (experiment 2, Tables 1 and 2), AA incidence and severity in SOP-pretreated rats were not difTerent from FtA-pretreated controls (Tables t and 2), This points to the specificity of the SNP effect in AA, It has been postulated that suppression of autoimmune disease in animals is usually caused by the induction of tolerance to the autoimmune disease-inducing antigen (Higgins & Weiner, 1988;Thomson et al, 1988;Clayton et al, 1989), i,e, the protection against mycobacteria-induced arthritis after pretreatment with whole mycobacteria or the 65-kD HSP, is due to induction of tolerance (Grey & Waksman, 1967;Cozine et al, 1972;van den Broek et al, 1989), This led us to investigate the cellular immune response of the rats to SNP, SOP and M. tuberculosis in vivo and in vitro after 35 days of pretreatment but before induction of AA and also 35 days after induction of AA, Before induction of AA, SNP-pretreated rats showed a DTH to SNP, but not to M. tuberculosis (Table 3), Normal rats and FIA-pretreated rats did not show a DTH to SNP, An in vitro proliferative response of splenic MNC to both SNP and M. tuberculosis is found in SNP-pretreated rats, but not in normal or FtA-pretreated rats (Table 3), Interestingly, no crossreactivities between SOP and SNP or M. tuberculosis were observed (Table 3), This is consistent with the fact that T cell clones A2b and A2c do not recognize the epitope without the N-terminal threonine (van der , Therefore it can be concluded that the threonine at position of 180 ofthe 65-kD mycobacterial HSP is important for immunogenicity of the nonapeptide.…”

“…Erythrocytes were eliminated by Ficoll-Paque gradients. Adherent cells were removed by l-h incubation on Petri dishes (Falcon 3003) and by a further l-h incubation with nylon wool (van den Broek et al, 1989). After extensive washing, 5-10 x 10' nylon wool-enriched T cells were transferred intravenously to naive rats.…”

“…Recent studies have demonstrated that the dominant immunogenic epitopes of some T cell-mediated experimental autoimmune diseases can be precisely defined by using disease inducing T cell clones as tools (Zamvile;a/,, 1986;van Eden e^o/,, 1988), In adjuvant arthritis (AA), a model of autoimmune arthritis inducible in certain strains of rats such as in Lewis rats, by heatkilled Mycobacterium tuberculosis (Pearson, 1956;1964;Taurog, Argentieri & McReynolds, 1988), a 65-kD mycobacterial heat-shock protein (HSP) has been proposed to be involved in the pathogenesis of AA (van Eden et al, 1988), Administration of the 65-kD HSP led to protection against AA and streptococcal cell-wall-induced arthritis in Lewis rats (van Eden et al, 1988;van den Broek et al, 1989;Billingham et al, 1990). A nonapeptide (Thr-Phe-Gly-Leu-Gln-Leu-Glu-Leu-Thr), representing amino acid sequence 180-188 ofthe 65-kD mycobacterial HSP, has been suggested to carry the critical epitope(s) for A A because of its ability to stimulate the arthritis-inducing T cell clone A2b as well as the arthritis-protective T cell clone A2c in vitro (Holoshitz, Matitiau & Cohen, 1984;Cohen et at., 1985;van Eden et al, 1988;, Based on these observations, it was suspected that immunization with the Correspondence: Dr X,-D, Yang, R-1056.…”

Role of Heat Shock Proteins in Diseases and Their Therapeutic Potential

“…Protection against adjuvant arthritis in Lewis rats induced by immunization with self hsp60 peptide [52], protection against adjuvant arthritis by vaccination with mycobacterial hsp60 peptide cross reactive to self hsp60 [53] have confirmed the involvement of hsp60 in adjuvant arthritis. Similarly immunization with mycobacterial hsp60 conferred protection against streptococcal cell wall induced arthritis in Lewis rats [54]. The hsp60 also been implicated in rheumatoid arthritis (RA) of humans.…”