Heat shock protein 70: role in antigen presentation, and immune stimulation

被引:143
作者
Milani, V
Noessner, E
Ghose, S
Kuppner, M
Ahrens, B
Scharner, A
Gastpar, R
Issels, RD [1 ]
机构
[1] GSF Munich, Natl Res Ctr Environm & Hlth, KKG Hyperthermie, D-81377 Munich, Germany
[2] GSF Munich, Natl Res Ctr Environm & Hlth, Inst Mol Immunol, D-81377 Munich, Germany
[3] Univ Munich, Med Klin 3, Klinikum Grosshadern, D-81377 Munich, Germany
[4] Klinikum Univ Regensburg, D-93053 Regensburg, Germany
关键词
antigen presentation; dendritic cells; human model; tumour immunity; Toll-like receptor; hyperthermia;
D O I
10.1080/02656730210166140
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Heat shock proteins (HSP) when released into the extracellular milieu can act simultaneously as a source of antigen due to their ability to chaperone peptides and as a maturation signal for dendritic cells, thereby inducing DCs to cross-present antigens to CD8+ T-cells. HSP can also act independently from associated peptides, stimulating the innate immune system. Previous results regarding the activation of NK cells by HSP70 cell surface expression on tumour cells and soluble HSP70 will be further covered elsewhere within this issue. For cross-presentation, HSP70-peptide complexes (HSP70-PC) were used from two human melanoma cell lines that differ in the expression of the tumour-associated antigen tyrosinase. Purified HSP70-PC consists of both the constitutively expressed HSC70 and the inducible HSP70. HSP70-peptide complexes purified from tyrosinase positive (HSP70-PC/tyr(+)) human melanoma cells, incubated with immature DCs, results in the activation of HLA-*A0201-restricted tyrosinase peptide-specific T-cells. Receptor-mediated uptake of HSP70-PC by DCs and intracellular transport are required for efficient MHC class I restricted cross-presentation of chaperoned peptides. Demonstration of HSP70-PC mediated cross-presentation of such non-mutated naturally expressed tumour antigens is of special clinical interest with regard to hyperthermia. Tumour regression and improved local control have been shown within clinical phase II/III trials integrating regional hyperthermia combined with radiation and/or chemotherapy in multimodal treatment strategies. According to the proposed concept, local necrosis induced by hyperthermic treatment induces the release of HSPs, followed by uptake, processing and presentation of associated peptides by DCs. By acting as chaperone and a signal for DC maturation, HSP70-PC might efficiently prime circulating T-cells. Therefore, upregulating HSP70 and causing local necrosis in turnout tissue by hyperthermia offers great potential as a new approach to directly activate the immune system.
引用
收藏
页码:563 / 575
页数:13
相关论文
共 85 条
[1]   Toll-like receptors in the induction of the innate immune response [J].
Aderem, A ;
Ulevitch, RJ .
NATURE, 2000, 406 (6797) :782-787
[2]   The role of Toll-like receptors and MyD88 in innate immune responses [J].
Akira, S ;
Hoshino, K ;
Kaisho, T .
JOURNAL OF ENDOTOXIN RESEARCH, 2000, 6 (05) :383-387
[3]   Toll-like receptors: critical proteins linking innate and acquired immunity [J].
Akira, S ;
Takeda, K ;
Kaisho, T .
NATURE IMMUNOLOGY, 2001, 2 (08) :675-680
[4]  
Arnold-Schild D, 1999, J IMMUNOL, V162, P3757
[5]   Novel signal transduction pathway utilized by extracellular HSP70 -: Role of Toll-like receptor (TLR) 2 AND TLR4 [J].
Asea, A ;
Rehli, M ;
Kabingu, E ;
Boch, JA ;
Baré, O ;
Auron, PE ;
Stevenson, MA ;
Calderwood, SK .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (17) :15028-15034
[6]   HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine [J].
Asea, A ;
Kraeft, SK ;
Kurt-Jones, EA ;
Stevenson, MA ;
Chen, LB ;
Finberg, RW ;
Koo, GC ;
Calderwood, SK .
NATURE MEDICINE, 2000, 6 (04) :435-442
[7]   Dendritic cells and the control of immunity [J].
Banchereau, J ;
Steinman, RM .
NATURE, 1998, 392 (6673) :245-252
[8]   Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-κB pathway [J].
Basu, S ;
Binder, RJ ;
Suto, R ;
Anderson, KM ;
Srivastava, PK .
INTERNATIONAL IMMUNOLOGY, 2000, 12 (11) :1539-1546
[9]   CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin [J].
Basu, S ;
Binder, RJ ;
Ramalingam, T ;
Srivastava, PK .
IMMUNITY, 2001, 14 (03) :303-313
[10]   CD91: a receptor for heat shock protein gp96 [J].
Binder, RJ ;
Han, DK ;
Srivastava, PK .
NATURE IMMUNOLOGY, 2000, 1 (02) :151-155