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1.
Hoffmann TK Nakano K Elder EM Dworacki G Finkelstein SD Appella E Whiteside TL DeLeo AB 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(10):5938-5944
Alterations in the p53 gene occur frequently and can lead to accumulation of p53 protein in squamous cell carcinomas of the head and neck (SCCHN). Since accumulation of p53 is associated with enhanced presentation of wild-type sequence (wt) p53 peptides to immune cells, the development of pan vaccines against SCCHN has focused on wt p53 epitopes. We used the HLA-A2.1-restricted wt p53(264-272) epitope to generate CTL from circulating precursor T cells of HLA-A2.1(+) healthy donors and patients with SCCHN. Autologous peptide-pulsed dendritic cells were used for in vitro sensitization. CTL specific for the wt p53(264-272) peptide were generated from PBMC obtained from two of seven normal donors and three of seven patients with SCCHN. These CTL were HLA class I restricted and responded to T2 cells pulsed with p53(264-272) peptide as well as HLA-A2-matched SCCHN cell lines naturally presenting the epitope. Paradoxically, none of the tumors in the three patients who generated CTL could adequately present the epitope; two had a wt p53 genotype and no p53 protein accumulation, while the third tumor expressed a point mutation (R to H) in codon 273 that prevents presentation of the p53(264-272) epitope. In contrast, patients who did not generate CTL had tumors that accumulated altered p53 and potentially could present the p53(264-272) epitope. These findings suggest that in vivo, CTL specific for the wt p53(264-272) peptide might play a role in the elimination of tumor cells expressing this epitope and in immunoselection of epitope-loss tumor cells. Immunoselection of tumors that become resistant to anti-p53 immune responses has important implications for future p53-based vaccination strategies. 相似文献
2.
Kazuaki Chikamatsu Koichi Sakakura Goro Takahashi Atsushi Okamoto Nobuhiko Furuya Theresa L. Whiteside Albert B. DeLeo Keisuke Masuyama 《Cancer immunology, immunotherapy : CII》2009,58(9):1441-1448
Wild-type sequence (wt) p53 peptides are attractive candidates for broadly applicable cancer vaccines. Evidence has been accumulating
which indicates that CD4+ Th cells have an important role in generating and maintaining antitumor immune responses. To elucidate
the nature of CD4+ Th responses to wt p53 epitopes in patients with squamous cell carcinoma of the head and neck (SCCHN),
peripheral blood mononuclear cells (PBMCs) from HLA-DP5+ patients were stimulated with HLA-DP5-restricted wt p53 peptides,
p53108–122 or p53153–166, and tested for the release of IFN-γ and IL-5 in ELISPOT assays. Immunohistochemistry for p53 accumulation in tumors, and
ELISA for serum antibodies to p53 were also performed. Eleven (57.9%) of 19 HLA-DP5+ patients but none of 5 healthy donors
had detectable Th1 and/or Th2 responses to wt p53 peptides by ELISPOT assay. Among these 11 responding patients, 9 (81.8%)
and all 11 (100%) patients had a tumor burden and p53 accumulation, respectively. On the other hand, two responding patients
were in post-operative condition. Interestingly, among nine patients with a tumor burden, four patients with early disease
showed either Th1-polarized or mixed Th1/Th2 responses, while five patients with advanced disease showed either Th2-polarized
or mixed Th1/Th2 responses. Our results suggest that wt p53108–122 and p53153–166 peptides stimulate both Th1- and Th2-type CD4+ T cell responses in patients with SCCHN, and anti-p53 Th responses may persist
even after surgical resection of the tumor; however, the presence of a tumor and its progression may affect the nature of
immune responses to wt p53 peptides. 相似文献
3.
