Cell-secreted Gp96-Ig-peptide complexes induce lamina propria and intraepithelial CD8+ cytotoxic T lymphocytes in the intestinal mucosa

Štrbo, Nataša; Pahwa, Savita; Kolber, Michael A.; Gonzalez, Louis; Fisher, Eva; Podack, Eckhard R.

doi:10.1038/mi.2009.127

Cited by 24 publications

(47 citation statements)

References 47 publications

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“…Criteria for differential expression were an absolute change of Ͼ1.4-fold and a P value of Ͻ0.05, calculated using a moderated t test (see Materials and Methods). It has previously been described that the gp96-Ig vaccine approach (delivered by the intraperitoneal route) induces a strong mucosal immune response, while systemic immune responses are not significantly upregulated (13,14). Therefore, the observed lack of gene expression in whole blood during the vaccination phase was not surprising.…”

Section: Resultsmentioning

confidence: 92%

“…This heat shock protein, similar to soluble Hsfp and hsp65 (8,9), binds to and activates dendritic cells (10) and functions as a chaperone for tumor-secreted peptides. The modified form of gp96, gp96-Ig, secreted by tumors (11), results in an enhancement of tumor antigen crosspriming of CD8 cytotoxic T lymphocytes (CTLs) (12) and induces a mucosal immune response following intraperitoneal injection of transfected cells (13). When chaperoning simian immunodeficiency virus (SIV) peptides, gp96-Ig induces a strong multifunctional memory response in the rectal and vaginal mucosae of rhesus macaques (14).…”

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confidence: 99%

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Multiple Low-Dose Challenges in a Rhesus Macaque AIDS Vaccine Trial Result in an Evolving Host Response That Affects Protective Outcome

Selinger

Štrbo

Gonzalez

et al. 2014

Clin. Vaccine Immunol.

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dUsing whole-blood transcriptional profiling, we investigated differences in the host response to vaccination and challenge in a rhesus macaque AIDS vaccine trial. Samples were collected from animals prior to and after vaccination with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig loaded with simian immunodeficiency virus (SIV) peptides, either alone or in combination with a SIV-gp120 protein boost. Additional samples were collected following multiple low-dose rectal challenges with SIV mac251 . Animals in the boosted group had a 73% reduced risk of infection. Surprisingly, few changes in gene expression were observed during the vaccination phase. Focusing on postchallenge comparisons, in particular for protected animals, we identified a host response signature of protection comprised of strong interferon signaling after the first challenge, which then largely abated after further challenges. We also identified a host response signature, comprised of early macrophage-mediated inflammatory responses, in animals with undetectable viral loads 5 days after the first challenge but with unusually high viral titers after subsequent challenges. Statistical analysis showed that prime-boost vaccination significantly lowered the probability of infection in a time-consistent manner throughout several challenges. Given that humoral responses in the prime-boost group were highly significant prechallenge correlates of protection, the strong innate signaling after the first challenge suggests that interferon signaling may enhance vaccine-induced antibody responses and is an important contributor to protection from infection during repeated low-dose exposure to SIV.

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Section: Resultsmentioning

confidence: 92%

mentioning

confidence: 99%

Multiple Low-Dose Challenges in a Rhesus Macaque AIDS Vaccine Trial Result in an Evolving Host Response That Affects Protective Outcome

Selinger

Štrbo

Gonzalez

et al. 2014

Clin. Vaccine Immunol.

