An Overview of the Immune System and Technical Advances in Tumor Antigen Discovery and Validation

  • Mouldy Sioud
Protocol

Summary

The ability of the immune system to distinguish between self- and nonself antigens is controlled by mechanisms of central and peripheral tolerance. Although the induction and maintenance of tolerance is important for preventing autoimmunity, breaking self-tolerance is a crucial constituent for combating cancers. Cancer patients are able to develop spontaneous immune responses to tumors that they bear, however these responses are not suboptimal for eradicating tumors. Moreover, none of the current immune strategies is able to activate the immune system to respond against tumor cells as it responds against infectious agents. These observations have raised the question of how to activate immunity in cancer patients to a threshold required for tumor rejection. Because tolerance is emerging as a central obstacle for immune recognition of human tumor antigens, this chapter describes how T- and B-cells are generated and activated in the periphery. It also outlines the technical advances in tumor antigen discovery and validation.

Key Words

B-cell development B-cell receptor dendritic cells genomics germinal center immune tolerance immunoediting phage display proteomics serological analysis of recombinant tumor cDNA expression libraries (SEREX) T-cell development T-cell receptor tumor antigens 

References

  1. 1.
    Burnet, F. M. (1971) Immunological surveillance in neoplasia. Transplant. Rev. 7, 3–25.PubMedGoogle Scholar
  2. 2.
    Diefenbach, A. and Roulette, D. H. (2002) The innate immune response to tumors and its role in the induction of T-cell immunity. Immunol. Rev. 188, 9–21.CrossRefPubMedGoogle Scholar
  3. 3.
    Rosenberg, S. A. (1999) A new era for cancer immunotherapy based on the genes that encodes cancer antigens. Immunity 10, 281–287.CrossRefPubMedGoogle Scholar
  4. 4.
    Vose, B. M. and Moore, M. (1985) Human tumor-infiltrating lymphocytes: a marker of host response. Semin. Hematol. 22, 27–40.PubMedGoogle Scholar
  5. 5.
    Østenstad, B., Sioud, M., Schlichting, E., Lea, T., and Harboe, M. (1995) Freshly isolated tumour-infiltrating T-lymphocytes have a high cytotoxic potential, as measured by their ability to induce apoptosis in the target cell. Scand. J. Immunol. 41, 42–48.CrossRefPubMedGoogle Scholar
  6. 6.
    O’Neill, L. A. J. (2004) TLRs: Professor Mechnikov, sit on your hat. Trends Immunol. 25, 687–693.CrossRefPubMedGoogle Scholar
  7. 7.
    Janeway, C. A. (2001) How the immune system protects the host from infection. Microbes Infect. 3, 1167–1171.CrossRefPubMedGoogle Scholar
  8. 8.
    Janeway, C. A., Travers, P., Walport, M., and Shlomchik, M. (eds.) (2001) Immunobiology. The Immune System in Health and Disease. Garland Publishing, New York.Google Scholar
  9. 9.
    Matzinger, P. (1994) Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045.PubMedGoogle Scholar
  10. 10.
    Janeway, C. A. Jr. (1992) The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol. Today 13, 11–16.CrossRefPubMedGoogle Scholar
  11. 11.
    Singer, A. (2002) New perspectives on a developmental dilemma: the kinetic signalling model and the importance of signal duration for the CD4/Cd8 lineage decision. Curr. Opin. Immunol. 14, 207–215.CrossRefPubMedGoogle Scholar
  12. 12.
    Orkin, S. H. (2000) Diversification of haematopoitic stem cells to specific lineages. Nat. Rev. Genet. 1, 57–64.CrossRefPubMedGoogle Scholar
  13. 13.
    Izon, D. J., Punt, A. J., and Pear, W. S. (2002) Deciphering the role of Notch signalling in lymphocytes. Curr. Opin. Immunol. 14, 192–199.CrossRefPubMedGoogle Scholar
  14. 14.