The ability of variant peptides to reverse the nonresponsiveness of T lymphocytes to the wild-type sequence p53(264-272) epitope. 总被引:4,自引:0,他引:4
Thomas K Hoffmann Douglas J Loftus Koji Nakano Markus J Maeurer Kazuaki Chikamatsu Ettore Appella Theresa L Whiteside Albert B DeLeo 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(3):1338-1347
Recently, we observed that CTL specific for the wild-type (wt) sequence p53(264-272) peptide could only be expanded ex vivo from PBMC of a subset of the HLA-A2.1(+) normal donors or cancer patients tested. Surprisingly, the tumors of the responsive patients expressed normal levels of wt p53 and could be considered unlikely to present this epitope. In contrast, tumors of nonresponsive patients accumulated mutant p53 and were more likely to present this epitope. We sought to increase the responsive rate to the wt p53(264-272) peptide of PBMC obtained from normal donors and patients by identifying more immunogenic variants of this peptide. Two such variants were generated by amino acid exchanges at positions 6 (6T) and 7 (7W) of the peptide. These variants were capable of inducing T cells from PBMC of nonresponsive donors that recognized the parental peptide either pulsed onto target cells or naturally presented by tumors. TCR Vbeta analysis of two T cell lines isolated from bulk populations of effectors reactive against the wt p53(264-272) peptide, using either the parental or the 7W variant peptide, indicated that these T cells were expressing identical TCR Vbeta13.6/complementarity-determining region 3/J region sequences. This finding confirms the heteroclitic nature of at least one of the variant peptides identified in this study. The use of variant peptides of the wt p53(264-272) epitope represents a promising approach to overcoming the nonresponsiveness of certain cancer patients to this self epitope, thereby enhancing its potential use in tumor vaccines for appropriately selected cancer patients. 相似文献
4.
Fedoseyeva EV Boisgérault F Anosova NG Wollish WS Arlotta P Jensen PE Ono SJ Benichou G 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(11):5641-5651
We analyzed CD4+ T helper responses to wild-type (wt) and mutated (mut) p53 protein in normal and tumor-bearing mice. In normal mice, we observed that although some self-p53 determinants induced negative selection of p53-reactive CD4+ T cells, other p53 determinants (cryptic) were immunogenic. Next, BALB/c mice were inoculated with J774 syngeneic tumor cell line expressing mut p53. BALB/c tumor-bearing mice mounted potent CD4+ T cell responses to two formerly cryptic peptides on self-p53. This response was characterized by massive production of IL-5, a Th2-type lymphokine. Interestingly, we found that T cell response was induced by different p53 peptides depending upon the stage of cancer. Mut p53 gene was shown to contain a single mutation resulting in the substitution of a tyrosine by a histidine at position 231 of the protein. Two peptides corresponding to wt and mutated sequences of this region were synthesized. Both peptides bound to the MHC class II-presenting molecule (Ed) with similar affinities. However, only mut p53.225-239 induced T cell responses in normal BALB/c mice, a result strongly suggesting that high-affinity wt p53.225-239 autoreactive T cells had been eliminated in these mice. Surprisingly, CD4+ T cell responses to both mut and wt p53.225-239 peptides were recorded in J774 tumor-bearing mice, a phenomenon attributed to the recruitment of low-avidity p53.225-239 self-reactive T cells. 相似文献
5.
Chow MT Dhanji S Cross J Johnson P Teh HS 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(8):5098-5104
H2-M3-restricted CD8+ T cells provide early protection against bacterial infections. In this study, we demonstrate that activated H2-M3-restricted T cells provide early signals for efficient CD4+ T cell priming. C57BL/6 mice immunized with dendritic cells coated with the MHC class II-restricted listeriolysin O peptide LLO(190-201) (LLO) generated CD4+ T cells capable of responding to Listeria monocytogenes (LM) infection. Inclusion of a H2-M3-restricted formylated peptide fMIGWII (fMIG), but not MHC class Ia-restricted peptides, during immunization with LLO significantly increased IFN-gamma-producing CD4+ T cell numbers, which was associated with increased protection against LM infection. Studies with a CD4+ T cell-depleting mAb indicate that the reduction in bacterial load in fMIG plus LLO immunized mice is likely due to augmented numbers of LLO-specific CD4+ T cells, generated with the help of H2-M3-restricted CD8+ T cells. We also found that augmentation of LLO-specific CD4+ T lymphocytes with H2-M3-restricted T cells requires presentation of LLO and fMIG by the same dendritic cells. Interestingly, the augmented CD4+ T cell response generated with fMIG also increased primary LM-specific responses by MHC class Ia-restricted CD8 T cells. Coimmunization with LLO and fMIG also increases the number of memory Ag-specific CD4+ T cells. We also demonstrate that CD8 T cells restricted to another MHC class Ib molecule, Qa-1, whose human equivalent is HLA-E, are also able to enhance Ag-specific CD4+ T cell responses. These results reveal a novel function for H2-M3- and Qa-1-restricted T cells; provision of help to CD4+ Th cells during the primary response. 相似文献
6.
