Heat shock protein-peptide complexes elicit cytotoxic T-lymphocyte and antibody responses specific for bovine herpesvirus 1

Navaratnam, Manjula; Deshpande, Muralidhar; Hariharan, Mangala J.; Zatechka, Douglas S.; Srikumaran, Subramaniam

doi:10.1016/s0264-410x(00)00381-9

Cited by 52 publications

(35 citation statements)

References 35 publications

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“…We have previously shown that HSP110 in a complex with ICD could generate ICD-specific Ab responses in A2/Kb transgenic mice. Others also reported that gp96 isolated from a syngeneic cell line transduced with BHV-1 glycoprotein D induced glycoprotein D-specific Abs (33). However, we used recombinant HSP110 rather than cell-derived HSP110, and then loaded it with a large Ag, ICD, which comprises numerous epitopes, including Th epitopes as well as B cell defined epitopes.…”

Section: Discussionmentioning

confidence: 99%

HSP110-HER2/neu Chaperone Complex Vaccine Induces Protective Immunity Against Spontaneous Mammary Tumors in HER-2/neu Transgenic Mice

Manjili¹,

Wang²,

Chen³

et al. 2003

The Journal of Immunology

105

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Heat shock proteins (HSPs) are shown to be strong immunoadjuvants, eliciting both innate and adaptive immune responses against cancers. HSP110 is related in sequence to HSP70 and is ∼4-fold more efficient in binding to and stabilizing denatured protein substrates compared with HSP70. In the present study we evaluated the ability of a heat shock complex of HSP110 with the intracellular domain (ICD) of human HER-2/neu to elicit effective antitumor immune responses and to inhibit spontaneous mammary tumors in FVB-neu (FVBN202) transgenic mice. The HSP110-ICD complex was capable of breaking tolerance against the rat neu protein and inhibiting spontaneous mammary tumor development. This vaccine induced ICD-specific IFN-γ and IL-4 production. Depletion studies revealed that CD8+ T cells were involved in protection against challenge with mouse mammary tumors, whereas CD4+ T cells revealed partial protection. Increased IgG2a Ab titer in the sera of tumor-free animals after vaccination and elevated CD4+ CD25+ regulatory T cells in the PBL of tumor-bearing animals suggested that IFN-γ-producing Th1 cells may be responsible for partial protection of CD4+ T cells against the mammary tumor challenge, whereas CD4+CD25+ regulatory T cells (Th2 cells) may suppress the antitumor immune responses. Together, these results suggest that HSP110-ICD complex can elicit effective IFN-γ-producing T cells against spontaneous mammary tumors and that up-regulation of CD4+ CD25+ regulatory T cells may prevent complete eradication of the tumor following immunotherapy.

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Section: Discussionmentioning

confidence: 99%

HSP110-HER2/neu Chaperone Complex Vaccine Induces Protective Immunity Against Spontaneous Mammary Tumors in HER-2/neu Transgenic Mice

Manjili¹,

Wang²,

Chen³

et al. 2003

The Journal of Immunology

105

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“…In posing this question, it should again be reiterated that in vitro assembled complexes of gp96 and synthetic peptides are efficiently internalized through APCs and their bound peptides re-presented on MHC class I molecules to yield peptide-specific T cell activation (Blachere et al 1993;Srivastava et al 1994;Navaratnam et al 2001;Berwin et al 2002;Hilf et al 2002;Staib et al 2004). These findings are of clear immunotherapeutic significance, particularly in light of recent findings demonstrating the validity of this approach in human cell-based assays (Staib et al 2004).…”

Section: A Brief History Of the Life Of A Peptidementioning

confidence: 99%

The messenger and the message: gp96 (GRP94)-peptide interactions in cellular immunity

Nicchitta¹,

Carrick²,

Baker-LePain³

2004

Cell Stress Chaper

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Vaccination of mice with tumor-derived stress proteins, such as Hsp70 and gp96 (GRP94), can elicit antitumor immune responses, yielding a marked suppression of tumor growth and metastasis. The molecular basis for this response is proposed to reflect a peptide-binding function for these proteins. In this view, stress proteins bind the antigenic peptide repertoire of their parent cell, and when provided to the immune system, tumor-derived stress proteinpeptide complexes are processed by antigen-presenting cells (APCs) to yield the subsequent activation of tumordirected cytotoxic T lymphocyte activity. This model predicts that stress proteins, whose primary intracellular function concerns the proper folding and assembly of nascent polypeptides, intersect with the cellular pathways responsible for the generation, processing, or assembly (or all) of peptide antigens onto nascent major histocompatability class I molecules. Recent insights into the pathways for peptide generation now allow this hypothesis to be critically examined, which is the subject of this review.

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“…Thus, defined antigenic peptides derived from viral Ags (6 -8), tumor Ags (9), mycobacterial Ags (10), model Ags (11), or minor histocompatibility Ags (12) have been isolated from gp96, hsp90, or hsp70. Furthermore, immunological evidence has been reported for association of these same HSPs with well-characterized epitopes of viral Ags (7,8), tumor Ags (13)(14)(15), or model Ags (11,16). Peptide-binding sites of hsp70 (17,18) and gp96 (19,20) have been demonstrated by crystallography and modeling studies.…”

mentioning

confidence: 93%

Specific Immunogenicity of Heat Shock Protein gp96 Derives from Chaperoned Antigenic Peptides and Not from Contaminating Proteins

Binder

Kelly

Vatner

et al. 2007

The Journal of Immunology

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The peptide-binding property of MHC is central to adaptive immunological functions. A similar property of heat shock proteins (HSPs) hsp70 and hsp90 has been implicated in Ag presentation by MHC and in cross-priming. The peptide-binding pocket of hsp70 has been characterized structurally and functionally and a peptide-binding site in gp96 (of hsp90 family) has been defined. Nonetheless, questions persist whether the specific immunogenicity of HSP preparations derives from the peptides chaperoned by the HSPs or by proteins contaminating the HSP preparations. Because absolute purity of a protein preparation is a metaphysical concept, other approaches are necessary to address the question. In this study, we demonstrate that the specific immunogenicity of gp96 preparations isolated from cells expressing β-galactosidase derives from the MHC I epitope precursors associated with the gp96 and not from contaminating β-galactosidase protein nor unassociated fragments derived from it. Although the observations here are limited to a single HSP and antigenic peptides chaperoned by it, they can be extended broadly.

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Heat shock protein-peptide complexes elicit cytotoxic T-lymphocyte and antibody responses specific for bovine herpesvirus 1

Cited by 52 publications

References 35 publications

HSP110-HER2/neu Chaperone Complex Vaccine Induces Protective Immunity Against Spontaneous Mammary Tumors in HER-2/neu Transgenic Mice

HSP110-HER2/neu Chaperone Complex Vaccine Induces Protective Immunity Against Spontaneous Mammary Tumors in HER-2/neu Transgenic Mice

The messenger and the message: gp96 (GRP94)-peptide interactions in cellular immunity

Specific Immunogenicity of Heat Shock Protein gp96 Derives from Chaperoned Antigenic Peptides and Not from Contaminating Proteins

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