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*
Epimmune, Inc., San Diego, CA 92121;
Takara, Otsu, Shiga, Japan;
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
§
Malaria Program, Naval Medical Research Institute, Bethesda, MD 20889;
¶
Cytel Corporation, San Diego, CA 92121; and
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La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
The peptide binding specificities of HLA-DRB1*0401, DRB1*0101, and DRB1*0701 have been analyzed by the use of large collections of synthetic peptides corresponding to naturally occurring sequences. The results demonstrated that nearly all peptides binding to these DR molecules bear a motif characterized by a large aromatic or hydrophobic residue in position 1 (Y, F, W, L, I, V, M) and a small, noncharged residue in position 6 (S, T, C, A, P, V, I, L, M). In addition, allele-specific secondary effects and secondary anchors were defined, and these parameters were utilized to derive allele-specific motifs and algorithms. By the combined use of such algorithms, peptides capable of degenerate DRB1*0101, DRB1*0401, and DRB1*0701 binding were identified. Additional experiments utilizing a panel of quantitative assays specific for nine additional common DR molecules identified a large set of DR molecules, which includes at least the DRB1*0101, DRB1*0401, DRB1*0701, DRB5*0101, DRB1*1501, DRB1*0901, and DRB1*1302 allelic products, characterized by overlapping peptide-binding repertoires. These results have implications for understanding the molecular interactions involved in peptide-DR binding, as well as the genetic and structural basis of MHC polymorphism. These results also have potential practical implications for the development of epitope-based prophylactic and therapeutic vaccines.
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J. A. Hill, S. Southwood, A. Sette, A. M. Jevnikar, D. A. Bell, and E. Cairns Cutting Edge: The Conversion of Arginine to Citrulline Allows for a High-Affinity Peptide Interaction with the Rheumatoid Arthritis-Associated HLA-DRB1*0401 MHC Class II Molecule J. Immunol., July 15, 2003; 171(2): 538 - 541. [Abstract] [Full Text] [PDF]
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A. Suri, J. J. Walters, O. Kanagawa, M. L. Gross, and E. R. Unanue Specificity of peptide selection by antigen-presenting cells homozygous or heterozygous for expression of class II MHC molecules: The lack of competition PNAS, April 29, 2003; 100(9): 5330 - 5335. [Abstract] [Full Text] [PDF]
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T. Tatsumi, L. S. Kierstead, E. Ranieri, L. Gesualdo, F. P. Schena, J. H. Finke, R. M. Bukowski, V. Brusic, J. Sidney, A. Sette, et al. MAGE-6 Encodes HLA-DR{beta}1*0401-presented Epitopes Recognized by CD4+ T Cells from Patients with Melanoma or Renal Cell Carcinoma Clin. Cancer Res., March 1, 2003; 9(3): 947 - 954. [Abstract] [Full Text] [PDF]
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U. Malhotra, S. Holte, T. Zhu, E. Delpit, C. Huntsberry, A. Sette, R. Shankarappa, J. Maenza, L. Corey, and M. J. McElrath Early Induction and Maintenance of Env-Specific T-Helper Cells following Human Immunodeficiency Virus Type 1 Infection J. Virol., February 15, 2003; 77(4): 2663 - 2674. [Abstract] [Full Text] [PDF]
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 M. Jacquemin, V. Vantomme, C. Buhot, R. Lavend'homme, W. Burny, N. Demotte, P. Chaux, K. Peerlinck, J. Vermylen, B. Maillere, et al. CD4+ T-cell clones specific for wild-type factor VIII: a molecular mechanism responsible for a higher incidence of inhibitor formation in mild/moderate hemophilia A Blood, February 15, 2003; 101(4): 1351 - 1358. [Abstract] [Full Text] [PDF]
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E. H. Slager, M. Borghi, C. E. van der Minne, C. A. Aarnoudse, M. J. E. Havenga, P. I. Schrier, S. Osanto, and M. Griffioen CD4+ Th2 Cell Recognition of HLA-DR-Restricted Epitopes Derived from CAMEL: A Tumor Antigen Translated in an Alternative Open Reading Frame J. Immunol., February 1, 2003; 170(3): 1490 - 1497. [Abstract] [Full Text] [PDF]
