Humanlike Immune Response of Human Leukocyte Antigen–DR3 Transgenic Mice to Staphylococcal Enterotoxins: A Novel Model for Superantigen Vaccines

DaSilva, Luis; Welcher, Brent; Ulrich, Robert G.; Aman, M. Javad; David, Chella S.; Bavari, Sina

doi:10.1086/340828

Cited by 66 publications

(60 citation statements)

References 52 publications

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“…By contrast, the humanized HLA class II-tg mice have shown high sensitivity to bacterial SAgs; T cells from these mice respond vigorously to bacterial SAgs in a way similar to human T cells without any manipulation, suggesting a SAg presentation pattern comparable to that in humans (24,25). Several studies have used HLA-tg mice to investigate immune responses to SAgs and SAgproducing bacteria (20, 24 -26).…”

Section: Discussionmentioning

confidence: 99%

“…This difference relates, in part, to the lower binding affinity of SAgs to murine MHC class II as compared with human HLA class II (21). The advent of the HLA class II transgenic (HLA-tg) mice provided an opportunity to study the pathogenesis of GAS in a readily manipulated animal model with a sensitivity to SAgs similar to that of humans (22)(23)(24)(25)(26). Indeed, several studies have shown that HLA-tg mice mount potent responses to GAS SAgs (20,23,25,27,28).…”

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confidence: 99%

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HLA Transgenic Mice Provide Evidence for a Direct and Dominant Role of HLA Class II Variation in Modulating the Severity of Streptococcal Sepsis

Nooh

El-Gengehi

Kansal

et al. 2007

The Journal of Immunology

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Our epidemiologic studies on invasive Group A Streptococci (GAS) infections identified specific HLA class II haplotypes/alleles conferring high-risk or protection from streptococcal toxic shock syndrome with a strong protection conferred by the DRB1*15/DQB1*06 haplotype. We used HLA-transgenic mice to provide an in vitro and in vivo validation for the direct role of HLA class II allelic variation in streptococcal toxic shock syndrome. When splenocytes from mice expressing the protective HLA-DQB1*06 (DQ6) allele were stimulated with a mixture of streptococcal superantigens (SAgs), secreted by the prevalent M1T1 strain, both proliferative and cytokine responses were significantly lower than those of splenocytes from mice expressing the neutral DRB1*0402/DQB1*0302 (DR4/DQ8) alleles (p < 0.001). In crisscross experiments, the presentation of SAgs to pure T cells from either the DQ6 or the DR4/DQ8 mice resulted in significantly different levels of response depending on the HLA type expressed on the APCs. Presentation by HLA-DQ6 APCs elicited significantly lower responses than the presentation by HLA-DR4/DQ8 APCs. Our in vitro data were supported by in vivo findings, as the DQ6 mice showed significantly longer survival post-i.v. infection with live M1T1 GAS (p < 0.001) and lower inflammatory cytokine responses as compared with the DR4/DQ8 mice (p < 0.01). The data presented here provide evidence for a direct role of HLA class II molecules in modulating responses to GAS SAgs and underscore the dominant role of HLA class II allelic variation in potentiating the severity of GAS systemic infections.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

HLA Transgenic Mice Provide Evidence for a Direct and Dominant Role of HLA Class II Variation in Modulating the Severity of Streptococcal Sepsis

Nooh

El-Gengehi

Kansal

et al. 2007

The Journal of Immunology

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“…Challenging HLA-II transgenic mice with SAgs thorough several different routes elicits robust SIRS and renders them highly susceptible to TSS. [40][41][42][43][44][45][46][47][48][49] One of our HLA-II transgenic lines that expresses HLA-DR3 is extremely sensitive to SEB. HLA-DR3 transgenic mice readily die of SEB-induced TSS without D-galN sensitization.…”