    Wilson, A., MacDonald, H. R., and Radtke, F. (2001) Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. J. Exp. Med. 194, 1003–1012.CrossRefPubMedGoogle Scholar
  15. 15.
    Aifantis, I., Azogui, O., Feinberg, J., Saint-Ruf, C., Buer, J., and von Boehmer, H. (1998) On the role of the pre-T-cell receptor in αβ versus γδ T lineage commitment. Immunity 9, 649–655.CrossRefPubMedGoogle Scholar
  16. 16.
    Iritani, B. M., Alberola-Il, J., Forbush, K. A., and Perimutter, R. M. (1999) Distinct signals mediate maturation and allelic exclusion in lymphocytes progenitors. Immunity 10, 713–722.CrossRefPubMedGoogle Scholar
  17. 17.
    Muljo, S. A. and Schlissel, M. S. (2000) Pre-B and pre-T-cell receptors: conservation of strategies in regulating early lymphocyte development. Immunol. Rev. 175, 80–93.CrossRefPubMedGoogle Scholar
  18. 18.
    Sleckman, B. and Khor, B. (2002) Allelic exclusion at the TCRb locus. Curr. Opin. Immunol. 14, 230–324.CrossRefPubMedGoogle Scholar
  19. 19.
    Myklebust, J. H., Smeland, S. M., Josefsen, D., and Sioud, M. (2000) Protein kinase C-alpha isoform is involved in erythropoietin-induced erythroid differentiation of CD34(+) progenitor cells from human bone marrow. Blood 95, 510–518.PubMedGoogle Scholar
  20. 20.
    Padovan, E., Casorati, G., Dellabona, P., Meyer, S., Brockhaus, M., and Lanzavecchia, A. (1993) Expression of two T cell receptor alpha chains: dual receptor T cells. Science 262, 422–424.CrossRefPubMedGoogle Scholar
  21. 21.
    Heath, W. R., Carbone, F. R., Bertolino, P., Kelly, J., Cose, S., and Miller, J. F. (1995) Expression of two T cell receptor alpha chains on the surface of normal murine T cells. Eur. J. Immunol. 25, 1617–1623.CrossRefPubMedGoogle Scholar
  22. 22.
    He, X., Janeway, C. A. Jr., Levine, M., et al. (2002) Dual receptor T cells extend the immune repertoire for foreign antigens. Nat. Immunol. 3, 127–134.CrossRefPubMedGoogle Scholar
  23. 23.
    Kretz-Rommel, A. and Rubin, R. L. (2000) Disruption of positive selection of thymocytes causes autoimmunity. Nature Med. 6, 298–305.CrossRefPubMedGoogle Scholar
  24. 24.
    Nemazee, D. (2000) Receptor selection in B and T lymphocytes. Annu. Rev. Immunol. 18, 19–51.CrossRefPubMedGoogle Scholar
  25. 25.
    Hardy, R. R. and Hayakawa, K. (2001) B cell development pathways. Annu. Rev. Immunol. 19, 521–621.CrossRefGoogle Scholar
  26. 26.
    Gay, D., Saunders, T., Camper, S., and Weigert, M. (1993) Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177, 999.CrossRefPubMedGoogle Scholar
  27. 27.
    Tiegs, S. L., Russell, D. M., and Nemazee, D. (1993) Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177, 1009.CrossRefPubMedGoogle Scholar
  28. 28.
    Casali, P. and Diaz, M. (2006) Somatic immunoglobulin hypermutation. Curr. Opin. Immunol. 14, 235–240.Google Scholar
  29. 29.
    Durandy, A. and Honjo, T. (2001) Human genetic defects in class-switch recomnination (hyper-IgM syndromes). Curr. Opin. Immunol. 13, 543–548.CrossRefPubMedGoogle Scholar
  30. 30.
    Nemazee, D. and Weigert, M. (2000) Revising B cell receptors. J. Exp. Med. 191, 1813–1817.CrossRefPubMedGoogle Scholar
  31. 31.
