- Email: [email protected]
Chaperonin 10 for rheumatoid arthritis
Correspondence
published as a separate editorial, with a citation to the scientific article. Citing journal deadlines, the authors declined to discuss that approach and made the decision to remove the article from CDC clearance. For a CDC scientist to be listed as coauthor, CDC policy requires that the article complete the scientific clearance process. We at CDC are proud of our long history of efforts to prevent and control sexually transmitted infections, and we are committed to strengthening public health research and practice in this vitally important area. We declare that we have no conflict of interest.
*Deborah Birx, William C Levine [email protected] Global AIDS Program, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA 1 2
Horton R. Reviving reproductive health. Lancet 2006; 368: 1549. Low N, Broutet N, Adu-Sarkodie Y, et al. Global control of sexually transmitted infections. Lancet 2006; 368: 2001–16.
Chaperonin 10 for rheumatoid arthritis Daina Vanags and colleagues (Sept 2, p 855)1 report that chaperonin 10 is effective in the treatment of the symptoms of rheumatoid arthritis without serious adverse effects. I have some concerns about the safety of this therapeutic strategy. Experimental studies in several different human and murine in-vitro systems have shown that chaperonin 10 inhibits lipopolysaccharide-induced secretion of the proinflammatory cytokines tumour necrosis factor α and interleukin 6, and the proinflammatory chemokine RANTES.2 These molecules are known to have important roles in the pathogenesis of rheumatoid arthritis. Heat-shock proteins such as HSP60, which is a target of chaperonin 10, are source of “danger” signals, and have prerequisite roles in the signalling of the innate and adaptive immune systems of tissue damage induced by www.thelancet.com Vol 368 December 2, 2006
various insults, such as infection and toxins. Therefore, chaperonin 10 might inhibit the host’s defence mechanism against infections. Additionally, several reports show that chaperonin 10 is involved in the carcinogenesis of some tumours, such as those of the ovary and colon.3,4 Akyol and colleagues3 suggested that the production and release of HSP10 is an essential factor in the suppression of Tcell activation, allowing the tumour to escape immune surveillance. Further clinical studies with many patients for a longer period are needed to dispel the apprehension about the risk of development of severe infections and tumour progression with chaperonin 10 therapy. I declare that I have no conflict of interest.
Hiroshi Okamoto [email protected] Institute of Rheumatology, Tokyo Women’s Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan 1
2
3
4
Vanags D, Williams B, Johnson B, et al. Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a doubleblind randomised trial. Lancet 2006; 368: 855–63. Johnson BJ, Le TT, Dobbin CA, et al. Heat shock protein 10 inhibits lipopolysaccharide-induced inflammatory mediator production. J Biol Chem 2005; 280: 4037–47. Akyol S, Gercel-Taylor C, Reynolds LC, Taylor DD. HSP-10 in ovarian cancer: expression and suppression of T-cell signaling. Gynecol Oncol 2006; 101: 481–86. Cappello F, Bellafiore M, David S, Anzalone R, Zummo G. Ten kilodalton heat shock protein (HSP10) is overexpressed during carcinogenesis of large bowel and uterine exocervix. Cancer Lett 2003; 196: 35–41.
Daina Vanags and colleagues1 did not investigate changes in the expression of Toll-like receptors (TLRs) on the membrane of peripheral-blood mononuclear cells in the patients recruited for their chaperonin 10 trial. Down-regulation of TLR2 or TLR4 could suggest the “endotoxin tolerance” effect, nowadays renamed “cross-tolerance”, although this has been previously excluded in vitro by Johnson and colleagues.2 Briefly, longterm exposure to lipopolysaccharide or other TLR ligands induces tolerance in intracellular signalling pathways, which
is often associated with a loss of TLR surface expression. For neutrophils, this means a stop in respiratory bursts,3 which might contribute to the therapeutic effect in autoimmune diseases such as rheumatoid arthritis. Given this background, I suggest that the same therapeutic effect could be achieved with small-molecule ligands of TLRs. Synthetic molecules generally behave as haptens and potentially reduce the risk of development of neutralising antibodies during longterm treatments. To this regard, I argue that the neutralising ability of antibodies against heat-shock protein 70 induced by repeated intravenous infusions cannot be estimated on the basis of maintenance of response alone, since no consistent dose-effect relation could be established for the patients on different doses. I declare that I have no conflict of interest.
Daniele Focosi [email protected] Division of Hematology, University of Pisa, via Roma 56, I-56100 Pisa, Italy 1
2
3
Vanags D, Williams B, Johnson B, et al. Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a doubleblind randomised trial. Lancet 2006; 368: 855–63. Johnson BJ, Le TT, Dobbin CA, et al. Heat shock protein 10 inhibits lipopolysaccharide-induced inflammatory mediator production. J Biol Chem 2005; 280: 4037–47. Parker LC, Jones EC, Prince LR, et al. Endotoxin tolerance induces selective alterations in neutrophil function. J Leukoc Biol 2005; 78: 1301–05.
