Background Chaperonin 10 (heat shock protein 10, XToll™) has anti-inflammatory properties related to the inhibition of Toll-like receptor signalling pathways. Our aim was to establish whether chaperonin 10 is safe and effective in the treatment of rheumatoid arthritis. Methods In this randomised, double-blind, multicentre study, 23 patients with moderate to severe active rheumatoid arthritis receiving disease-modifying antirheumatic drugs were randomly allocated to three treatment groups receiving intravenous chaperonin 10 twice weekly for 12 weeks at doses of 5 mg (n=8), 7·5 mg (8), or 10 mg (7). The primary outcomes were change in disease activity score (DAS28) and improvement of core disease measures (American College of Rheumatology response score) from baseline to week 12. All analyses were done by intention to treat. This study is registered with the Australian Clinical Trials Registry, number ACTRNO12606000041550. Findings Primary endpoint measures improved from day 14 in all groups and continued to improve to day 84. By end of study, a 20% improvement of core disease measures was seen in six (86%, 95% CI 43-100), a 50% improvement in four (57%, 14-86), and a 70% improvement in two (29%, 0-57) patients given the highest dose of chaperonin 10. Clinical remission (as defined by a DAS28 <2·6) was achieved in three (13%) of 23 patients. Three individuals dropped out during the study: one in the 5 mg group (rheumatoid arthritis not controlled), one in the 7·5 mg group (adverse event), and one in the 10 mg group (lost to follow-up). The most common adverse events were exacerbation of rheumatoid arthritis (both during and after the study) and upper respiratory tract infection. Only one adverse event was judged to be of severe intensity. Interpretation Chaperonin 10 seems to be well tolerated and efficacious in treatment of the symptoms of rheumatoid arthritis, at least in the short term.

Background Chaperonin 10 (heat shock protein 10, XToll(TM)) has anti-inflammatory properties related to the inhibition of Toll-like receptor signalling pathways. Our aim was to establish whether chaperonin 10 is safe and effective in the treatment of rheumatoid arthritis.Methods in this randomised, double-blind, multicentre study, 23 patients with moderate to severe active rheumatoid arthritis receiving disease-modifying antirheumatic drugs were randomly allocated to three treatment groups receiving intravenous chaperonin 10 twice weekly for 12 weeks at doses of 5 mg (n=8), 7.5 mg (8), or 10 mg (7). The primary outcomes were change in disease activity score (DAS28) and improvement of core disease measures (American College of Rheumatology response score) from baseline to week 12. All analyses were done by intention to treat. This study is registered with the Australian Clinical Trials Registry, number ACTRNO12606000041550.Findings Primary endpoint measures improved from day 14 in all groups and continued to improve to day 84. By end of study, a 20% improvement of core disease measures was seen in six (86%, 95% Cl 43-100), a 50% improvement in four (57%, 14-86), and a 70% improvement in two (29%, 0-57) patients given the highest dose of chaperonin 10. Clinical remission (as defined by a DAS28 <2.6) was achieved in three (13%) of 23 patients. Three individuals dropped out during the study: one in the 5 mg group (rheumatoid arthritis not controlled), one in the 7.5 mg group (adverse event), and one in the 10 mg group (lost to follow-up). The most common adverse events were exacerbation of rheumatoid arthritis (both during and after the study) and upper respiratory tract infection. Only one adverse event was judged to be of severe intensity.Interpretation Chaperonin 10 seems to be well tolerated and efficacious in treatment of the symptoms of rheumatoid arthritis, at least in the short term.

