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Immunology |
Department of Medicine and Melanoma Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213 [H. M. Z., K. C., E. W., J. M. K.]; Protein Engineering and Research Department, CEA-Saclay, 91191 Gif sur Yvette, France [B. M., S. P-M., F. C.]; Kent Ridge Digital Labs, Singapore 119613 [V. B.]; Biostatistics, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213 [S. L.]; Immunologic Monitoring and Cellular Products Laboratory, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213 [J. B.]; and Indianapolis Cancer Research Institute, Indianapolis, Indiana 46202 [T. L.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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50% of patients with NY-ESO-1+ tumors (1
, 9)
. The induction of primary NY-ESO-1-specific CD8+ T-cell responses has been reported after intradermal peptide vaccination in patients with NY-ESO-1+ tumors (10)
. We have previously reported a peptide-based strategy to identify novel DR4-restricted tumor-derived peptides recognized by CD4+ T cells (11) . In doing so, we have already identified several DR4-restricted peptide sequences, including peptide NY-ESO-1 119–143 (7) . Here we develop a strategy to identify those sequences that can be broadly presented by multiple DR alleles among peptide sequences initially identified as DR4-restricted. In particular, we demonstrate that peptide NY-ESO-1 119–143 not only binds to multiple DR alleles, but also stimulates CD4+ T-cell responses when presented at the surface of these molecules. We also observed that peptide NY-ESO-1 119–143, which stimulated in vitro strong Th1-type T-cell responses, could also induce Th2-type CD4+ T-cell responses from PBLs of normal donors and melanoma patients.
These findings support the use of the NY-ESO-1 119–143 peptide as a cancer vaccine for a large number of patients with NY-ESO-1-expressing tumors.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The T2.DR4 cell line was generated through transfection of HLA-DRB1*0401 cDNA into T2 cells (18) . The T2.DR4 cell line is HLA-DM deficient, making its cell surface DRB1*0401 complexes receptive to loading by exogenous peptides. The homozygous B-EBV-transformed cell lines MGAR and POER were provided by Dr. Penelope Morel (UPCI, Pittsburgh, PA). DR-transfected mouse cells, i.e., L.DR1, L.DR3, L.DR7, and L.DR53 were a gift of Dr. Robert Karr (Searle, Inc., St. Louis, MO). All cell lines were cultured in RPMI 1640 (Life Technologies) supplemented with 10% FCS, L-arginine (116 mg/liter), L-asparagine (36 mg/liter), and L-glutamine (216 mg/liter). The HB55 and HB95 hybridomas, which secrete the L243 anti-HLA-DR (class II) mAb and the W6/32 anti-HLA-A, B, C (class I) mAb, respectively, were purchased from the American Type Culture Collection (Rockville, MD).
Peptide Synthesis.
The NY-ESO-1-derived peptides were synthesized using standard Fmoc chemistry by the University of Pittsburgh Peptide Synthesis Facility (Shared Resource), were >90% pure as indicated by analytical HPLC, and were validated for identity by mass spectrometry. Lyophilized peptides were dissolved in PBS-10% DMSO or 100% DMSO at a concentration of 2 mg/ml and stored at -20°C until use. Synthesis of NY-ESO-1 peptides was based on the sequence of a NY-ESO-1 gene published by Chen et al. (Ref. 4
; GenBank accession no. U87459). The peptides used in the binding assays were synthesized using Fmoc chemistry as described previously (13)
. Biotinylated peptides were obtained by reaction with biotinyl-6-aminocaproic acid (Fluka Chimie, St. Quentin Fallavier, France) on their NH2 termini. All of these peptides were purified by reverse-phase HPLC on a C18 Vydac column, and their quality was assessed by electrospray mass spectroscopy and analytical HPLC.
Recombinant Proteins.
The full-length NY-ESO-1 and SSX recombinant proteins were produced in baculovirus and were kindly provided by Drs. Lloyd J. Old and Gerd Ritter (Ludwig Institute for Cancer Research, New York Branch, New York, NY).
Purification of HLA-DR Molecules.
