Abstract
The involvement of heat shock proteins in immune response is categorized into four distinct paradigms. In the First Paradigm, HSP derived from foreign organisms act as classical foreign antigens, and they elicit immune response to the non-conserved HSP epitopes. The Second Paradigm refers to instances where the host responds to self HSP to which there is no central or peripheral tolerance. The Third Paradigm involves molecular mimicry, where cross-reactivity between an HSP and another protein leads to an immune response to the latter under conditions which elicit an immune response to the former, such as infection with a bacterium whose immunodominant antigen is an HSP. The Fourth Paradigm refers to situations where an HSP-antigen complex elicits an effective response to the antigen andnot to the HSP. Thus the HSP acts as a carrier for the antigenic peptide. The role of HSP in recognition by γδ T cells may also fall into this paradigm. In this article, the Fourth Paradigm is considered as a crucial element in the development of vaccines against cancers and infectious diseases, and is analyzed through the prism of the observed association of hsp70 species with antigenic peptides.
Similar content being viewed by others
References
Barrios, C., Lussow, A. R., van Embden, J., Van der Zee, R., Rappuoli, R., Constantino, P., Louis, J. A., Lambert, P. H., and Del Giudice, G., Mycobacterial heat shock proteins as carrier molecules II: The use of the 70 kDa mycobacterial heat shock protein as carrier for conjugated vaccines can circumvent the need for adjuvants and BCG priming. Eur. J. Immun.22 (1992) 1365–1372.
Behr, C., Sarthou, J. L., Rogier, C., Trape, J. F., Dat, M. H., Michel, J. C., Aribot, G., Dieye, A., Claverie, J. M., and Druihle, P., Antibodies and reactive T cells against the malaria heat-shock protein Pf72/HSP70-1 and derived peptides in individuals continuously exposed to Plasmodium falciparum. J. Immun.149 (1992) 3321–3330.
Blachere, N. E., Udono, H., Janetzki, S., Li Z., Heike, M., and Srivastava, P. K., Heat shock protein vaccines against cancer. J. Immunotherapy14 (1993) 352–356.
Blander, S. J., and Horwitz, M., Major cytoplasmic membrane protein of Legionella pneumophila, a genus common antigen and member of the hsp60 family of heat shock proteins, induces protective immunity in a guinea pig model of Legionnaires' disease. J. invest. Dermat. 91 (1993) 717–23.
Cossart, P., and Mengaud, J., Listeria monocytogenes. A model system for the molecular study of intracellular parasitism. Molec. Biol. Med.6 (1989) 463–474.
Davenport, M. P., McKenzie, K. R., Basten, A., and Britton, W. J., The variable C-terminal region of the Mycobacterium leprae. 70-kilodalton heat shock protein is the target for humoral immune responses. Infect. Immun.60 (1992) 1170–1177.
Del Guidice, G., Experientia50 (1994) 1061–1066.
Ferrarini, M., Heltai, S., Zocchi, M. R., and Rugarli, C., Unusual expression and localization of heat shock proteins in human tumor cells. Int. J. Cancer51 (1992) 613–619.
Flynn, G. C., Chappell, T. G., and Rothman, J. E., Peptide binding and release by proteins implicated as catalysts of protein assembly. Science245 (1989) 385–390.
Fu, Y. X., Vollmer, B., Katalaradi, H., Heyborne, K., Reardon, C., Miles, C., O'Brien, R., and Born, W., Structural requirements for peptides that stimulate a sub-set of gamma delta T cells. J. Immun.152 (1994) 1578–1588.
Germain, R. N., MHC-dependent antigen processing and peptide presentation: Providing ligands for T lymphocyte activation. Cell76 (1994) 287–300.
Harboe, M., and Quayle, A. J., Heat shock proteins: friend and foe? Clin. expl. Immun.86 (1991) 2–5.
Houghton, A. N., Cancer antigens: Immune recognition of self and altered self. J. expl. Med.180 (1994) 1–4.
Jones, D. B., Coulson, A. F., and Duff, G. W., Sequence homologies between hsp60 and autoantigens. Immun. Today.14 (1993) 115–118.
Kellner, H., Wen, J., Wang, J., Raybourne, R. B., Williams, K. M., and Yu, D. T., Serum antibodies from patient with ankylosing spondylitis and Reiter's syndrome are reactive with HLA-B27 cells transfected with the Mycobacterium tuberculosis hsp60 gene. Infect. Immun.62 (1994) 484–491.
Koga, T., Wand-Wurttenberger, A., De Bruyn, J., Munk, M. E., Schoel, B., and Kaufmann, S. H. E., T cells against a bacterial heat shock protein recognize stressed macrophages. Science245 (1989) 1112–1115.