    Ferber, I., Schonrich, G., Schenkel, J., Mellor, A. L., Hammerling, G. J., and Arnold, B. (1994) Levels of peripheral T cell tolerance induced by different doses of tolerogen. Science 263, 674–676.CrossRefPubMedGoogle Scholar
  32. 32.
    Goodnow, C. C., Cryster, J. G., Hartley, S. B., et al. (1995) Self-tolerance checkpoints in B lymphocyte development. Adv. Immunol. 59, 279–368.CrossRefPubMedGoogle Scholar
  33. 33.
    Maloy, K. J. and Powrie, F. (2001) Regulatory T cells in the control of immune pathology. Nat. Immunol. 2, 816–822.CrossRefPubMedGoogle Scholar
  34. 34.
    Shortman, K. and Liu, Y. J. (2002) Mouse and human dendritic cell subtypes. Nat. Rev. Immunol. 2, 151–161.CrossRefPubMedGoogle Scholar
  35. 35.
    Cooper, C. J., Turk, G. L., Sun, M., Farr, A. G., and Fink, P. J. (2004) Cutting edge: TCR revisison occurs in germinal centers. J. Immunol. 173, 6532–6536.PubMedGoogle Scholar
  36. 36.
    Ernst, B., Lee, D. S., Chang, J. M., Sprent, J., and Surch, C. D. (1999) The peptide ligands mediating positive selection in the thymus control T-cell survival and homeostatic proliferation in the periphery. Immunity 11, 173–181.CrossRefPubMedGoogle Scholar
  37. 37.
    Dorfman, J. R. and Germain, R. N. (2002) MHC-dependent survival of naïve T cells? A complicated answer to a simple question. Microbes Infect. 4, 547–554.CrossRefPubMedGoogle Scholar
  38. 38.
    Stoltze, L., Nussbaum, A. K., Sijts, A., Emmerich, N. P., Kloetzel, P. M., and Schild, H. (2000) The function of the proteasome system in MHC class I antigen processing. Immunol. Today 21, 317–319.CrossRefPubMedGoogle Scholar
  39. 39.
    Uebel, S. and Tampe, R. (1999) Specificity of the proteasome and the TAP transporter. Curr. Opin. Immunol. 11, 203–208.CrossRefPubMedGoogle Scholar
  40. 40.
    Bertolino, P. and Rabourdin-Combe, C. (1996) The MHC class II-associated invariant chain: a molecule with multiple roles in MHC class II biosynthesis and antigen presentation to CD4+ T cells. Crit. Rev. Immunol. 16, 359–379.PubMedGoogle Scholar
  41. 41.
    Greenfield, E. A., Nguyen, K. A., and Kuchroo, V. K. (1998) CD28/B7 costimulation: a review. Crit. Rev. Immunol. 18, 389–418.PubMedGoogle Scholar
  42. 42.
    Hogg, N. and Landis, R. C. (1993) Adhesion molecules in cell interactions. Curr. Opin. Immunol. 5, 383–390.CrossRefPubMedGoogle Scholar
  43. 43.
    Chen, L. (2004) Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat. Rev. Immunol. 4, 336–347.CrossRefPubMedGoogle Scholar
  44. 44.
    Clark, E. A. and Ledbetter, J. A. (1994) How B and T cells talk to each other. Nature 367, 425–428.CrossRefPubMedGoogle Scholar
  45. 45.
    Stevens, T. L., Bossie, A., Sanders, V. M., et al. (1988) Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature 334, 255–258.CrossRefPubMedGoogle Scholar
  46. 46.
    Swain, S. L., Bradley, L. M., Croft, M., et al. (1991) Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol. Rev. 123, 115–144.CrossRefPubMedGoogle Scholar
  47. 47.
    Bonifacio, E., Scirpoli, M., Kredel, K., Föchtenbusch, M., and Ziegler, A.-G. (1999) Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation. J. Immunol. 163, 525–532.PubMedGoogle Scholar
  48. 48.
    Weiner, H. L. (2001) Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol. Rev. 182, 207–214.CrossRefPubMedGoogle Scholar
  49. 49.