Junji Yatsuda Atsushi Irie Kumiko Harada Yayoi Michibata Hirotake Tsukamoto Satoru Senju Yusuke Tomita Akira Yuno Masatoshi Hirayama Mohammad Abu Sayem Naoki Takeda Isao Shibuya Shinji Sogo Fumihiro Fujiki Haruo Sugiyama Masatoshi Eto Yasuharu Nishimura 《PloS one》2013,8(12)
Reports have shown that activation of tumor-specific CD4+ helper T (Th) cells is crucial for effective anti-tumor immunity and identification of Th-cell epitopes is critical for peptide vaccine-based cancer immunotherapy. Although computer algorithms are available to predict peptides with high binding affinity to a specific HLA class II molecule, the ability of those peptides to induce Th-cell responses must be evaluated. We have established HLA-DR4 (HLA-DRA*01:01/HLA-DRB1*04:05) transgenic mice (Tgm), since this HLA-DR allele is most frequent (13.6%) in Japanese population, to evaluate HLA-DR4-restricted Th-cell responses to tumor-associated antigen (TAA)-derived peptides predicted to bind to HLA-DR4. To avoid weak binding between mouse CD4 and HLA-DR4, Tgm were designed to express chimeric HLA-DR4/I-Ed, where I-Ed α1 and β1 domains were replaced with those from HLA-DR4. Th cells isolated from Tgm immunized with adjuvant and HLA-DR4-binding cytomegalovirus-derived peptide proliferated when stimulated with peptide-pulsed HLA-DR4-transduced mouse L cells, indicating chimeric HLA-DR4/I-Ed has equivalent antigen presenting capacity to HLA-DR4. Immunization with CDCA155-78 peptide, a computer algorithm-predicted HLA-DR4-binding peptide derived from TAA CDCA1, successfully induced Th-cell responses in Tgm, while immunization of HLA-DR4-binding Wilms'' tumor 1 antigen-derived peptide with identical amino acid sequence to mouse ortholog failed. This was overcome by using peptide-pulsed syngeneic bone marrow-derived dendritic cells (BM-DC) followed by immunization with peptide/CFA booster. BM-DC-based immunization of KIF20A494-517 peptide from another TAA KIF20A, with an almost identical HLA-binding core amino acid sequence to mouse ortholog, successfully induced Th-cell responses in Tgm. Notably, both CDCA155-78 and KIF20A494-517 peptides induced human Th-cell responses in PBMCs from HLA-DR4-positive donors. Finally, an HLA-DR4 binding DEPDC1191-213 peptide from a new TAA DEPDC1 overexpressed in bladder cancer induced strong Th-cell responses both in Tgm and in PBMCs from an HLA-DR4-positive donor. Thus, the HLA-DR4 Tgm combined with computer algorithm was useful for preliminary screening of candidate peptides for vaccination. 相似文献
7.