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show abstract

“…Our present study is supported by work of Podack and colleagues showing that enforced secretion of gp96 from tumor cells enhances the generation of antitumor CD8 T cell responses. In those reports, CD11c + cells were identified as the necessary APCs for the immune response (40,41). …”

Section: Discussionmentioning

confidence: 99%

Establishment of Tumor-Associated Immunity Requires Interaction of Heat Shock Proteins with CD91

Zhou

Messmer

Binder

2014

Cancer Immunology Research

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Host antitumor adaptive immune responses are generated as a result of the body’s immunosurveillance mechanisms. How the antitumor immune response is initially primed remains unclear, given that soluble tumor antigens generally are quantitatively insufficient for cross-priming and tumors lack the classical pathogen-associated molecular patterns (PAMPs) to activate costimulation and initiate cross-priming. We explored the interaction of the tumor-derived heat-shock proteins (HSP) with their common receptor (CD91) on antigen presenting cells (APCs) as a mechanism for host-priming of T cell-mediated antitumor immunity. Using targeted genetic disruption of the interaction between HSPs and CD19, we demonstrated that specific ablation of CD91 in APCs prevented the establishment of antitumor immunity. The antitumor immunity was also inhibited when the transfer of tumor-derived HSPs to APCs was prevented using an endogenous inhibitor of CD91. Inhibition was manifested in a reduction of cross-presentation of tumor-derived antigenic peptides in the lymph nodes providing a molecular basis for the observed immunity associated with tumor development. Our findings demonstrate that early in tumor development, the HSP-CD91 pathway is critical for the establishment of antitumor immunity.

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“…Over the last two decades, Dr. Podack and his group have developed an innovative vaccine approach based on a genetically modified form of the endoplasmic reticulum (ER) chaperone gp96, the fusion protein gp96-Ig. The gp96-Ig vaccine is composed of live, but replication incompetent cells, containing the antigens of interest and secreting gp96-Ig, which has been introduced into the cell by transfection and G418-selection [40–48]. Secreted gp96-Ig chaperones peptides (gp96 pep -Ig) come into ER via the TAP transporter [49].…”

Section: Generation Of Humanized Micementioning

confidence: 99%

“…In murine studies, nonhuman primates and in cancer patients, we have shown that gp96-Ig-based vaccines generate CD8 CTL responses to gp96-Ig-chaperoned, antigenic peptides derived from SIV or HIV and to other test antigens. Immune responses ensue systemically and are especially powerful in the intestinal, rectal and vaginal mucosa [40, 47, 51]. …”

Section: Generation Of Humanized Micementioning

confidence: 99%

Humanized mice: novel model for studying mechanisms of human immune-based therapies

2013

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The lack of relevant animal models is the major bottleneck for understanding human immunology and immunopathology. In the last few years, a novel model of humanized mouse has been successfully employed to investigate some of the most critical questions in human immunology. We have set up and tested in our laboratory the latest technology for generating mice with a human immune system by reconstituting newborn immunodeficient NOD/SCID-γc-/- mice with human fetal liver-derived hematopoietic stem cells. These humanized mice have been deemed most competent as human models in a thorough comparative study with other humanized mouse technologies. Lymphocytes in these mice are of human origin while other hematopoietic cells are chimeric, partly of mouse and partly of human origin. We demonstrate that human CD8 T lymphocytes in humanized mice are fully responsive to our novel cell-based secreted heat shock protein gp96HIV-Ig vaccine. We also show that the gp96HIV-Ig vaccine induces powerful mucosal immune responses in the rectum and the vagina, which are thought to be required for protection from HIV infection. We posit the hypothesis that vaccine approaches tested in humanized mouse models can generate data rapidly, economically and with great flexibility (genetic manipulations are possible), to be subsequently tested in larger nonhuman primate models and humans.

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Cell-secreted Gp96-Ig-peptide complexes induce lamina propria and intraepithelial CD8+ cytotoxic T lymphocytes in the intestinal mucosa

Cited by 24 publications

References 47 publications

Multiple Low-Dose Challenges in a Rhesus Macaque AIDS Vaccine Trial Result in an Evolving Host Response That Affects Protective Outcome

Multiple Low-Dose Challenges in a Rhesus Macaque AIDS Vaccine Trial Result in an Evolving Host Response That Affects Protective Outcome

Establishment of Tumor-Associated Immunity Requires Interaction of Heat Shock Proteins with CD91

Humanized mice: novel model for studying mechanisms of human immune-based therapies

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