Heat shock protein 10 (Hsp10) and heat shock protein 60 (Hsp60) were originally described as essential mitochondrial proteins involved in protein folding. However, both proteins have also been shown to have a number of extracellular immunomodulatory activities. Here we show that purified recombinant human Hsp10 incubated with cells in vitro reduced lipopolysaccharide (LPS)-induced nuclear factor-kappaB activation and secretion of several inflammatory mediators from RAW264.7 cells, murine macrophages, and human peripheral blood mononuclear cells. Induction of tolerance by contaminating LPS was formally excluded as being responsible for Hsp10 activity. Treatment of mice with Hsp10 before endotoxin challenge resulted in the reduction of serum tumor necrosis factor-alpha and RANTES (regulated upon activation, normal T cell expressed and secreted) levels and an elevation of serum interleukin-10 levels. Hsp10 treatment also delayed mortality in a murine graft-versus-host disease model, where gut-derived LPS contributes to pathology. We were unable to confirm previous reports that Hsp10 has tumor growth factor properties and suggest that Hsp10 exerts anti-inflammatory activity by inhibiting Toll-like receptor signaling possibly by interacting with extracellular Hsp60.

Background: Chaperonin 10 (Cpn10) is a mitochondrial protein essential for protein folding. In vitro studies have also shown that Cpn10 reduces production of pro-inflammatory cytokines and chemokines, and up-regulates interleukin-10 in response to agonist stimulation of Toll-like receptors. A protective effect for Cpn10 in experimental autoimmune encephalomyelitis has been demonstrated with suppression of inflammatory markers. Here we report the first clinical trials of this agent administered intravenously in human subjects. Methods: Two dose ranging and tolerability studies were undertaken in 16 healthy volunteers (Phase Ia - single doses of 1 mg, 2.5 mg, 5 mg or 10 mg with 1:3 subjects receiving placebo) and 10 patients with multiple sclerosis (Phase Ib - 5 daily doses of 2.5 mg or 5 mg with 1:4 patients receiving placebo) using a double-blind, randomised design. Intravenous administration was over 10 minutes. Adverse events, clinical data, pharmacodynamic and pharmacological parameters were monitored. Results: There were no serious adverse events and no discernible trends observed for other adverse events. The half-life of Cpn10 was approximately one hour and suppression of TNF-a production in a peripheral blood mononuclear cell assay was seen when blood was taken 8-hr post dose. A peak dose pharmacodynamic effect was seen at 5 mg. No significant increase in anti-Cpn10 antibodies was seen. There was no discernable clinical effect in the multiple sclerosis volunteers. Conclusions: Cpn10 is well tolerated when administered intravenously to both healthy and multiple sclerosis affected human subjects. Anticipated modulation of the innate immune system was observed in both healthy and affected subjects.

Highly purified isoaccepting species of transfer ribonucleic acid (tRNA) were prepared by use of a polyacrylamide substituted with nitrobenzeneboronic acid functional groups. This method exploits the well-known ability of boronic acids to complex with RNA cis-diols. tRNA isoacceptors were obtained by enzymatically acylating a mixture of tRNA species with a single amino acid and passing the mixture over a solid-state nitrobenzeneboronic acid at pH 6.5 or 7.0. Pure aminoacyl-tRNA eluted at the column liquid volume, and unacylated tRNA species were bound. The bound species were recovered by lowering the pH of the eluant to 4.5. This procedure is uncomplicated, rapid, and applicable to nearly all tRNA isoacceptors. It does not chemically modify the tRNA(s) of interest or adversely affect their ability to be aminoacylated. Since boronic acids must be ionized to complex with cis-1,2-diols, boronic acid derivatives were prepared which ionize at a pH compatible with the stability of the aminoacyl bond. Two isomeric benzeneboronic acids with pKas of 6.8 and 7.4 were synthesized by introducing electron-withdrawing nitro groups into the aromatic ring. The addition of succinyl side chains permitted the nitrobenzeneboronic acids to be coupled to aminoethylpolyacrylamide. The properties of the nitrobenzeneboronic acid substituted acrylamide were illustrated by enriching phenylalanyl-tRNA at pH 7.0 to greater than 95% purity (1.63 nmol of phenylalanine accepted per A260 unit of tRNA) and seryl-tRNA isoacceptors at pH 6.5 to essentially theoretical purity (1.58 nmol of serine accepted per A260 unit of tRNA.