HLA-DR molecules were purified from homozygous EBV cell lines by affinity chromatography using the monomorphic mAb L243 coupled to protein A-Sepharose CL 4B gel (Amersham Pharmacia Biotech, Orsay, France) as described previously (13
, 14)
.
HLA-DR Peptide-binding Assays.
HLA-DR molecules were diluted in 10 mM phosphate, 150 mM NaCl, 1 mM DM, 10 mM citrate, 0.003% thimerosal buffer with an appropriate biotinylated peptide and serial dilutions of competitor peptides. Samples (100 µl/well) were incubated in 96-well polypropylene plates (Nunc, Roskilde, Denmark) at 37°C for 24 h, except for the peptides produced by the DRB1*0301, DRB1*1501, DRB1*1301, and DRB4*0101 alleles, which were incubated 72 h. After pH neutralization, samples were applied to 96-well Maxisorp ELISA plates (Nunc) previously coated with 10 µg/ml mAb L243. They were incubated on the antibody-coated plates for 2 h at room temperature. Bound biotinylated peptides were detected by a streptavidin-alkaline phosphatase conjugate (Amersham, Little Chalfont, United Kingdom) and 4-methylumbelliferyl phosphate as substrate (Sigma Chemical Co., St. Quentin Fallavier, France). Fluorescence (emission at 450 nm; excitation at 365 nm) was measured by a Fluorolite 1000 fluorometer (Dynex, Issy les Moulineaux, France). Maximal binding was determined by incubating the biotinylated peptide with the MHC II molecule in the absence of competitor. Binding specificity for each HLA-DR was ensured by the choice of the biotinylated peptides as described previously (14)
. Data were expressed as the concentration of peptide that prevented binding of 50% of the labeled peptide (IC50).
Induction of CD4+ T Cells with Peptides.
The induction of CD4+ T cells in vitro with the NY-ESO-1-derived peptides was performed as reported previously (7
, 11)
. The CD4+ T cells were cloned by limiting dilution using allogeneic PBL and EBV-B cells as feeders in the presence of IL-2 and phytohemagglutinin and were subsequently tested for specificity in IFN-
ELISPOT assays. The CD4+ T-cell clones were maintained by restimulation every 2 weeks, by alternating irradiated allogeneic PBL and EBV-B cells or autologous peptide-pulsed DCs as stimulators.
Induction of CD4+ T Cells with Protein.
The induction of CD4+ T cells with proteins was performed as described previously (7)
. The stimulated CD4+ T cells were analyzed for specificity in ELISPOT assays at day 21.
Assessment of T-Cell Responses to Peptides and Tumor Cells.
The recognition of APCs pulsed with peptides and tumor cells was assessed by ELISPOT assays specific for hu-IFN- and IL-5. For the ELISPOT assays, multiscreen HA plates (Millipore, Bedford, MA) were coated with 10 µg/ml of either mAb antihuman IFN- (1-D1K; Mabtech, Stockholm, Sweden) or mAb antihuman IL-5 (BD-PharMingen) in PBS (Life Technologies, Inc.) overnight at 4°C. Unbound mAb was removed by four successive washings with PBS. After the plates were blocked with RPMI-10% human serum (1 h at 37°C), CD4+ T cells were seeded in triplicate (104 for bulk CD4+ T cells and 103 for CD4+ T cell clones) in multiscreen HA plates. Nonirradiated T2.DR4 cells or L cells (7.5 x 104) or melanoma cells (25 x 103) were added. Synthetic peptides were then added at indicated concentrations into ELISPOT assays after APCs were seeded. Control wells contained unstimulated T cells, T cells in the presence of unloaded T2.DR4 cells, L cells, or tumor cells alone. Alternatively, 25 x 103 protein-loaded DCs were added to 5 x 103 CD4+ T-cell clones per well. Culture medium was AIM-V at a final volume of 200 µl/well. After incubation at 37°C in 5% CO2 for either 40 h (IFN- ELISPOT assays) or 20 h (IL-5 ELISPOT assays), cells were removed by washings with PBS-0.05% Tween 20 (PBS-T). Captured cytokine was detected at sites of its secretion by incubation for 4 h with either biotinylated mAb anti-hIFN- (7-B6–1; Mabtech) at 2 µg/ml or mAb anti-hIL-5 (JES1–5A10; BD-PharMingen) in PBS-0.5% BSA. Plates were washed six times with PBS-T, and avidin-peroxidase complex, diluted 1:100 (Vectastain Elite Kit: Vector, Burlingame, CA), was added for 1 h at room temperature. Unbound complex was removed by three successive washings with PBS-T and three with PBS alone. Peroxidase staining was performed with 3-amino-9-ethyl-carbazole (Sigma) or alternatively with 3,3,5'-tetramethylbenzidine (Vector Laboratories) for 4 min and stopped by rinsing the plates under running tap water. Spot numbers and spot sizes were automatically determined with the use of computer-assisted video image analysis as described previously (15)
.