Induction of human cytotoxic T lymphocytes that preferentially recognise tumour cells bearing a conformational p53 mutant 总被引:1,自引:0,他引:1
McArdle SE Rees RC Mulcahy KA Saba J McIntyre CA Murray AK 《Cancer immunology, immunotherapy : CII》2000,49(8):417-425
The tumour-suppressor gene p53 is pivotal in the regulation of apoptosis, and point mutations within p53 are the commonest genetic alterations in human cancers. Cytotoxic T lymphocytes (CTL) recognise peptide-MHC complexes on
the surface of tumour cells and bring about lysis. Therefore, p53-derived peptides are potential candidates for immunisation
strategies designed to induce antitumour CTL in patients. Conformational changes in the p53 protein, generated as a result
of point mutations, frequently expose the 240 epitope, RHSVV (amino acids 212–217), which may be processed differently from
the wild-type protein resulting in an altered MHC-associated peptide repertoire recognised by tumour-specific CTL. In this
study 42 peptides (37 overlapping nonameric peptides, from amino acids 193–237 and peptides 186–194, 187–197, 188–197, 263–272,
264–272, possessing binding motifs for HLA-A2) derived from the wild-type p53 protein sequence were assayed for their ability
to stabilise HLA-A2 molecules in MHC class I stabilisation assays. Of the peptides tested, 24 stabilised HLA-A2 molecules
with high affinity (fluorescence ratio>1.5) at 26 °C, and five (187–197, 193–200, 217–224, 263–272 and 264–272) also stabilised
the complexes at 37 °C. Peptides 188–197, 196–203 and 217–225 have not previously been identified as binders of HLA-A2 molecules
and, of these, peptide 217–225 stabilised HLA-A2 molecules with the highest fluorescence ratio. Peptide 217–225 was chosen
to generate HLA-A2-restricted CTL in vitro; peptide 264–272 was used as a positive control. The two primary CTL thus generated
(CTL-217 using peptide 217–225; and CTL-264 using peptide 264–272) were capable of specifically killing peptide-pulsed T2
or JY cells. In order to determine whether these peptides were endogenously processed and to test the hypothesis that mutants
expressing different protein conformations would generate an alternative peptide repertoire at the cell surface, a panel of
target cells was generated. HLA-A2+ SaOs-2 cells were transfected with p53 cDNA containing point mutations at either position 175 (R → H) or 273 (R → H) (SaOs-2/175
and SaOs-2/273). Two HLA-A2-negative cell lines, A431 and SKBr3, naturally expressing p53 mutations at positions 273 and 175
respectively, were transfected with a cDNA encoding HLA-A2. The results showed that primary CTL generated in response to both
peptides were capable of killing SaOs-2/175 and SKBr3-A2 cells, which possess the same mutation, but not SaOs-2/273, A431-A2
or SKBr3 cells transfected with control vector. This suggests that these peptides are presented on the surface of SaOs-2/175
and SKBr3-A2 cells in a conformation-dependent manner and represent potentially useful target peptides for immunotherapy.
Received: 23 March 2000 / Accepted: 22 June 2000 相似文献
8.
Nishikawa H Qian F Tsuji T Ritter G Old LJ Gnjatic S Odunsi K 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(10):6340-6346
We have recently reported that NY-ESO-1-specific naive CD4+ T cell precursors exist in most individuals but are suppressed by CD4+CD25+ regulatory T cells (Tregs), while memory CD4+ T cell effectors against NY-ESO-1 are found only in cancer patients with spontaneous Ab responses to NY-ESO-1. In this study, we have analyzed mechanisms of CD4+ T cell induction following peptide vaccination in relation to susceptibility to Tregs. Specific HLA-DP4-restricted CD4+ T cell responses were elicited after vaccination with NY-ESO-1(157-170) peptide (emulsified in IFA) in patients with NY-ESO-1-expressing epithelial ovarian cancer. These vaccine-induced CD4+ T cells were detectable from effector/memory populations without requirement for in vitro CD4+CD25+ T cell depletion. However, they were only able to recognize NY-ESO-1(157-170) peptide but not naturally processed NY-ESO-1 protein and had much lower avidity compared with NY-ESO-1-specific pre-existing naive CD4+CD25- T cell precursors or spontaneously induced CD4+ T cell effectors of cancer patients with NY-ESO-1 Ab. We propose that vaccination with NY-ESO-1(157-170) peptide recruits low-avidity T cells with low sensitivity to Tregs and fails to modulate the suppressive effect of Tregs on high-avidity NY-ESO-1-specific T cell precursors. 相似文献
9.
Zeng G Touloukian CE Wang X Restifo NP Rosenberg SA Wang RF 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(2):1153-1159
In previous studies, the shared cancer-testis Ag, NY-ESO-1, was demonstrated to be recognized by both Abs and CD8+ T cells. Gene expression of NY-ESO-1 was detected in many tumor types, including melanoma, breast, and lung cancers, but was not found in normal tissues, with the exception of testis. In this study, we describe the identification of MHC class II-restricted T cell epitopes from NY-ESO-1. Candidate CD4+ T cell peptides were first identified using HLA-DR4 transgenic mice immunized with the NY-ESO-1 protein. NY-ESO-1-specific CD4+ T cells were then generated from PBMC of a patient with melanoma stimulated with the candidate peptides in vitro. These CD4+ T cells recognized NY-ESO-1 peptides or protein pulsed on HLA-DR4+ EBV B cells, and also recognized tumor cells expressing HLA-DR4 and NY-ESO-1. A 10-mer peptide (VLLKEFTVSG) was recognized by CD4+ T cells. These studies provide new opportunities for developing more effective vaccine strategies by using tumor-specific CD4+ T cells. This approach may be applicable to the identification of CD4+ T cell epitopes from many known tumor Ags recognized by CD8+ T cells. 相似文献
10.
