2002 Fiscal Year Final Research Report Summary
Immuno-gene therapy by secreted gp96-Ig fusion protein
| Project/Area Number |
13670584
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
YAMAZAKI Koichi Hokkaido Univ. Med. Hospital, Assistant Prof., 医学部附属病院, 講師 (20312358)
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| Co-Investigator(Kenkyū-buntansha) |
AKITA Hirotoshi Hokkaido Univ. Grad. School of Med. Prof., 大学院・医学部研究科, 教授 (70222528)
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| Project Period (FY) |
2001 – 2002
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| Keywords | secreted heat shock fusion protein / gp96 / immuno-gene therapy / CD8 CTL / tumor rejection |
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| Research Abstract |
Gp96 has useful properties as tumor vaccine for the generation of CD8 CTL independent of MHC restriction. We have developed a secreted form of gp96-Ig (gp96-Ig) by deleting the endoplasmic reticulum retention signal, KDEL, and replacing it with the Fc portion of murine IgG_1. Tumor cells transfected with and overexpressing gp96-Ig were less tumorigenic, compared to wild type tumors. Immunization of mice with the murine lymphoma E.G7 transfected with gp96-Ig (E.G7-gp96-Ig), but not with irradiated E.G7, induced immunity to subsequent challenge with E.G7. Depletion studies showed that CD8^+ cells were required for E.G7-gp96-Ig rejection throughout induction phase and effector phase, but not CD4^+ cells or macrophages. In this study, we examined the immunotherapeutical potency by gp96-Ig gene-transfected tumor cells. E.G7 was established in C57BL/6 mice for three days. Daily injections, beginning on day 4, of gp96-Ig-transduced tumor cells suppressed tumor growth remarkably when compared
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to PBS treatment or to treatment with control tumors treatment with control tumors secreting gp96-Ig. Beginning vaccination on day 5 after tumor transplantation, successful therapy required a vaccination schedule of two daily injections of E.G7-gp96-lg. In a Jung tumor model. LLC, LLC-gp96-Ig vaccines were equally effective as gp96 purified from LLC cells and comparable to IL-12-transduced tumor cells (LLC/1L12). There were no synergistic effects by a 1:1 mixture of LLC-gp96-Ig and LLC/IL12, suggesting that the two vaccines may act through similar cellular mechanisms. CD4^+ T cells were not required for vaccines by gp96-Ig-transduced tumor cells. CD8^+ cytotoxic activities specific for wild type tumor cells were induced by vaccines with gp96-Ig-transduced tumor cells. Moreover, adoptively transferred, ovalbumin specific T-cell receptor (TCR) transgenic CD8^+ cells (OT-1) responded with clonal expansion to the immunization with EG7-gp96-Ig. Our data suggest that tumors secreting gp96-Ig may be useful as potent anti tumor vaccines. Less
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Research Products
(10 results)
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[Publications] Masutani M, Suzuki J, Matsuda T, Dochin A, Sadaoka K, Nomura A, Ohira K, Takahashi T, Yamazaki K, Dosaka-Akita H, Nishimura M, Kawakami Y.: "Increased apoptosis associated with depressed type of early intestinal gastric cancer"Jpn J Cancer Res. 92. 1214-1219 (2001)
Description
「研究成果報告書概要(欧文)」より
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