Statistical Analysis.
For statistical analysis of the ELISPOT data, comparisons of CD4+ T-cell immunoreactivity were performed with one-sided Wilcoxon rank-sum tests (the Wilcoxon test is preferred to the t test for these comparisons because of the small sample sizes; Refs. 16
, 17
). For the comparison of one triplicate to another, where all of the counts in the first triplicate are larger than all of the counts in the second, the P from the Wilcoxon test is 0.05. P = 0.05 was considered significant and is indicated with an asterisk (*) in relevant figures.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Ref. 7
). In agreement with these data, NY-ESO-1 119–143 binds well to DRB1*0401 (Table 1)
. Interestingly, peptide NY-ESO-1 119–143 was also able to bind very efficiently to multiple peptides produced by DR alleles, including DRB1*0101, DRB1*0701, DRB1*1101, DRB1*1501, DRB3*0101 (also known as DR52), DRB4*0101 (DR53), and DRB5*0101 (DR51). The binding activities of the shortest peptide sequences revealed that peptide NY-ESO-1 119–143 contains a number of binding determinants. For DR4 and DR7, peptides NY-ESO-1 121–138, NY-ESO-1 119–133, and NY-ESO-1 123–137 exhibit equivalent activity to peptide NY-ESO-1 119–143, whereas peptide NY-ESO-1 129–143 is less active. DR1 and DR11 accommodate mainly peptides NY-ESO-1 121–138 and NY-ESO-1 123–137, and only peptide NY-ESO-1 129–143 binds to DR53. Moreover, it was not possible to delineate the binding determinants with this set of short peptides for the DR15 and DRB5 molecules because none of them is as active as peptide NY-ESO-1 119–143. Altogether, peptide NY-ESO-1 119–143 appears extremely rich in HLA-DR-restricted determinants.
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ELISPOT assays. As APCs in the IFN- ELISPOT assays, we used L cells, which have genetically been engineered to express either DR1 (L.DR1) or DR3 (L.DR3) or DR4 (L.DR4), DR7 (L.DR7), or DR53 (L.DR53). Alternatively, we also used the DRB1* 1101+ homozygous EBV lymphoblastoid cell line, POER.
Bulk CD4+ T cells from donors 1 and 2 that were stimulated with the NY-ESO-1 119–143 peptide specifically recognized L.DR7 cells pulsed with NY-ESO-1 peptides 119–143, 121–138, 123–137, or 115–132 (the data obtained with the cells of donor 1 are presented in Fig. 1
). These CD4+ T cells also displayed reactivity against the L.DR53 cells pulsed with peptide NY-ESO-1 119–143, but not with peptides NY-ESO-1 121–138, 123–137, or 115–132. These CD4+ T cells also displayed reactivity against the DR7-matched and the DR53-matched NY-ESO-1+ melanoma cell lines UPCI-MEL 591.8 and UPCI-MEL 527.1, respectively. This tumor reactivity was partially inhibited by the addition of anti-HLA-DR mAb (L243) but not by anti-HLA-A, B, C mAb. No immunoreactivity was observed in the presence of the NY-ESO-1-, HLA-DR53-matched tumor cell line, UPCI-136.1 (data not shown). Moreover, the CD4+ T cells pulsed with NY-ESO-1 peptides 121–138, 123–137, or 115–132 did not exhibit significant reactivity against L.DR53 cells pulsed with the relevant peptide. No IFN- ELISPOT reactivity developed in wells containing L.DR7 or L.DR53 cells in the absence of added CD4+ T cells (data not shown).