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E. Boritz, B. E. Palmer, B. Livingston, A. Sette, and C. C. Wilson Diverse Repertoire of HIV-1 p24-Specific, IFN-{gamma}-Producing CD4+ T Cell Clones Following Immune Reconstitution on Highly Active Antiretroviral Therapy J. Immunol., January 15, 2003; 170(2): 1106 - 1116. [Abstract] [Full Text] [PDF]
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F. A. Castelli, C. Buhot, A. Sanson, H. Zarour, S. Pouvelle-Moratille, C. Nonn, H. Gahery-Segard, J.-G. Guillet, A. Menez, B. Georges, et al. HLA-DP4, the Most Frequent HLA II Molecule, Defines a New Supertype of Peptide-Binding Specificity J. Immunol., December 15, 2002; 169(12): 6928 - 6934. [Abstract] [Full Text] [PDF]
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C. L. Day, G. M. Lauer, G. K. Robbins, B. McGovern, A. G. Wurcel, R. T. Gandhi, R. T. Chung, and B. D. Walker Broad Specificity of Virus-Specific CD4+ T-Helper-Cell Responses in Resolved Hepatitis C Virus Infection J. Virol., November 13, 2002; 76(24): 12584 - 12595. [Abstract] [Full Text] [PDF]
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J. D. Lippolis, F. M. White, J. A. Marto, C. J. Luckey, T. N. J. Bullock, J. Shabanowitz, D. F. Hunt, and V. H. Engelhard Analysis of MHC Class II Antigen Processing by Quantitation of Peptides that Constitute Nested Sets J. Immunol., November 1, 2002; 169(9): 5089 - 5097. [Abstract] [Full Text] [PDF]
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J. Sidney, M.-F. del Guercio, S. Southwood, and A. Sette The HLA Molecules DQA1*0501/B1*0201 and DQA1*0301/B1*0302 Share an Extensive Overlap in Peptide Binding Specificity J. Immunol., November 1, 2002; 169(9): 5098 - 5108. [Abstract] [Full Text] [PDF]
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H. Kobayashi, R. Omiya, M. Ruiz, E. Huarte, P. Sarobe, J. J. Lasarte, M. Herraiz, B. Sangro, J. Prieto, F. Borras-Cuesta, et al. Identification of an Antigenic Epitope for Helper T Lymphocytes from Carcinoembryonic Antigen Clin. Cancer Res., October 1, 2002; 8(10): 3219 - 3225. [Abstract] [Full Text] [PDF]
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R. Omiya, C. Buteau, H. Kobayashi, C. V. Paya, and E. Celis Inhibition of EBV-Induced Lymphoproliferation by CD4+ T Cells Specific for an MHC Class II Promiscuous Epitope J. Immunol., August 15, 2002; 169(4): 2172 - 2179. [Abstract] [Full Text] [PDF]
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I. Caro-Aguilar, A. Rodriguez, J. M. Calvo-Calle, F. Guzman, P. De la Vega, M. Elkin Patarroyo, M. R. Galinski, and A. Moreno Plasmodium vivax Promiscuous T-Helper Epitopes Defined and Evaluated as Linear Peptide Chimera Immunogens Infect. Immun., July 1, 2002; 70(7): 3479 - 3492. [Abstract] [Full Text] [PDF]
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B. R. Mothe, J. Sidney, J. L. Dzuris, M. E. Liebl, S. Fuenger, D. I. Watkins, and A. Sette Characterization of the Peptide-Binding Specificity of Mamu-B*17 and Identification of Mamu-B*17-Restricted Epitopes Derived from Simian Immunodeficiency Virus Proteins J. Immunol., July 1, 2002; 169(1): 210 - 219. [Abstract] [Full Text] [PDF]
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B. Livingston, C. Crimi, M. Newman, Y. Higashimoto, E. Appella, J. Sidney, and A. Sette A Rational Strategy to Design Multiepitope Immunogens Based on Multiple Th Lymphocyte Epitopes J. Immunol., June 1, 2002; 168(11): 5499 - 5506. [Abstract] [Full Text] [PDF]
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 B. Schuler-Thurner, E. S. Schultz, T. G. Berger, G. Weinlich, S. Ebner, P. Woerl, A. Bender, B. Feuerstein, P. O. Fritsch, N. Romani, et al. Rapid Induction of Tumor-specific Type 1 T Helper Cells in Metastatic Melanoma Patients by Vaccination with Mature, Cryopreserved, Peptide-loaded Monocyte-derived Dendritic Cells J. Exp. Med., May 20, 2002; 195(10): 1279 - 1288. [Abstract] [Full Text] [PDF]