    Shevach, E. M. (2001) Certified professionals: CD4(+)CD25(+) suppressor T cells. J. Exp. Med. 193, F41–F46.CrossRefPubMedGoogle Scholar
  50. 50.
    Pardoll, D. (2003) Does the immune system see tumors as foreign or self? Annu. Rev. Immunol. 21, 807–839.CrossRefPubMedGoogle Scholar
  51. 51.
    Boon, T. and Kellermann, O. (1977) Rejection by syngeneic mice of cell variants obtained by mutagenesis of a malignant teratocarcinoma cell line. Proc. Natl. Acad. Sci. USA 74, 272–275.CrossRefPubMedGoogle Scholar
  52. 52.
    Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J., and Schreiber, R. D. (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998.CrossRefPubMedGoogle Scholar
  53. 53.
    Rosenberg, S. A., Yang, J. C., and Restifo, N. P. (2004) Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915.CrossRefPubMedGoogle Scholar
  54. 54.
    Pfreundschuh, M., Shiku, H., Takahashi, T., et al. (1978) Serological analysis of cell surface antigens of malignant human brain tumors. Proc. Natl. Acad. Sci. USA 75, 5122–5126.CrossRefPubMedGoogle Scholar
  55. 55.
    Van Bleek, G. M. and Natheson, S. G. (1990) Isolation of an endogenously processed immunodominant viral peptide from the class I H-2Kb molecule. Nature 348, 213–216.CrossRefPubMedGoogle Scholar
  56. 56.
    Falk, K., Rotzschke, O., Stevanovic, S., Jung, G., and Rammensee, H. G. (1991) Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351, 290–296.CrossRefPubMedGoogle Scholar
  57. 57.
    van der Bruggen, P., Traversari, C., Chomez, P., et al. (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254, 1643–1647.CrossRefPubMedGoogle Scholar
  58. 58.
    Sahin, U., Tureci, O., Chen, Y. T., et al. (1998) Expression of multiple cancer/testis (CT) antigens in breast cancer and melanoma: basis for polyvalent CT vaccine strategies. Int. J. Cancer 78, 387–389.CrossRefPubMedGoogle Scholar
  59. 59.
    Sahin, U., Tureci, O., Schmitt, H., et al. (1995) Human neoplasms elicit multiple specific immune responses in the autologous host. Proc. Natl. Acad. Sci. USA 92, 11,810–11,813.CrossRefPubMedGoogle Scholar
  60. 60.
    Jäger, D., Stockert, E., Gure, A. O., et al. (2001) Identification of a tissue-specific putative transcription factor in breast tissue by serological screening of a breast cancer library. Cancer Res. 61, 6197–6204.Google Scholar
  61. 61.
    Jäger, D., Jäger, E., and Knuth, A. (2001) Immune responses to tumour antigens: implications for antigen specific immunotherapy of cancer. J. Clin. Pathol. 54, 669–674.PubMedGoogle Scholar
  62. 62.
    Dybwad, A., Førre, Ø., Kjeldsen-Kragh, J., Natvig, J. B., and Sioud, M. (1993) Identification of new B cell epitopes in the sera of rheumatoid arthritis using a random nanopeptide phage library. Eur. J. Immunol. 23, 3189–3193.CrossRefPubMedGoogle Scholar
  63. 63.
    Smith, G. P. (1985) Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228, 1315–1317.CrossRefPubMedGoogle Scholar
  64. 64.
    Smith, G. P. (1993) Surface display and peptide libraries. Gene 128, 1–2.CrossRefGoogle Scholar
  65. 65.
    Felici, F., Luzzago, A., Monaci, P., Nicosia, A., Sollazzo, M., and Traboni, C. (1995) Peptide and protein display on the surface of filamentous bacteriophage. Biotechnol. Annu. Rev. 1, 149–183.CrossRefPubMedGoogle Scholar
  66. 66.
    Crameri, R. and Suter, M. (1993) Display of biologically active proteins on the surface of filamentous phages: a cDNA cloning system for selection of functional gene products linked to the genetic information responsible for their production. Gene 137, 69–75.CrossRefPubMedGoogle Scholar
  67. 67.