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. These CD4+ T cells also recognized the DR11-matched NY-ESO-1+ melanoma cell line, UPCI-MEL 591.8.
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. These CD4+ T cells also displayed reactivity against the NY-ESO-1+ autologous melanoma cell line, UPCI-MEL 285.1; this reactivity was partially inhibited by the addition of anti-HLA-DR mAb (L243) but not anti-HLA-A, B, C mAb.
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DCs Loaded with Recombinant NY-ESO-1 Protein Stimulate CD4+ T Cells That Recognize the NY-ESO-1 119–143 Peptide from a DRB1*0701/DRB4*0101+ Normal Donor.
Peripheral blood mononuclear cells from a DRB1*0701+/DRB4*0101+ normal donor (patient 2) were stimulated with DCs loaded with protein NY-ESO-1 (as indicated in "Material and Methods"). The responder cell cultures were then restimulated on a weekly basis with the irradiated autologous protein-fed DCs used in the primary stimulation. After three restimulations, the immunoreactivities of the T-cell cultures were analyzed in IFN- ELISPOT assays. T cells that were stimulated with the protein-pulsed DCs specifically recognized L.DR7 pulsed with peptide NY-ESO-1 119–143 (Fig. 4)
. These CD4+ T cells also displayed reactivity against L.DR7 cells pulsed with peptide NY-ESO-1 121–138 or peptide NY-ESO-1 123–137 and against the HLA-DR53-matched melanoma cell line, UPCI-MEL 285.1; this reactivity was inhibited by the addition of anti-HLA-DR mAb (L243) but not anti-HLA-A, B, C mAb.
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ELISPOT assay. These CD4+ T cells recognized autologous DCs previously loaded with the NY-ESO-1 protein (Fig. 5)
. Unloaded DCs and the DCs fed with the recombinant SSX protein served as baseline and peptide controls, respectively.
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in the presence of APCs pulsed with the NY-ESO-1 119–143 peptide as well as DR4+, NY-ESO-1+ melanoma cell lines. We tested the ability of these CD4+ T cells to also exhibit a Th2-type response. Clones 10/4 and 11/4 did not produce IL-5 in the presence of T2.DR4 pulsed with peptide NY-ESO-1 119–143 or the autologous melanoma cell line 527.1 and thus appeared to be Th1-type clones. However, bulk CD4+ T cells previously shown to specifically produce IFN- spots in the presence of NY-ESO-1 119–143 peptide-pulsed APCs or the autologous melanoma cells also produced IL-5 spots (Fig. 6)
. These data indicate the ability of peptide NY-ESO-1 119–143 to stimulate both Th1- and Th2-type CD4+ T-cell responses. Of note, peptide NY-ESO-1 119–143 was not recognized by anti-NY-ESO-1 serum antibodies; we failed to detect any reactivity in ELISA assays with serum of patient UPCI-MEL 527 (data not shown). However, we have detected a high level of antibody against the NY-ESO-1 protein in the serum of this patient. Similar data were observed in a series of experiments done with PBLs of an HLA-DRB1*0101/DRB1*0401 patient with melanoma (UPCI-MEL 285) and two HLA-DRB1*0701/DRB1*1101 normal donors (data not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We demonstrated the good binding capabilities of peptide NY-ESO-1 119–143 to five molecules of the most commonly expressed alleles encoded by the HLA-DRB1 genes (i.e., DRB1*0101, DRB1*0401, DRB1*0701, DRB1*1101, and DRB1*1501). These molecules are expressed by nearly 46.1% of the American-Caucasian population. We have also shown that NY-ESO-1 119–143 binds well to the HLA allele molecules DRB3*0101, DRB4*0101, and DRB5*0101. These molecules have the advantage of being less polymorphic and occurring with high frequency in the Caucasian population (Table 1)
. Unlike peptide NY-ESO-1 119–143, the shortest sequences that we and others have reported previously (i.e., NY-ESO-1 119–133, 121–138, and 123–137) exhibit little, if any, reactivity for the DR53 molecule and exhibit intermediate binding properties with DR15 and the B3 and B5 molecules. This may be explained by the existence of a peptide-binding sequence in the COOH-terminal amino acid portion of peptide NY-ESO-1 119–143 that is able to bind to DR53 and the B5 molecules. In this regard, our binding data show that the NY-ESO-1 129–143 peptide sequence has the capability to bind to the B3 and DR53 molecules. Several peptides capable of broadly binding to many class II allele molecules have been reported (13
, 18, 19, 20, 21, 22)
. In the field of cancer immunology, HER2/neu and MAGE-3 have been shown to give rise to promiscuous DR epitopes (23
, 24) .
