Abstract
Toxic shock syndrome (TSS) results from the host’s overwhelming inflammatory response and cytokine storm mainly due to superantigens (SAgs). There is no effective specific therapy. Application of immunoglobulins has been shown to improve the outcome of the disease and to neutralize SAgs both in vivo and in vitro. However, in most experiments that have been performed, antiserum was either pre-incubated with SAg, or both were applied simultaneously. To mirror more closely the clinical situation, we applied a multiple dose (over five days) lethal challenge in a rabbit model. Treatment with toxic shock syndrome toxin 1 (TSST-1) neutralizing antibody was fully protective, even when administered late in the course of the challenge. Kinetic studies on the effect of superantigen toxins are scarce. We performed in vitro kinetic studies by neutralizing the toxin with antibodies at well-defined time points. T-cell activation was determined by assessing T-cell proliferation (3H-thymidine incorporation), determination of IL-2 release in the cell supernatant (ELISA), and IL-2 gene activation (real-time PCR (RT-PCR)). Here we show that T-cell activation occurs continuously. The application of TSST-1 neutralizing antiserum reduced IL-2 and TNFα release into the cell supernatant, even if added at later time points. Interference with the prolonged stimulation of proinflammatory cytokines is likely to be in vivo relevant, as postexposure treatment protected rabbits against the multiple dose lethal SAg challenge. Our results shed new light on the treatment of TSS by specific antibodies even at late stages of exposure.
Highlights
Sepsis is the most common cause of death in critically ill patients, and it results from the overwhelming inflammatory response of the host [1], as well as from the inability of the immune system to limit bacterial spread during an ongoing infection
We first examined whether rabbits could be protected against multiple dose lethal challenge with rTSST-1 by pre-incubation of toxin with antiserum before application
Studying the kinetics of IL-2 secretion after rTSST-1 wt exposure, we found that the highest concentration of IL-2 in our system was detected at 24 h in the supernatant of the cultures
Summary
Sepsis is the most common cause of death in critically ill patients, and it results from the overwhelming inflammatory response of the host [1], as well as from the inability of the immune system to limit bacterial spread during an ongoing infection. SAg-specific antibodies from pooled sera could suppress T-cell proliferation in vitro and protect mice against SAg-induced TSS [31] In these previous studies, the toxin-neutralizing effect of antibodies was mostly analyzed by in vivo and in vitro systems in which antibodies were present before toxin challenge (e.g., through vaccination): Antibodies and toxins were applied either simultaneously or after pre-incubation, or antibodies were given after a single challenge with toxin. TSST-1 wild-type (rTSST-1 wt) within a five-day period in a rabbit multiple dose challenge model, mimicking the clinical situation of systemic Gram-positive bacterial infection with continuous exposure to toxins over a longer time period. In this model, treatment with neutralizing antibodies given late in the course of toxin challenge fully protected from toxin-induced lethality. Neutralization of the toxin stops cytokine gene transcription completely, if given within the first hours after toxin exposure
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