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*
Laboratorio di Immunologia dei Tumori and Cancer Immunotherapy and Gene Therapy Program,
Unità di Epidemiologia, and
Università Vita e Salute, Istituto Scientifico H San Raffaele, Milan, Italy
Apoptosis allows the clearance of unwanted cells from living
tissues without causing inflammation. Processing of phagocytosed
apoptotic cells yields Ags that access the cytosol and the MHC class I
pathway of engulfing cells and are recognized by Ag-specific CTL. We
show here that injection of apoptotic RMA cells, a syngeneic T cell
lymphoma, into C57BL/6 mice results in priming of a functional and
long-lasting tumor-specific immune response. Cross-priming of CTLs by
apoptotic cells requires CD4+ T cell help. Apoptotic cells,
however, are at least 20-fold less immunogenic than nonreplicating live
cells. Immunogenicity of apoptotic cells is proportional to the number
of cells injected, correlates with the serum concentration of IL-10 and
IL-1ß cytokines, and is enhanced in IL-10 knockout mice. Moreover,
immunization with dendritic cells (DCs), but not macrophages (M
),
pulsed with apoptotic cells primes tumor-specific CTLs and confers
protection against a tumor challenge. Our findings demonstrate that
tumor cells undergoing apoptosis are, though scarcely, immunogenic in
vivo, outline the different roles of M and DCs in the physiologic
clearance of unwanted cells, and have implications in designing
immunomodulating vaccines.
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S. A. Ali, J. Lynam, C. S. McLean, C. Entwisle, P. Loudon, J. M. Rojas, S. E. B. McArdle, G. Li, S. Mian, and R. C. Rees Tumor Regression Induced by Intratumor Therapy with a Disabled Infectious Single Cycle (DISC) Herpes Simplex Virus (HSV) Vector, DISC/HSV/Murine Granulocyte-Macrophage Colony-Stimulating Factor, Correlates with Antigen-Specific Adaptive Immunity J. Immunol., April 1, 2002; 168(7): 3512 - 3519. [Abstract] [Full Text] [PDF]
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L. M. Stuart, M. Lucas, C. Simpson, J. Lamb, J. Savill, and A. Lacy-Hulbert Inhibitory Effects of Apoptotic Cell Ingestion upon Endotoxin-Driven Myeloid Dendritic Cell Maturation J. Immunol., February 15, 2002; 168(4): 1627 - 1635. [Abstract] [Full Text] [PDF]
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B. M. Janjic, G. Lu, A. Pimenov, T. L. Whiteside, W. J. Storkus, and N. L. Vujanovic Innate Direct Anticancer Effector Function of Human Immature Dendritic Cells. I. Involvement of an Apoptosis-Inducing Pathway J. Immunol., February 15, 2002; 168(4): 1823 - 1830. [Abstract] [Full Text] [PDF]
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G. Lu, B. M. Janjic, J. Janjic, T. L. Whiteside, W. J. Storkus, and N. L. Vujanovic Innate Direct Anticancer Effector Function of Human Immature Dendritic Cells. II. Role of TNF, Lymphotoxin-{alpha}1{beta}2, Fas Ligand, and TNF-Related Apoptosis-Inducing Ligand J. Immunol., February 15, 2002; 168(4): 1831 - 1839. [Abstract] [Full Text] [PDF]
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D. Masse, C. Voisine, F. Henry, S. Cordel, I. Barbieux, R. Josien, K. Meflah, M. Gregoire, and B. Lieubeau Increased Vaccination Efficiency with Apoptotic Cells by Silica-induced, Dendritic-like Cells Cancer Res., February 1, 2002; 62(4): 1050 - 1056. [Abstract] [Full Text] [PDF]
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P. Castiglioni, A. Martin-Fontecha, G. Milan, V. Tomajer, F. Magni, J. Michaelsson, C. Rugarli, A. Rosato, and M. Bellone Apoptosis-dependent Subversion of the T-Lymphocyte Epitope Hierarchy in Lymphoma Cells Cancer Res., February 1, 2002; 62(4): 1116 - 1122. [Abstract] [Full Text] [PDF]
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K. Kawahata, Y. Misaki, M. Yamauchi, S. Tsunekawa, K. Setoguchi, J.-i. Miyazaki, and K. Yamamoto Peripheral Tolerance to a Nuclear Autoantigen: Dendritic Cells Expressing a Nuclear Autoantigen Lead to Persistent Anergic State of CD4+ Autoreactive T Cells After Proliferation J. Immunol., February 1, 2002; 168(3): 1103 - 1112. [Abstract] [Full Text] [PDF]
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R. Kammerer, D. Stober, P. Riedl, C. Oehninger, R. Schirmbeck, and J. Reimann Noncovalent Association with Stress Protein Facilitates Cross-Priming of CD8+ T Cells to Tumor Cell Antigens by Dendritic Cells J. Immunol., January 1, 2002; 168(1): 108 - 117. [Abstract] [Full Text] [PDF]
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M. J. Gough, A. A. Melcher, A. Ahmed, M. R. Crittenden, D. S. Riddle, E. Linardakis, A. N. Ruchatz, L. M. Emiliusen, and R. G. Vile Macrophages Orchestrate the Immune Response to Tumor Cell Death Cancer Res., October 1, 2001; 61(19): 7240 - 7247. [Abstract] [Full Text] [PDF]