In a series of in vitro experiments with DCs and PBLs from melanoma patients and normal donors, we have confirmed the implications of the binding data and demonstrated the immunogenicity of peptide NY-ESO-1 119–143 at the surface of several DR molecules. In particular, we demonstrated the capability of peptide NY-ESO-1 119–143 to stimulate melanoma-reactive CD4+ T cells that recognized this peptide in the context of the HLA-DR4, -DR7, -DR11, and -DR53 molecules. We also demonstrated that the CD4+ T cells from a DRB1*0701/DRB4*0101+ (DR53) normal donor, stimulated in vitro with DCs fed with the NY-ESO-1 protein, recognized NY-ESO-1 peptide at the surface of the DR7 and DR53 molecules. This indicates that peptide NY-ESO-1 119–143 contains epitopes that are processed and presented at the surface of multiple DR molecules. This set of experiments also confirmed the ability of these epitopes to stimulate melanoma-reactive CD4+ T cells when presented at the surface of these DR molecules.
We demonstrated the ability of the NY-ESO-1 119–143 peptide sequence to stimulate both Th1- and Th2-type CD4+ T cells. Both cell types have been shown to play an antitumor role in vivo. Adoptive transfer of either Th1 or Th2 T cells from Ovalbumin-specific T-cell receptor-transgenic mice induced tumor regression (25) . Two different mechanisms may pertain to these subsets because Th1 cells were able to stimulate antitumor CTL responses, whereas Th2 cells induced tumor necrosis. In a recent report, the administration of Th1 and Th2 cell clones to a TAA (P 815 AB) induced tumor rejection, with quantitative rather than qualitative differences in the antitumor activities of both types of cells (26) . In this study, both types of cells initiated CTL responses and required the presence of CD8+ T cells. The rejection of P815 tumors following adoptive transfer with either type of clone (Th1 or Th2) induced a strong immunological memory. Of note, tumor-specific shared antigens or cancer-testis antigens, such as NY-ESO-1, display an expression pattern very similar to the P815 AB antigen, which is an immunogenic TAA of murine mastocytoma cells. This may suggest that both Th1 and Th2 responses directed against NY-ESO-1-derived epitopes could be important in eliciting antitumor responses in vivo.
Both the immunogenicity of the NY-ESO-1 gene products and the pan-DR promiscuity of peptide NY-ESO-1 119–143 support its relevance as a potential immunogen for cancer vaccines designed to treat a large number of patients with NY-ESO-1+ tumors. NY-ESO-1 is expressed by 50% of breast and prostate carcinomas and 30% of metastatic melanoma, non-small cell lung cancer, bladder, and head and neck tumors (27) . Here, we demonstrated the ability of peptide NY-ESO-1 119–143 to be presented at the surface of multiple DR molecules expressed altogether by 91.6% of the Caucasian-American population. Therefore, peptide NY-ESO-1 119–143 will be clinically relevant in 45.8% of Caucasian patients with breast or prostate cancers and 27.5% of Caucasian patients with melanoma or lung and head and neck cancers.
Given the role of CD4+ T cells in maintaining CD8+ T-cell responses and the potential direct antitumor effector function of CD4+ T cells, peptide NY-ESO-1 119–143 is a reasonable vaccine candidate for the in vivo induction of both tumor-reactive CD4+ and CD8+ T cells.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by NIH Grant CA 56774 (to J. M. K.), a Clinical Trial Grant/Melanoma Initiative from the Cancer Research Institute (to J. M. K.), the Competitive Medical Research Fund of the University of Pittsburgh Medical Center, and a Cancer Research Institute/Elaine R. Shepard Memorial Fellowship (to H. M. Z.). 
