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ABSTRACT: GD3, a ganglioside expressed on melanoma, is the only tumour-associated glycolipid described to date that can induce a CD1d-restricted natural killer T (NKT)-cell response. We analysed the fine specificity of GD3-reactive NKT cells and discovered that immunization with GD3 induced two populations of GD3-reactive NKT cells. One population was CD4+ CD8- and was specific for GD3; the other population was CD4- CD8- and cross-reacted with GM3 in a CD1d-restricted manner, but did not cross-react with GM2, GD2, or lactosylceramide. This indicated that the T-cell receptors reacting with GD3 recognize glucose-galactose linked to at least one N-acetyl-neuraminic acid but will not accommodate a terminal N-acetylgalactosamine. Immunization with GM2, GM3, GD2, or lactosylceramide did not induce an NKT-cell response. Coimmunization of GM3-loaded antigen-presenting cells (APCs) with GD3-loaded APCs suppressed the NKT-cell response to GD3 in a CD1d-restricted manner. This suppressive effect was specific for GM3 and was a local effect lasting 2-4 days. In vitro, GM3-loaded APCs also suppressed the interleukin-4 response, but not the interferon-gamma response, of NKT cells to alpha-galactosylceramide. However, there was no effect on the T helper type 2 responses of conventional T cells. We found that this suppression was not mediated by soluble factors. We hypothesize that GM3 induces changes to the APC that lead to suppression of T helper type 2-like NKT-cell responses.
Immunology 02/2008; 123(1):145-55. · 3.32 Impact Factor
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ABSTRACT: When chaperoning tumour antigens, glucose-regulated protein 170 (GRP170) is capable of inducing effective antitumour immune responses. In the present study, we determined whether such immunoadjuvant properties of GRP170 also involve the ability to induce 'danger signals' through interaction with APC. We prepared recombinant GRP170 in the baculovirus expression system with low endotoxin concentration at which LPS did not have any effect on dendritic cells (DC). We showed that GRP170 binds DC in a receptor-mediated fashion and induces DC to upregulate the expression of MHC class II, CD86 and CD40 molecules, and to secrete pro-inflammatory cytokines. GRP170 also induced expression of CD40 molecules in a B16F10 cell line, whereas LPS failed to do so. These findings show that GRP170 acts as a danger signal through its interaction with DC, regardless of its endotoxin component.
Immunology and Cell Biology 05/2006; 84(2):203-8. · 3.66 Impact Factor
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John G Facciponte,
Xiang-Yang Wang,
Ian J MacDonald, Jun-eui Park,
Hilal Arnouk,
Melissa J Grimm,
Ying Li,
Hyung Kim,
Masoud H Manjili,
Douglas P Easton,
John R Subjeck
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ABSTRACT: Several heat shock proteins (HSPs) act as potent adjuvants for eliciting anti-tumor immunity. HSP-based tumor vaccine strategies have been highly successful in animal models and are undergoing testing in clinical trials. It is generally accepted that HSPs, functioning as chaperones for tumor antigens, elicit tumor-specific adaptive immune responses. HSPs also appear to induce innate immune responses in an antigen-independent fashion. Innate responses generated by HSPs may contribute to anti-tumor immunity. Immunologically active chaperones with anti-tumor activity are referred to as "immunochaperones". Here, we review the studies that address the role of structural domains or regions of the immunochaperones HSP70 and GP96 that may be involved in the induction of adaptive or innate immune responses.
Cancer Immunology and Immunotherapy 04/2006; 55(3):339-46. · 3.70 Impact Factor
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ABSTRACT: When used as vaccines, tumor-derived stress proteins can elicit antitumor immune responses. For members of the hsp70 superfamily, like grp170, this seems to be due to (a) the chaperoning of antigenic peptide by the stress protein and (b) the binding of the stress protein to receptor(s) on antigen-presenting cells (APC) and subsequent antigen presentation. This suggests that domains exist on the stress protein for each function. In this study, we determine the ability of grp170 and its structural domains to (a) bind to and present melanoma-associated antigen gp100 to the immune system and (b) to bind to receptors on APCs. A direct correlation between chaperone function, binding to APCs in a receptor-like manner, and antitumor immunity was observed. Two mutants that share no common sequence, yet are both effective in their antitumor activities, compete with one another for APC binding. Studies of other members of the hsp70 superfamily, hsp110 and hsp70, or their domain deletion mutants, further confirmed that APC binding segregates with chaperoning function and not sequence. Therefore, these studies suggest that molecular chaperoning is involved in stress protein interactions with APCs, antigen binding, and in eliciting antitumor immunity, thus bridging this ancient function of stress proteins in prokaryotes to their ability to elicit immunity in higher organisms.
Cancer Research 02/2006; 66(2):1161-8. · 7.86 Impact Factor