Lamb, J. R., Ivanyi, J., Rees, A. D. M., Rothbard, J., Howland, K., Young, R. A., and Young, D. B., Mapping of T cells epitopes using recombinant antigens and synthetic peptides. EMBO J.6 (1987) 1245–1249.
Lamb, J. R., Bal, V., Mendez-Samperio, P., Mehlert, A. S. A., Rothbard, J., Jindal, S., Young, R. A., and Young, D. B., Stress proteins may provide a link between the immune response to infection and autoimmunity. Int. Immun.1 (1989) 191–196.
Li, Z., and Srivastava, P. K., Tumor Rejection Antigen Gp96/Grp94 is An ATPase: Implications for protein folding and antigen presentation. EMBO J.12 (1993) 3143–3151.
Li, Z., and Srivastava, P. K., Heat shock proteins and antigen processing, in: MHC Molecules: Structural and Functional Aspects. Eds. H.-G. Rammense and G. Hammerling. BIM Press94 (1994) 37–47.
Lussow, A. R., Barrios, C., van Embden, J., Van der Zee, R., Verdini, A. S., Pessi, A., Louis, J.A., Lambert, P. H., and Del Giudice, G., Mycobacterial heat shock proteins as carrier molecules. Eur. J. Immun.21 (1991) 2297–2302.
Maki, R. G., Old, L. J., and Srivastava, P. K., Human homologue of murine tumor rejection antigen Gp96: Analysis of regulatory and coding regions and relationship to stress-induced proteins. Proc. natl Acad. Sci. USA87 (1990) 5658–5662.
Matthews, R. C., The 14th C. L. Oakley Lecture. Candida albicans HSP 90: link between protective and auto immunity. J. med. Microbiol.36 (1992) 367–370.
Multhoff, G., Bolzler, C., Meier, T., Wiesnet, M., and Issels, R. D., Cell surface expression of a heat inducible 72 kDa heat shock protein (hsp72) antigenic epitope on human tumor cells but not on normal cells, in: Biology of Heat Shock Proteins and Chaperones, p 330. Cold Spring Harbour Laboratory, Cold Spring Harbour
Munk, M. E., Schoel, B., Modrow, S., Karr, R. W., Young, R. A., and Kaufmann, S. H. E., T lymphocytes from healthy individuals with specificity to self-epitopes shared by the mycobacterial and human 65 kDa heat shock protein. J. Immun.143 (1989) 2844–2849.
Mustafa, A. S., Lundin, K. E., and Oftung, F., Human T cells recognize mycobacterial heat shock proteins in the context of multiple HLA-DR molecules: studies with healthy subjects vaccinated with Mycobacterium bovis BCG and Mycobacterium leprae. Infect. Immun.61 (1993) 5294–5301.
Nossal, G. J. V., Negative selection of lymphocytes. Cell76 (1994) 229–240.
O'Brien, R., Happ, M. P., Dallas, A., Cranfill, R., Hall, L., Lang, J., Fu, X.-Y., Kubo, R., and Born, W., Recognition of a single hsp60 epitope by an entire subset of γδ T lymphocytes. Immun. Rev.121 (1991) 155–170.
Ottenhoff, T. H. and De Vries, R. R., Antigen reactivity and autoreactivity: two sides of the cellular immune response induced by mycobacteria. Curr. Topics Microbiol. Immun.155 (1990) 111–21.
Ovary, Z., and Benacerraf, B., Immunological specificity of the secondary response with dinitrophenyleated proteins. Proc. Soc. expl Biol. Med.114 (1963) 72–76.
Palladino, M. A., Srivastava, P. K., Oettgen, H. F., and DeLeo, A. B., Expression of a shared tumor-specific antigen by two chemically induced BALB/c sarcomas. I. Detection by a cloned cytotoxic T cell line. Cancer Res.47 (1987) 5074–5079.
Pardoll, D. M., The new look of tumor antigen in the 90's. Nature369 (1994) 357–358.
Pervin, K., Childerstone, A., Shinnick, T., Mizushima, Y., van der Zee, R., Hasan, A., Vaughan, R., and Lehner, T., T cell epitope expression of mycobacterial and homologous human 65 kDa heat shock protein peptides in short term cell lines from patients with Behcet's disease. J. Immun.151 (1993) 2273–282.
Pierce, S. K., Experientia50 (1994) 1026–1030.
Raff, M., Role of thymus-derived lymphocytes in the secondary humoral immune response in mice. Nature226 (1970) 1257–1258.
Rambukkana, A., Yong, S., and Das, P. K., Identification of a novel B-cell epitope of restricted specificity on the hsp 65-kDa protein of Mycobacterium tuberculosis. FEMS Microbiol Immun.3 (1991) 39–45.
