JAC Advance Access originally published online on December 1, 2006
Journal of Antimicrobial Chemotherapy 2007 59(1):159-160; doi:10.1093/jac/dkl462
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Correspondence |
Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation—author's response
Department of Infectious Diseases and Immunity, Hammersmith Hospital, Imperial College London Du Cane Road, London W12 0NN, UK
*Correponding author. Tel: +44-208-383-3135; Fax: +44-208-383-3394; E-mail: s.sriskandan{at}imperial.ac.uk
Keywords: bacterial infections , models , septic shock , Streptococcus pyogenes , immunology , immunomodulators
Sir,
The failure of Rajagopalan et al.1 to demonstrate any effect of intravenous immunoglobulin (IVIg) in vitro is perplexing, as several investigators have demonstrated the inhibitory properties of IVIg on superantigen-induced T cell mitogenesis and blast formation in vitro.2–6 Although variation in IVIg source may partly explain their results, the correspondents used only a single concentration of IVIg (1 mg/mL) in their in vitro tests and therefore cannot draw firm conclusions about activity. Furthermore, they used higher concentrations of superantigen than were present in Streptococcus pyogenes supernatants used in our study.7
Using the same batch of IVIg used in our original report,7 IVIg 0.5 mg/mL was sufficient to cause 50% inhibition of 10 ng/mL staphylococcal enterotoxin B (SEB)- or streptococcal pyrogenic exotoxin A (SPEA)-induced T-cell proliferation. Importantly, when the concentration of SEB was raised to 10 µg/mL, inhibition required concentrations of 5 mg/mL IVIg (L. Faulkner and S. Sriskandan, unpublished data), illustrating the importance of conducting a dose–response. This is reinforced by the report by Schrage et al.,6 who required a concentration range of 1–5 mg/mL IVIg to demonstrate the inhibition of 12 different superantigens. Moreover, these authors found that most commercial IVIg preparations had even better neutralizing activity than the preparation used in our study, reaffirming the point regarding the source of IVIg.
The main purpose of our study was to evaluate IVIg action on inflammation and outcome in S. pyogenes infection, rather than to re-evaluate the in vitro activity of IVIg against purified superantigens. For this reason, the superantigen-inhibiting properties of IVIg were assessed as a preliminary step only. Culture supernatants were used rather than purified superantigens, as these are representative of both the mixture of superantigens and concentrations that prevail in patients.8 Streptococcal mitogenic exotoxin Z (‘SMEZ’) is active at 10 fg/mL and is normally found in nature at levels of less than 10 pg/mL,8,9 whereas Rajagopalan et al. used a superantigen concentration several logs in excess of this. Although not the major focus, our data showed unequivocally that IVIg could quantitatively inhibit the mitogenic actions of the superantigens produced by S. pyogenes both in vitro and, from the infection studies, in vivo as well. Nonetheless, IVIg 1 mg/kg was insufficient to completely neutralize superantigen mitogenicity during S. pyogenes infection.7 It is therefore perhaps unsurprising that Rajagopalan et al. found that proportionate expansion of T-cell subsets expressing relevant TCR Vß families was unaltered in mice treated with 1 mg/kg IVIg as this may simply be a consequence of residual Vß-specific effects, notwithstanding quantitative effects of IVIg on mitogenicity and blast formation.
The key questions arising from our study include, first, whether the modulation of inflammation and bacterial clearance provided by IVIg in S. pyogenes-infected HLA-DQ8 mice has anything to do with the ability of IVIg to inhibit superantigen-induced mitogenesis? IVIg has several additional potentially protective actions, and studies are on-going to evaluate these. Secondly, it remains unclear if IVIg can confer additional benefit to ‘gold standard’ therapy in human streptococcal toxic shock, as, in HLA-DQ8 mice, this was not evident.
Transparency declarations
Imperial College London was awarded a research grant (2000–2002) from Baxter Healthcare. The author declares no additional competing interests.
References
1 Rajagopalan G, Patel R, Kaveri SV, et al. Comment on: Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation. J Antimicrob Chemother doi:10.1093/jac/dkl430.
2 Takei S, Arora YK, Walker SM. (1993) Intravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by staphylococcal toxin superantigens. J Clin Invest 91:602–7.[ISI][Medline]
3 Skansen-Saphir U, Andersson J, Bjork L, et al. (1994) Lymphokine production induced by streptococcal pyrogenic exotoxin-A is selectively down-regulated by pooled human IgG. Eur J Immunol 24:916–22.[ISI][Medline]
4 Baudet V, Hurez V, Lapeyre C, et al. (1996) Intravenous immunoglobulin (IVIg) modulates the expansion of Vß3+ and Vß17+ T cells induced by staphylococcal enterotoxin B superantigen in vitro. Scand J Immunol 43:277–82.[ISI][Medline]
5 Darenberg J, Soderquist B, Normark BH, et al. (2004) Differences in potency of intravenous polyspecific immunoglobulin G against streptococcal and staphylococcal superantigens: implications for therapy of toxic shock syndrome. Clin Infect Dis 38:836–42.[CrossRef][ISI][Medline]
6 Schrage B, Duan G, Yang LP, et al. (2006) Different preparations of intravenous immunoglobulin vary in their efficacy to neutralize streptococcal superantigens: implications for treatment of streptococcal toxic shock syndrome. Clin Infect Dis 43:743–6.[CrossRef][ISI][Medline]
7
Sriskandan S, Ferguson M, Elliot V, et al. (2006) Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation. J Antimicrob Chemother 58:117–24.
8 Proft T, Sriskandan S, Yang L, et al. (2003) Superantigens and streptococcal toxic shock syndrome. Emerg Infect Dis 9:1211–8.[ISI][Medline]
9
Unnikrishnan M, Altmann D, Proft T, et al. (2002) The streptococcal superantigen SMEZ is the major immunoactive agent of Streptococcus pyogenes. J Immunol 169:2561–9.
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