    Jespers, L. S., Messens, J. H., De Keyser, A., et al. (1995) Surface expression and ligand-based selection of cDNAs fused to filamentous phage gene VI. Biotechnology 13, 378–382.CrossRefPubMedGoogle Scholar
  68. 68.
    Sioud, M., Hansen, M. H., and Dybwad, A. (2000) Profiling the immune responses in patient sera with peptide and cDNA display libraries. Int. J. Mol. Med. 6, 123–128.PubMedGoogle Scholar
  69. 69.
    Castognoli, L., Zucconi, A., Quondam, M., et al. (2001) Alternative bacteriophage display systems. Comb. Chem. High Throughput Screen. 4, 121–133.Google Scholar
  70. 70.
    Rosenberg, A., Griffin, K., Studier, F. W., et al. (1996) T7Select Phage Display System: A powerful new protein display system based on bacteriophage T7. Innovations 6, 1–6.Google Scholar
  71. 71.
    Sche, P. P., McKenzie, K. M., White, J. D., and Austin, D. J. (1999) Display cloning: functional identification of natural product receptors using cDNA-phage display. Chem. Biol. 6, 707–716.CrossRefPubMedGoogle Scholar
  72. 72.
    Hansen, M. H., Østenstad, Ø., and Sioud, S. (2001) Identification of immunogenic antigens using a phage-displayed cDNA library from an invasive ductal breast carcinoma tumour. Int. J. Oncol. 19, 1303–1309.PubMedGoogle Scholar
  73. 73.
    Sioud, M., Førre, Ø., and Dybwad, A. (1996) Selection of ligands for polyclonal antibodies from random peptide libraries: potential identification of (auto)antigens that may trigger B and T cell responses in autoimmune diseases. Clin. Immunol. Immunopathol. 79, 105–114.CrossRefPubMedGoogle Scholar
  74. 74.
    Dybwad, A., Bogen, A., Natvig, J. B., Førre, Ø., and Sioud, M. (1995) Peptide phage libraries can be an efficient tool for identifying antibody ligands for polyclonal antisera. Clin. Exp. Immunol. 102, 438–442.CrossRefPubMedGoogle Scholar
  75. 75.
    Hansen, M. H., Østenstad, B., and Sioud, M. (2001) Antigen-specific IgG antibodies in stage IV long-term survival breast cancer patients. Mol. Med. 7, 230–239.PubMedGoogle Scholar
  76. 76.
    Sioud, M. and Hansen, M. H. (2001) Profiling the immune response in patients with breast cancer by phage-displayed cDNA libraries. Eur. J. Immunol. 31, 716–725.CrossRefPubMedGoogle Scholar
  77. 77.
    Boublik, Y., Di Bonito, P., and Jones, I. M. (1995) Eukaryotic virus display: engineering the major surface glycoprotein of the Autographa californica nuclear polyhedrosis virus (AcNPV) for the presentation of foreign proteins on the virus surface. Biotechnology 13, 1079–1084.CrossRefPubMedGoogle Scholar
  78. 78.
    Russel, S. J., Hawkins, R. E., and Winter, G. (1993) Retroviral vectors displaying functional antibody fragments. Nucleic Acids Res. 21, 1081–1085.CrossRefGoogle Scholar
  79. 79.
    Boder, E. T. and Wittrup, K. D. (1997) Yeast surface display for screening combinatorial polypeptide libraries. Nat. Biotechnol. 15, 553–557.CrossRefPubMedGoogle Scholar
  80. 80.
    Wadle, A., Mischo, A., Imig, J., et al. (2005) Serological identification of breast cancer-related antigens from a Saccharomyces cerevisiae surface display library. Int. J. Cancer 117, 104–113.CrossRefPubMedGoogle Scholar
  81. 81.
    Velculescu, V. E., Zhang, L., Vogelstein, B., and Kinzler, K. W. (1995) Serial analysis of gene expression. Science 270, 484–487.CrossRefPubMedGoogle Scholar
  82. 82.