See Department of Error page 1964
Authors’ reply Hiroshi Okamoto refers to a study by Aykol and colleagues,1 which shows that serum samples from patients with ovarian cancer that contain chaperonin 10 immunoreactivity can reduce the expression of T-cell CD3-zeta. We interpret these findings as the identification of another potential immunomodulatory aspect of chaperonin 10, but not proof that chaperonin 10 can precipitate a tumour or influence tumour growth. We have carefully investigated the growth of a panel of tumour cells
e-mail submissions to [email protected]
1961
published as a separate editorial, with a citation to the scientific article. Citing journal deadlines, the authors declined to discuss that approach and made the decision to remove the article from CDC clearance. For a CDC scientist to be listed as coauthor, CDC policy requires that the article complete the scientific clearance process. We at CDC are proud of our long history of efforts to prevent and control sexually transmitted infections, and we are committed to strengthening public health research and practice in this vitally important area. We declare that we have no conflict of interest.
*Deborah Birx, William C Levine [email protected] Global AIDS Program, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA 1 2
Horton R. Reviving reproductive health. Lancet 2006; 368: 1549. Low N, Broutet N, Adu-Sarkodie Y, et al. Global control of sexually transmitted infections. Lancet 2006; 368: 2001–16.
Chaperonin 10 for rheumatoid arthritis Daina Vanags and colleagues (Sept 2, p 855)1 report that chaperonin 10 is effective in the treatment of the symptoms of rheumatoid arthritis without serious adverse effects. I have some concerns about the safety of this therapeutic strategy. Experimental studies in several different human and murine in-vitro systems have shown that chaperonin 10 inhibits lipopolysaccharide-induced secretion of the proinflammatory cytokines tumour necrosis factor α and interleukin 6, and the proinflammatory chemokine RANTES.2 These molecules are known to have important roles in the pathogenesis of rheumatoid arthritis. Heat-shock proteins such as HSP60, which is a target of chaperonin 10, are source of “danger” signals, and have prerequisite roles in the signalling of the innate and adaptive immune systems of tissue damage induced by www.thelancet.com Vol 368 December 2, 2006
various insults, such as infection and toxins. Therefore, chaperonin 10 might inhibit the host’s defence mechanism against infections. Additionally, several reports show that chaperonin 10 is involved in the carcinogenesis of some tumours, such as those of the ovary and colon.3,4 Akyol and colleagues3 suggested that the production and release of HSP10 is an essential factor in the suppression of Tcell activation, allowing the tumour to escape immune surveillance. Further clinical studies with many patients for a longer period are needed to dispel the apprehension about the risk of development of severe infections and tumour progression with chaperonin 10 therapy. I declare that I have no conflict of interest.
Hiroshi Okamoto [email protected] Institute of Rheumatology, Tokyo Women’s Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan 1
2
3
4
Vanags D, Williams B, Johnson B, et al. Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a doubleblind randomised trial. Lancet 2006; 368: 855–63. Johnson BJ, Le TT, Dobbin CA, et al. Heat shock protein 10 inhibits lipopolysaccharide-induced inflammatory mediator production. J Biol Chem 2005; 280: 4037–47. Akyol S, Gercel-Taylor C, Reynolds LC, Taylor DD. HSP-10 in ovarian cancer: expression and suppression of T-cell signaling. Gynecol Oncol 2006; 101: 481–86. Cappello F, Bellafiore M, David S, Anzalone R, Zummo G. Ten kilodalton heat shock protein (HSP10) is overexpressed during carcinogenesis of large bowel and uterine exocervix. Cancer Lett 2003; 196: 35–41.
Daina Vanags and colleagues1 did not investigate changes in the expression of Toll-like receptors (TLRs) on the membrane of peripheral-blood mononuclear cells in the patients recruited for their chaperonin 10 trial. Down-regulation of TLR2 or TLR4 could suggest the “endotoxin tolerance” effect, nowadays renamed “cross-tolerance”, although this has been previously excluded in vitro by Johnson and colleagues.2 Briefly, longterm exposure to lipopolysaccharide or other TLR ligands induces tolerance in intracellular signalling pathways, which
is often associated with a loss of TLR surface expression. For neutrophils, this means a stop in respiratory bursts,3 which might contribute to the therapeutic effect in autoimmune diseases such as rheumatoid arthritis. Given this background, I suggest that the same therapeutic effect could be achieved with small-molecule ligands of TLRs. Synthetic molecules generally behave as haptens and potentially reduce the risk of development of neutralising antibodies during longterm treatments. To this regard, I argue that the neutralising ability of antibodies against heat-shock protein 70 induced by repeated intravenous infusions cannot be estimated on the basis of maintenance of response alone, since no consistent dose-effect relation could be established for the patients on different doses. I declare that I have no conflict of interest.
Daniele Focosi [email protected] Division of Hematology, University of Pisa, via Roma 56, I-56100 Pisa, Italy 1
2
3
Vanags D, Williams B, Johnson B, et al. Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a doubleblind randomised trial. Lancet 2006; 368: 855–63. Johnson BJ, Le TT, Dobbin CA, et al. Heat shock protein 10 inhibits lipopolysaccharide-induced inflammatory mediator production. J Biol Chem 2005; 280: 4037–47. Parker LC, Jones EC, Prince LR, et al. Endotoxin tolerance induces selective alterations in neutrophil function. J Leukoc Biol 2005; 78: 1301–05.
See Department of Error page 1964
Authors’ reply Hiroshi Okamoto refers to a study by Aykol and colleagues,1 which shows that serum samples from patients with ovarian cancer that contain chaperonin 10 immunoreactivity can reduce the expression of T-cell CD3-zeta. We interpret these findings as the identification of another potential immunomodulatory aspect of chaperonin 10, but not proof that chaperonin 10 can precipitate a tumour or influence tumour growth. We have carefully investigated the growth of a panel of tumour cells
e-mail submissions to [email protected]
1961