CD4-8- dendritic cells prime CD4+ T regulatory 1 cells to suppress antitumor immunity 总被引:1,自引:0,他引:1
Zhang X Huang H Yuan J Sun D Hou WS Gordon J Xiang J 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(5):2931-2937
It is clear that dendritic cells (DCs) are essential for priming of T cell responses against tumors. However, the distinct roles DC subsets play in regulation of T cell responses in vivo are largely undefined. In this study, we investigated the capacity of OVA-presenting CD4-8-, CD4+8-, or CD4-8+ DCs (OVA-pulsed DC (DC(OVA))) in stimulation of OVA-specific T cell responses. Our data show that each DC subset stimulated proliferation of allogeneic and autologous OVA-specific CD4+ and CD8+ T cells in vitro, but that the CD4-8- DCs did so only weakly. Both CD4+8- and CD4-8+ DC(OVA) induced strong tumor-specific CD4+ Th1 responses and fully protective CD8+ CTL-mediated antitumor immunity, whereas CD4-8- DC(OVA), which were less mature and secreted substantial TGF-beta upon coculture with TCR-transgenic OT II CD4+ T cells, induced the development of IL-10-secreting CD4+ T regulatory 1 (Tr1) cells. Transfer of these Tr1 cells, but not T cells from cocultures of CD4-8- DC(OVA) and IL-10-/- OT II CD4+ T cells, into CD4-8+ DC(OVA)-immunized animals abrogated otherwise inevitable development of antitumor immunity. Taken together, CD4-8- DCs stimulate development of IL-10-secreting CD4+ Tr1 cells that mediated immune suppression, whereas both CD4+8- and CD4-8+ DCs effectively primed animals for protective CD8+ CTL-mediated antitumor immunity. 相似文献
11.
G Ferlazzo A Wesa W Z Wei A Galy 《Journal of immunology (Baltimore, Md. : 1950)》1999,163(7):3597-3604
Dendritic cells (DC) can be generated in vitro from monocytes (M-DC) or from CD34+ hemopoietic progenitor cells (CD34-DC) but their precursors are not equivalent cells, prompting a comparison of the functional capacities of these APC. Both types of DCs established from the same individuals using the same cytokines displayed a comparable phenotype of mature DC (CD1a+, CD83+, CD86+, CD4+, HLA-DR++, CD14-, CD15- ) and were equally potent stimulators of allogeneic T cell proliferation, being both more powerful than immature M-DCs. An autologous panel of APCs produced in HLA-A2+ individuals, including CD34-DC, M-DC, monocytes, and EBV-lymphoid cell line was comparatively evaluated for presentation of the Erb-B2 peptide E75 to a CTL line. After short exposures (5 h) to E75-loaded APCs, similar levels of intracellular IFN-gamma were induced in Ag-specific CD8+ T cells regardless of APC type. In sustained cultures (4-14 days), more Ag-specific T cells were obtained when peptide was presented on CD34-DC (p < 0.05) rather than on M-DC, EBV-lymphoid cell lines, or monocytes, and these effects were dose-dependent. Activated T cells expressed 4-1BB, and the presence of 4-1BB-Ig fusion protein partially blocked Ag-specific CD8+ cell activation after CD34-DC or M-DC presentation. Our results show that 34-DC have a preferential capacity to activate CD8+ T cells and that this property is not strictly correlated to their ability to induce allogeneic T cell proliferation but due to mechanisms that remain to be defined. 相似文献
12.