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 S. Demaria, M. D. Volm, R. L. Shapiro, H. T. Yee, R. Oratz, S. C. Formenti, F. Muggia, and W. F. Symmans Development of Tumor-infiltrating Lymphocytes in Breast Cancer after Neoadjuvant Paclitaxel Chemotherapy Clin. Cancer Res., October 1, 2001; 7(10): 3025 - 3030. [Abstract] [Full Text] [PDF]
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E. M. Sotomayor, I. Borrello, F.-M. Rattis, A. G. Cuenca, J. Abrams, K. Staveley-O'Carroll, and H. I. Levitsky Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression Blood, August 15, 2001; 98(4): 1070 - 1077. [Abstract] [Full Text] [PDF]
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L. Tourneur, B. Malassagne, F. Batteux, M. Fabre, S. Mistou, E. Lallemand, P. Lores, and G. Chiocchia Transgenic Expression of CD95 Ligand on Thyroid Follicular Cells Confers Immune Privilege upon Thyroid Allografts J. Immunol., August 1, 2001; 167(3): 1338 - 1346. [Abstract] [Full Text] [PDF]
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F. Santiago-Schwarz, P. Anand, S. Liu, and S. E. Carsons Dendritic Cells (DCs) in Rheumatoid Arthritis (RA): Progenitor Cells and Soluble Factors Contained in RA Synovial Fluid Yield a Subset of Myeloid DCs That Preferentially Activate Th1 Inflammatory-Type Responses J. Immunol., August 1, 2001; 167(3): 1758 - 1768. [Abstract] [Full Text] [PDF]
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I. Motta, F. Andre, A. Lim, J. Tartaglia, W. I. Cox, L. Zitvogel, E. Angevin, and P. Kourilsky Cross-Presentation by Dendritic Cells of Tumor Antigen Expressed in Apoptotic Recombinant Canarypox Virus-Infected Dendritic Cells J. Immunol., August 1, 2001; 167(3): 1795 - 1802. [Abstract] [Full Text] [PDF]
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H. Feng, Y. Zeng, L. Whitesell, and E. Katsanis Stressed apoptotic tumor cells express heat shock proteins and elicit tumor-specific immunity Blood, June 1, 2001; 97(11): 3505 - 3512. [Abstract] [Full Text] [PDF]
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 M. L. Mbow, N. Zeidner, R. D. Gilmore Jr., M. Dolan, J. Piesman, and R. G. Titus Major Histocompatibility Complex Class II-Independent Generation of Neutralizing Antibodies against T-Cell-Dependent Borrelia burgdorferi Antigens Presented by Dendritic Cells: Regulation by NK and {gamma}{delta} T Cells Infect. Immun., April 1, 2001; 69(4): 2407 - 2415. [Abstract] [Full Text] [PDF]
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C. C. Norbury, M. F. Princiotta, I. Bacik, R. R. Brutkiewicz, P. Wood, T. Elliott, J. R. Bennink, and J. W. Yewdell Multiple Antigen-Specific Processing Pathways for Activating Naive CD8+ T Cells In Vivo J. Immunol., April 1, 2001; 166(7): 4355 - 4362. [Abstract] [Full Text] [PDF]
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S. R. Goth and R. S. Stephens Rapid, Transient Phosphatidylserine Externalization Induced in Host Cells by Infection with Chlamydia spp. Infect. Immun., February 1, 2001; 69(2): 1109 - 1119. [Abstract] [Full Text] [PDF]
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M. Shaif-Muthana, C. McIntyre, K. Sisley, I. Rennie, and A. Murray Dead or Alive: Immunogenicity of Human Melanoma Cells When Presented by Dendritic Cells Cancer Res., November 1, 2000; 60(22): 6441 - 6447. [Abstract] [Full Text]
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P. R. Taylor, A. Carugati, V. A. Fadok, H. T. Cook, M. Andrews, M. C. Carroll, J. S. Savill, P. M. Henson, M. Botto, and M. J. Walport A Hierarchical Role for Classical Pathway Complement Proteins in the Clearance of Apoptotic Cells In Vivo J. Exp. Med., July 31, 2000; 192(3): 359 - 366. [Abstract] [Full Text] [PDF]
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T. K. Hoffmann, N. Meidenbauer, G. Dworacki, H. Kanaya, and T. L. Whiteside Generation of Tumor-specific T Lymphocytes by Cross-Priming with Human Dendritic Cells Ingesting Apoptotic Tumor Cells Cancer Res., July 1, 2000; 60(13): 3542 - 3549. [Abstract] [Full Text]
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U. Yrlid and M. J. Wick Salmonella-induced Apoptosis of Infected Macrophages Results in Presentation of a Bacteria-encoded Antigen after Uptake by Bystander Dendritic Cells J. Exp. Med., March 20, 2000; 191(4): 613 - 624. [Abstract] [Full Text] [PDF]
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B. Sauter, M. L. Albert, L. Francisco, M. Larsson, S. Somersan, and N. Bhardwaj Consequences of Cell Death: Exposure to Necrotic Tumor Cells, but Not Primary Tissue Cells or Apoptotic Cells, Induces the Maturation of Immunostimulatory Dendritic Cells J. Exp. Med., February 7, 2000; 191(3): 423 - 434. [Abstract] [Full Text] [PDF]
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V. Russo, S. Tanzarella, P. Dalerba, D. Rigatti, P. Rovere, A. Villa, C. Bordignon, and C. Traversari Dendritic cells acquire the MAGE-3 human tumor antigen from apoptotic cells and induce a class I-restricted T cell response PNAS, February 29, 2000; 97(5): 2185 - 2190. [Abstract] [Full Text] [PDF]
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