    Lash, A. E., Tolstoshev, C. M., Wagner, L., et al. (2000) SAGEmap; a public gene expression resource. Genome Res. 10, 1051–1060.CrossRefPubMedGoogle Scholar
  83. 83.
    Boon, K., Osorio, E. C., Greenhut, S. F., et al. (2002) An anatomy of normal and malignant gene expression. Proc Natl. Acad. Sci. USA 99, 11,287–11,292.CrossRefPubMedGoogle Scholar
  84. 83a.
    Loging, W.T. et al. (2000) Identifying potential tumor markers and antigens by database mining and rapid expression screening. Genome Res. 10, 1393–1402.CrossRefPubMedGoogle Scholar
  85. 84.
    Segal, E., Fiedman, N., Kaminski, N., Regev, A., and Koller, D. (2005) From signatures to models: understanding cancer using microarrays. Nat. Genet. 37, S38–S45.CrossRefPubMedGoogle Scholar
  86. 85.
    Leirdal, M., Shadidy, M., Røsok, Ø., and Sioud, M. (2004) Identification of genes differentially expressed in breast cancer cell line SKBR3: Potential identification of new prognostic biomarkers. Int. J. Mol. Med. 14, 217–222.PubMedGoogle Scholar
  87. 86.
    de Hoog, C. L. and Mann, M. (2004) Proteomics. Annu. Rev. Genomics Hum. Genet. 5, 267–293.CrossRefPubMedGoogle Scholar
  88. 87.
    Sioud, A. and Sørensen, D. (2003) Generation of an effective anti-tumor immunity after immunization with xenogeneic antigens. Eur. J. Immunol. 33, 38–45.CrossRefPubMedGoogle Scholar
  89. 88.
    Davis, I. D., Jefford, M., Parente, P., and Cebon, J. (2003) Rational approaches to human cancer immunotherapy. J. Leukoc. Biol. 73, 3–29.CrossRefPubMedGoogle Scholar
  90. 89.
    Zou, W. (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. 5, 263–274.Google Scholar
  91. 90.
    Sioud, M. (2004) Therapeutic siRNAs. Trends Pharmacol. Sci. 25, 22–28.CrossRefPubMedGoogle Scholar
  92. 91.
    Golgher, D., Jones, E., Powrie, F., Elliot, T., and Gallimore, A. (2002) Depletion of CD25 regulatory cells uncovers immune responses to shared murine tumour rejection antigens. Eur. J. Immunol. 32, 3267–3275.CrossRefPubMedGoogle Scholar
  93. 92.
    Dudley, M. E., Wunderlich, J. R., Robbins, P. F., et al. (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854.CrossRefPubMedGoogle Scholar
  94. 93.
    Wiernik, P. H. (1976) Spontaneous regression of hematologic cancers. Natl. Cancer Inst. Monogr. 44, 35–38.PubMedGoogle Scholar
  95. 94.
    Sioud, M. (2002) How does autoimmunity cause tumor regression? A potential mechanism involving cross-reaction through epitope mimicry. Mol. Med. 8, 115–119.PubMedGoogle Scholar
  96. 95.
    Banchereau, J. and Steinman, R. M. (1998) Dendritic cells and the control of immunity. Nature 392, 245–252.CrossRefPubMedGoogle Scholar
  97. 96.
    Langenkamp, A., Messi, M., Lanzavecchia, A., and Sallusto, F. (2000) Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat. Immunol. 1, 311–316.CrossRefPubMedGoogle Scholar
  98. 97.
    Steinman, R. M., Hawiger, D., and Nussenzweig, M. C. (2003) Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711.CrossRefPubMedGoogle Scholar
  99. 98.
    Sioud, M. (2005) Induction of inflammatory cytokines and interferon responses by double-stranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization. J. Mol. Biol. 348, 1079–1090.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Mouldy Sioud
    • 1
  1. 1.Department of Immunology, Institute for Cancer Research, The Norwegian Radium HospitalUniversity of OsloOsloNorway

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