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 C. Buteau, S. N. Markovic, and E. Celis Challenges in the Development of Effective Peptide Vaccines for Cancer Mayo Clin. Proc., April 1, 2002; 77(4): 339 - 349. [Abstract] [PDF]
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H. M. Zarour, B. Maillere, V. Brusic, K. Coval, E. Williams, S. Pouvelle-Moratille, F. Castelli, S. Land, J. Bennouna, T. Logan, et al. NY-ESO-1 119-143 Is a Promiscuous Major Histocompatibility Complex Class II T-Helper Epitope Recognized by Th1- and Th2-Type Tumor-reactive CD4+ T Cells Cancer Res., January 1, 2002; 62(1): 213 - 218. [Abstract] [Full Text] [PDF]
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J. L. Dzuris, J. Sidney, H. Horton, R. Correa, D. Carter, R. W. Chesnut, D. I. Watkins, and A. Sette Molecular Determinants of Peptide Binding to Two Common Rhesus Macaque Major Histocompatibility Complex Class II Molecules J. Virol., November 15, 2001; 75(22): 10958 - 10968. [Abstract] [Full Text] [PDF]
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H. Kobayashi, J. Lu, and E. Celis Identification of Helper T-Cell Epitopes That Encompass or Lie Proximal to Cytotoxic T-Cell Epitopes in the gp100 Melanoma Tumor Antigen Cancer Res., October 1, 2001; 61(20): 7577 - 7584. [Abstract] [Full Text] [PDF]
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L. Guilherme, S. E. Oshiro, K. C. Fae, E. Cunha-Neto, G. Renesto, A. C. Goldberg, A. C. Tanaka, P. M. A Pomerantzeff, M. H. Kiss, C. Silva, et al. T-Cell Reactivity against Streptococcal Antigens in the Periphery Mirrors Reactivity of Heart-Infiltrating T Lymphocytes in Rheumatic Heart Disease Patients Infect. Immun., September 1, 2001; 69(9): 5345 - 5351. [Abstract] [Full Text] [PDF]
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Y. Zhao, B. Gran23, C. Pinilla, S. Markovic-Plese, B. Hemmer, A. Tzou, L. W. Whitney, W. E. Biddison, R. Martin, and R. Simon Combinatorial Peptide Libraries and Biometric Score Matrices Permit the Quantitative Analysis of Specific and Degenerate Interactions Between Clonotypic TCR and MHC Peptide Ligands J. Immunol., August 15, 2001; 167(4): 2130 - 2141. [Abstract] [Full Text] [PDF]
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H. Kobayashi, Y. Song, D. S. B. Hoon, E. Appella, and E. Celis Tumor-reactive T Helper Lymphocytes Recognize a Promiscuous MAGE-A3 Epitope Presented by Various Major Histocompatibility Complex Class II Alleles Cancer Res., June 1, 2001; 61(12): 4773 - 4778. [Abstract] [Full Text] [PDF]
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C. C. Wilson, B. Palmer, S. Southwood, J. Sidney, Y. Higashimoto, E. Appella, R. Chesnut, A. Sette, and B. D. Livingston Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-Derived Helper T-Lymphocyte Epitopes J. Virol., May 1, 2001; 75(9): 4195 - 4207. [Abstract] [Full Text]
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M. A. Haque, J. W. Hawes, and J. S. Blum Cysteinylation of MHC Class II Ligands: Peptide Endocytosis and Reduction Within APC Influences T Cell Recognition J. Immunol., April 1, 2001; 166(7): 4543 - 4551. [Abstract] [Full Text] [PDF]
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J. Sidney, J. L. Dzuris, M. J. Newman, R. P. Johnson, K. Amitinder, C. M. Walker, E. Appella, B. Mothe, D. I. Watkins, and A. Sette Definition of the Mamu A*01 Peptide Binding Specificity: Application to the Identification of Wild-Type and Optimized Ligands from Simian Immunodeficiency Virus Regulatory Proteins J. Immunol., December 1, 2000; 165(11): 6387 - 6399. [Abstract] [Full Text] [PDF]
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B. Cochlovius, M. Stassar, O. Christ, L. Raddrizzani, J. Hammer, I. Mytilineos, and M. Zoller In Vitro and In Vivo Induction of a Th Cell Response Toward Peptides of the Melanoma-Associated Glycoprotein 100 Protein Selected by the TEPITOPE Program J. Immunol., October 15, 2000; 165(8): 4731 - 4741. [Abstract] [Full Text] [PDF]