2 To whom requests for reprints should be addressed, at the University of Pittsburgh Cancer Institute, Biomedical Science Tower, E 1051, 211 Lothrop Street, Pittsburgh, PA 15213-2582. Phone: (412) 648-9119; Fax: (412) 624-7794; E-mail: zarourhm{at}msx.upmc.edu
3 The abbreviations used are: TAA, tumor-associated antigen; Th, T-helper; PBL, peripheral blood lymphocyte; UPCI, University of Pittsburgh Cancer Institute; EBV; Epstein Barr virus; mAb, monoclonal antibody; HPLC, high-performance liquid chromatography; ELISPOT, enzyme-linked immunospot; IL, interleukin; DC, dendritic cell; APC, antigen-presenting cell.
Received 7/30/01. Accepted 11/ 1/01.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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K. Chamoto, T. Tsuji, H. Funamoto, A. Kosaka, J. Matsuzaki, T. Sato, H. Abe, K. Fujio, K. Yamamoto, T. Kitamura, et al. Potentiation of Tumor Eradication by Adoptive Immunotherapy with T-cell Receptor Gene-Transduced T-Helper Type 1 Cells Cancer Res., January 1, 2004; 64(1): 386 - 390. [Abstract] [Full Text] [PDF]
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K. Teramoto, K. Kontani, Y. Ozaki, S. Sawai, N. Tezuka, T. Nagata, S. Fujino, Y. Itoh, O. Taguchi, Y. Koide, et al. Deoxyribonucleic Acid (DNA) Encoding a Pan-Major Histocompatibility Complex Class II Peptide Analogue Augmented Antigen-specific Cellular Immunity and Suppressive Effects on Tumor Growth Elicited by DNA Vaccine Immunotherapy Cancer Res., November 15, 2003; 63(22): 7920 - 7925. [Abstract] [Full Text] [PDF]
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M. Rodolfo, R. Luksch, E. Stockert, Y.-T. Chen, P. Collini, T. Ranzani, C. Lombardo, P. Dalerba, L. Rivoltini, F. Arienti, et al. Antigen-Specific Immunity in Neuroblastoma Patients: Antibody and T-Cell Recognition of NY-ESO-1 Tumor Antigen Cancer Res., October 15, 2003; 63(20): 6948 - 6955. [Abstract] [Full Text] [PDF]
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M. Mandic, C. Almunia, S. Vicel, D. Gillet, B. Janjic, K. Coval, B. Maillere, J. M. Kirkwood, and H. M. Zarour The Alternative Open Reading Frame of LAGE-1 Gives Rise to Multiple Promiscuous HLA-DR-restricted Epitopes Recognized by T-helper 1-type Tumor-reactive CD4+ T Cells Cancer Res., October 1, 2003; 63(19): 6506 - 6515. [Abstract] [Full Text] [PDF]
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S. Gnjatic, D. Atanackovic, E. Jager, M. Matsuo, A. Selvakumar, N. K. Altorki, R. G. Maki, B. Dupont, G. Ritter, Y.-T. Chen, et al. Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: Correlation with antibody responses PNAS, July 22, 2003; 100(15): 8862 - 8867. [Abstract] [Full Text] [PDF]
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S. Gnjatic, D. Atanackovic, M. Matsuo, E. Jager, S. Y. Lee, D. Valmori, Y.-T. Chen, G. Ritter, A. Knuth, and L. J. Old Cross-Presentation of HLA Class I Epitopes from Exogenous NY-ESO-1 Polypeptides by Nonprofessional APCs J. Immunol., February 1, 2003; 170(3): 1191 - 1196. [Abstract] [Full Text] [PDF]
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K. S. Voo, T. Fu, H. E. Heslop, M. K. Brenner, C. M. Rooney, and R.-F. Wang Identification of HLA-DP3-restricted Peptides from EBNA1 Recognized by CD4+ T Cells Cancer Res., December 15, 2002; 62(24): 7195 - 7199. [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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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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