Induction of CTL and nonpolarized Th cell responses by CD8alpha(+) and CD8alpha(-) dendritic cells 总被引:3,自引:0,他引:3
Schlecht G Leclerc C Dadaglio G 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(8):4215-4221
Two distinct dendritic cell (DC) subpopulations have been evidenced in mice on the basis of their differential CD8alpha expression and their localization in lymphoid organs. Several reports suggest that CD8alpha(+) and CD8alpha(-) DC subsets could be functionally different. In this study, using a panel of MHC class I- and/or class II-restricted peptides, we analyzed CD4(+) and CD8(+) T cell responses obtained after i.v. injection of freshly purified peptide-pulsed DC subsets. First, we showed that both DC subsets efficiently induce specific CTL responses and Th1 cytokine production in the absence of CD4(+) T cell priming. Second, we showed that in vivo activation of CD4(+) T cells by CD8alpha(+) or CD8alpha(-) DC, injected i.v., leads to a nonpolarized Th response with production of both Th1 and Th2 cytokines. The CD8alpha(-) subset induced a higher production of Th2 cytokines such as IL-4 and IL-10 than the CD8alpha(+) subset. However, IL-5 was produced by CD4(+) T cells activated by both DC subsets. When both CD4(+) and CD8(+) T cells were primed by DC injected i.v., a similar pattern of cytokines was observed, but, under these conditions, Th1 cytokines were mainly produced by CD8(+) T cells, while Th2 cytokines were produced by CD4(+) T cells. Thus, this study clearly shows that CD4(+) T cell responses do not influence the development of specific CD8(+) T cell cytotoxic responses induced either by CD8alpha(+) or CD8alpha(-) DC subsets. 相似文献
13.
BACKGROUND: DC are commonly defined as HLA-DR+/Lin- cells that can be CD11c+ + + CD123+/ -, termed DC1/myeloid DC that induce a Th1 response, or CD11c- CD123+ + +, termed DC2/lymphoid DC that induce a Th2 response. However, significant heterogeneity within DC preparations is apparent and supports the existence of several distinct DC subpopulations. This study aimed to expand and characterize CD34+ DC for use in immunotherapy. METHODS: CD34+ cells were seeded at 1 x 10(5)/mL and expanded for 14 days in RPMI + 10% autologous plasma supplemented with GM-CSF, IL-4, Flt-3L and SCF. Maturation was induced with TNF-alpha and PGE2 for 2 days. DC were analyzed morphologically, phenotypically with a panel of MAb to lineage and DC markers, and functionally in MLR, T-cell assays and T-cell cytokine secretion by ELISA. RESULTS: Significant cellular expansion was observed: 60+/-5 x 10(6) DC from 1 x 10(6) CD34+ cells (n=28). Phenotypically DC were characterized as HLA-DR+ +, CD11c+ + +, CD80+ +, CD83+, CD86+ +, CD123+ +, CD15+ +, CD33+ +, BDCA-1+ +, CD4+ and Lin-. DC displayed potent allostimulatory capacity and efficient presentation of KLH and tetanus toxin. DC-primed T cells secreted IFN-gamma (Th1); however, no detectable IL-4 (Th2) was noted. DISCUSSION: We present features of CD34+ DC that have not been previously described. The CD34+ DC generated represent a population of myeloid DC functioning as DC1 but phenotypically expressing markers characteristic of both DC1 and DC2. This novel DC population is capable of inducing naive T-cell responses and can be expanded to clinically useful numbers. CD34+-derived DC represent attractive candidates for use in adoptive T-cell immunotherapy. 相似文献
14.
Sieling PA Ochoa MT Jullien D Leslie DS Sabet S Rosat JP Burdick AE Rea TH Brenner MB Porcelli SA Modlin RL 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(9):4790-4796
Both the CD4-CD8- (double negative) and CD4-CD8+ T cell lineages have been shown to contain T cells which recognize microbial lipid and glycolipid Ags in the context of human CD1 molecules. To determine whether T cells expressing the CD4 coreceptor could recognize Ag in the context of CD1, we derived CD4+ T cell lines from the lesions of leprosy patients. We identified three CD4+ Mycobacterium leprae-reactive, CD1-restricted T cell lines: two CD1b restricted and one CD1c restricted. These T cell lines recognize mycobacterial Ags, one of which has not been previously described for CD1-restricted T cells. The response of CD4+ CD1-restricted T cells, unlike MHC class II-restricted T cells, was not inhibited by anti-CD4 mAb, suggesting that the CD4 coreceptor does not impact positive or negative selection of CD1-restricted T cells. The CD4+ CD1-restricted T cell lines produced IFN-gamma and GM-CSF, the Th1 pattern of cytokines required for cell-mediated immunity against intracellular pathogens, but no detectable IL-4. The existence of CD4+ CD1-restricted T cells that produce a Th1 cytokine pattern suggests a contributory role in immunity to mycobacterial infection. 相似文献
15.