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H. Kobayashi, M. Wood, Y. Song, E. Appella, and E. Celis Defining Promiscuous MHC Class II Helper T-Cell Epitopes for the HER2/neu Tumor Antigen Cancer Res., September 1, 2000; 60(18): 5228 - 5236. [Abstract] [Full Text]
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R. G. Phelps, V. Jones, A. N. Turner, and A. J. Rees Properties of HLA class II molecules divergently associated with Goodpasture's disease Int. Immunol., August 1, 2000; 12(8): 1135 - 1143. [Abstract] [Full Text] [PDF]
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D. L. Doolan, S. Southwood, R. Chesnut, E. Appella, E. Gomez, A. Richards, Y. I. Higashimoto, A. Maewal, J. Sidney, R. A. Gramzinski, et al. HLA-DR-Promiscuous T Cell Epitopes from Plasmodium falciparum Pre-Erythrocytic-Stage Antigens Restricted by Multiple HLA Class II Alleles J. Immunol., July 15, 2000; 165(2): 1123 - 1137. [Abstract] [Full Text] [PDF]
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G. Zeng, C. E. Touloukian, X. Wang, N. P. Restifo, S. A. Rosenberg, and R.-F. Wang Identification of CD4+ T Cell Epitopes from NY-ESO-1 Presented by HLA-DR Molecules J. Immunol., July 15, 2000; 165(2): 1153 - 1159. [Abstract] [Full Text] [PDF]
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C. E. Touloukian, W. W. Leitner, S. L. Topalian, Y. F. Li, P. F. Robbins, S. A. Rosenberg, and N. P. Restifo Identification of a MHC Class II-Restricted Human gp100 Epitope Using DR4-IE Transgenic Mice J. Immunol., April 1, 2000; 164(7): 3535 - 3542. [Abstract] [Full Text] [PDF]
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C. Texier, S. Pouvelle, M. Busson, M. Herve, D. Charron, A. Menez, and B. Maillere HLA-DR Restricted Peptide Candidates for Bee Venom Immunotherapy J. Immunol., March 15, 2000; 164(6): 3177 - 3184. [Abstract] [Full Text] [PDF]
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E. Rajnavolgyi, N. Nagy, B. Thuresson, Z. Dosztanyi, A. Simon, I. Simon, R. W. Karr, I. Ernberg, E. Klein, and K. I. Falk A repetitive sequence of Epstein-Barr virus nuclear antigen 6 comprises overlapping T cell epitopes which induce HLA-DR-restricted CD4+ T lymphocytes Int. Immunol., March 1, 2000; 12(3): 281 - 293. [Abstract] [Full Text] [PDF]
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H. M. Zarour, J. M. Kirkwood, L. S. Kierstead, W. Herr, V. Brusic, C. L. Slingluff Jr., J. Sidney, A. Sette, and W. J. Storkus Melan-A/MART-151-73 represents an immunogenic HLA-DR4-restricted epitope recognized by melanoma-reactive CD4+ T cells PNAS, January 4, 2000; 97(1): 400 - 405. [Abstract] [Full Text] [PDF]
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 J. A. Zaia, J.G. P. Sissons, S. Riddell, D. J. Diamond, M.R. Wills, A.J. Carmichael, M.P. Weekes, M. Gandhi, C. La Rosa, M. Villacres, et al. Status of Cytomegalovirus Prevention and Treatment in 2000 Hematology, January 1, 2000; 2000(1): 339 - 355. [Abstract] [Full Text] [PDF]
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K. L. de Graaf, R. Weissert, P. Kjellen, R. Holmdahl, and T. Olsson Allelic variations in rat MHC class II binding of myelin basic protein peptides correlate with encephalitogenicity Int. Immunol., December 1, 1999; 11(12): 1981 - 1988. [Abstract] [Full Text] [PDF]
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L. Frasca, P. Del Porto, L. Tuosto, B. Marinari, C. Scotta, M. Carbonari, A. Nicosia, and E. Piccolella Hypervariable Region 1 Variants Act as TCR Antagonists for Hepatitis C Virus-Specific CD4+ T Cells J. Immunol., July 15, 1999; 163(2): 650 - 658. [Abstract] [Full Text] [PDF]
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 R. Wang, X. Wang, A. C. Atwood, S. L. Topalian, and S. A. Rosenberg Cloning Genes Encoding MHC Class II-Restricted Antigens: Mutated CDC27 as a Tumor Antigen Science, May 21, 1999; 284(5418): 1351 - 1354. [Abstract] [Full Text]
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