Rambukkana, A., Das, P. K., Witkamp, L., Yong, S., Meinardi, M., and Bos, J. D., Antibodies to mycobacterial 65 kDa heat shock protein and other immunodominant antigens in patients with psoriasis. J. invest. Dermat.100 (1993) 87–92.
Roop, R. M., Price, M. L., Dunn, B. E., Boyle, S. M., Sriranganathan, N., and Schurig, G. G., Molecular cloning and nucleotide sequence analysis of the gene encoding the immunoreactive Brucella abortus Hsp60 protein, BA6OK. Microb. Pathogenesis12 (1992) 47–62.
Sciammas, R., Johnson, R. M., Sperling, A. I., Brady, W., Linsley, P. S., Spear, P. G., and Fitch, F. W., Unique antigen recognition by a herpesvirus-specific TCR-gd cell. J. Immun.152 (1994) 5392–5397.
Srivastava, P. K., Peptide-binding heat shock proteins in the endoplasmic reticulum: Role in immune response to cancer and in antigen presentation. Adv. Cancer Res.62 (1993) 153–177.
Srivastava, P. K., Heat shock proteins as chaperones of unique and shared antigenic epitopes of human cancers: A novel approach to vaccination, in: Stress Proteins in Medicine. Ed. W. van Eden and D. B. Young. Marcel Dekker, Inc., (1994) in press.
Srivastava, P. K., and Das, M. R., Serologically unique surface antigen of a rat hepatoma is also its tumor-associated transplantation antigen. Int. J. Cancer33 (1984) 417–422.
Srivastava, P. K., and Maki, R. G., Stress-induced proteins in immune response to cancer. Curr. Topics Microbiol. Immun.167 (1991) 109–123.
Srivastava, P. K., and Old, L. J., Individually distinct antigens of chemically induced mouse tumors. Immun. Today9 (1988) 78–83.
Srivastava, P. K., DeLeo, A. B., and Old, L. J., Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc. natl Acad. Sci. USA83 (1986) 3407–3411.
Srivastava, P. K., Udono, H., Blachere, N. E., and Li, Z., Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics39 (1994) 93–98.
Tamura, Y., Tsuboi, N., Sato, N., and Kikuchi, K., 70 kDa heat shock cognate protein is a transformation associated antigen and a possible target for host's anti-tumor immunity. J. Immun.151 (1993) 5516–5524.
Udono, H., and Srivastava, P. K., Heat shock protein 70-associated peptides elicit specific cancer immunity. J. expl Med.178 (1993) 1391–1396.
Udono, H., Srivastava, P. K., Relative immunogenicities of Heat Shock Proteins gp96, hsp90 and hsp70 against chemically induced tumors. J. Immun.152 (1994) 5398–5403.
Udono, H., Levey, D. L., and Srivastava, P. K., Definition of T cell sub-sets mediating tumor-specific immunogenicity of cognate heat shock protein gp96. Proc. natl Acad. Sci. USA91 (1994) 3077–3081.
van Eden, W., Holoshitz, J., Nevo, Z., Frenkel, A., and Cohen, I. R., Arthritis induced by a T lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteroglycans. Proc. natl Acad. Sci. USA82 (1985) 5064–5067.
van Schooten, W. C., Elferink, D. G., Van-Embden, J., Anderson, D. C., De Vries, R. R., and Anderson, C. D., DR3-restricted T cells from different HLA. DR3. positive individuals recognize the same peptide (amino acids 2–12) of the mycobacterial 65kDa heat-shock protein. Eur. J. Immun.19 (1989) 2075–2079.
Wallace, G. R., Ball, A. E., MacFarlane, J., El Safi, S. H., Miles, M. A., and Kelly, J. M., Mapping of a visceral leishmaniasis, specific immunodominant B-cell epitope of Leishmania donovani Hsp70. Infect. Immun.60 (1992) 2688–2693.
Witkin, S., Jeremias, J., Toth, M., and Ledger, W. J., Cell-mediated immune response to the recombinant 57 kDa heat shock protein of Chlamydia trachomatis in women with salpingitis. J. infect. Dis.167 (1993) 1379–1383.
Young, D. B., The immune response to mycobacterial heat shock proteins. Autoimmunity7 (1990) 237–244.
Young, R. A., Stress proteins and immunology. A. Rev. Immun.8 (1990) 401–420.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Srivastava, P.K. Heat shock proteins in immune response to cancer: The Fourth Paradigm. Experientia 50, 1054–1060 (1994). https://doi.org/10.1007/BF01923461
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01923461