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confidence: 99%

Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

Tilahun

Marietta

et al. 2011

The American Journal of Pathology

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Among the exotoxins produced by Staphylococcus aureus and Streptococcus pyogenes, the superantigens (SAgs) are the most potent T-cell activators known to date. SAgs are implicated in several serious diseases including toxic shock syndrome (TSS), Kawasaki disease, and sepsis. However, the immunopathogenesis of TSS and other diseases involving SAgs are still not completely understood. The commonly used conventional laboratory mouse strains do not respond robustly to SAgs in vivo. Therefore, they must be artificially rendered susceptible to TSS by using sensitizing agents such as D-galactosamine (D-galN), which skews the disease exclusively to the liver and, hence, is not representative of the disease in humans. SAg-induced TSS was characterized using transgenic mice expressing HLA class II molecules that are extremely susceptible to TSS without D-galN. HLA-DR3 transgenic mice recapitulated TSS in humans with extensive multiple-organ inflammation affecting the lung, liver, kidneys, heart, and small intestines. Heavy infiltration with T lymphocytes (both CD4 ؉ and CD8؉), neutrophils, and macrophages was noted. In particular, the pathologic changes in the small intestines were extensive and accompanied by significantly altered absorptive functions of the enterocytes. In contrast to massive liver failure alone in the D-galN sensitization model of TSS, findings of the present study suggest that gut dysfunction might be a key pathogenic event that leads to high morbidity and mortality in humans with

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“…This synergistic action was observed whether the mouse antibodies or chimeric equivalents of the antibody pair were used. However, because it is well established that SEB-mediated effects are seen at much lower toxin concentrations in systems bearing human rather than mouse class II MHC (11,14), it was important to determine the ability of our pair of chimeric antibodies to neutralize SEB in HLA-DR3 transgenic mice, a more demanding and humanlike model system than conventional mice (11,44,45,50,51). Both chimeric antibodies effected neutralization in this transgenic model and, when used together, were synergistic in their neutralization of SEB in cultures derived from HLA-DR3 transgenic mice.…”

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confidence: 99%

Potent Neutralization of Staphylococcal Enterotoxin B by Synergistic Action of Chimeric Antibodies

et al. 2010

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Staphylococcal enterotoxin B (SEB), a shock-inducing exotoxin synthesized by Staphylococcus aureus, is an important cause of food poisoning and is a class B bioterrorism agent. SEB mediates antigen-independent activation of a major subset of the T-cell population by cross-linking T-cell receptors (TCRs) with class II major histocompatibility complex (MHC-II) molecules of antigen-presenting cells, resulting in the induction of antigen independent proliferation and cytokine secretion by a significant fraction of the T-cell population. Neutralizing antibodies inhibit SEB-mediated T-cell activation by blocking the toxin's interaction with the TCR or MHC-II and provide protection against the debilitating effects of this superantigen. We derived and searched a set of monoclonal mouse anti-SEB antibodies to identify neutralizing anti-SEB antibodies that bind to different sites on the toxin. A pair of non-cross-reactive, neutralizing anti-SEB monoclonal antibodies (MAbs) was found, and a combination of these antibodies inhibited SEB-induced T-cell proliferation in a synergistic rather than merely additive manner. In order to engineer antibodies more suitable than mouse MAbs for use in humans, the genes encoding the VL and VH gene segments of a synergistically acting pair of mouse MAbs were grafted, respectively, onto genes encoding the constant regions of human Ig and human IgG1, transfected into mammalian cells, and used to generate chimeric versions of these antibodies that had affinity and neutralization profiles essentially identical to their mouse counterparts. When tested in cultures of human peripheral blood mononuclear cells or splenocytes derived from HLA-DR3 transgenic mice, the chimeric human-mouse antibodies synergistically neutralized SEB-induced T-cell activation and cytokine production.

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Humanlike Immune Response of Human Leukocyte Antigen–DR3 Transgenic Mice to Staphylococcal Enterotoxins: A Novel Model for Superantigen Vaccines

Cited by 66 publications

References 52 publications

HLA Transgenic Mice Provide Evidence for a Direct and Dominant Role of HLA Class II Variation in Modulating the Severity of Streptococcal Sepsis

HLA Transgenic Mice Provide Evidence for a Direct and Dominant Role of HLA Class II Variation in Modulating the Severity of Streptococcal Sepsis

Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

Potent Neutralization of Staphylococcal Enterotoxin B by Synergistic Action of Chimeric Antibodies

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