A MAGE-3 peptide presented by HLA-DR1 to CD4+ T cells that were isolated from a melanoma patient vaccinated with a MAGE-3 protein 总被引:2,自引:0,他引:2
Zhang Y Chaux P Stroobant V Eggermont AM Corthals J Maillère B Thielemans K Marchand M Boon T Van Der Bruggen P 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(1):219-225
"Cancer-germline" genes such as those of the MAGE family are expressed in many tumors and in male germline cells, but are silent in normal tissues. They encode shared tumor-specific Ags, which have been used in therapeutic vaccination trials of cancer patients. MAGE-3 is expressed in 74% of metastatic melanoma and in 50% of carcinomas of esophagus, head and neck, bladder, and lung. We report here the identification of a new MAGE-3 peptide, which is recognized by three different CD4(+) T cell clones isolated from a melanoma patient vaccinated with a MAGE-3 protein. These clones, which express different TCRs, recognize an HLA-DR1 peptide ACYEFLWGPRALVETS, which corresponds to the MAGE-3(267-282) and the MAGE-12(267-282) protein sequences. One of the T cell clones, which expresses LFA-1 at a high level, lysed tumor cells expressing DR1 and MAGE-3. Another of these DR1-restricted CD4(+) clones recognized not only the MAGE-3/12 peptide but also homologous peptides encoded by genes MAGE-1, 2, 4, 6, 10, and 11. 相似文献
16.
Koya T Miyahara N Takeda K Matsubara S Matsuda H Swasey C Balhorn A Dakhama A Gelfand EW 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(5):2787-2796
CD4+ T cells, particularly Th2 cells, play a pivotal role in allergic airway inflammation. However, the requirements for interactions between CD4+ and CD8+ T cells in airway allergic inflammation have not been delineated. Sensitized and challenged OT-1 mice in which CD8+ T cells expressing the transgene for the OVA(257-264) peptide (SIINFEKL) failed to develop airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine elevation, or goblet cell metaplasia. OT-1 mice that received naive CD4+IL-4+ T cells but not CD4+IL-4- T cells before sensitization developed all of these responses to the same degree as wild-type mice. Moreover, recipients of CD4+IL-4+ T cells developed significant increases in the number of CD8+IL-13+ T cells in the lung, whereas sensitized OT-1 mice that received primed CD4+ T cells just before challenge failed to develop these responses. Sensitized CD8-deficient mice that received CD8+ T cells from OT-1 mice that received naive CD4+ T cells before sensitization increased AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged with allergen. In contrast, sensitized CD8-deficient mice receiving CD8+ T cells from OT-1 mice without CD4+ T cells developed reduced AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged. These data suggest that interactions between CD4+ and CD8+ T cells, in part through IL-4 during the sensitization phase, are essential to the development of CD8+IL-13+ T cell-dependent AHR and airway allergic inflammation. 相似文献
17.
Pedro A. Andrade Filho Daisuke Ito Albert B. DeLeo Robert L. Ferris 《Cancer immunology, immunotherapy : CII》2010,59(10):1561-1568
The TP53 tumor suppressor gene contains a well-studied polymorphism that encodes either proline (P) or arginine (R) at codon
72, and over half of the world’s population is homozygous for R at this codon. The wild-type sequence (wt) p53 peptide, p5365–73, has been identified as a CD8+ T cell-defined tumor antigen for use in broadly applicable cancer vaccines. However, depending
on the TP53 codon 72 polymorphism of the recipient, the induced responses to the peptides incorporating R (p5372R) or P (p5372P) can be “self” or “non-self.” Thus, we sought to determine which wt p5365–73 peptide should be used in wt p53-based cancer vaccines. Despite similar predicted HLA-A2-binding affinities, the p5372P peptide was more efficient than the p5372R peptide in HLA-A2 stabilization assays. In vitro stimulation (IVS) of CD8+ T cells obtained from healthy HLA-A2+ donors with these two peptides led to the generation of CD8+ T cell effectors in one-third of the samples tested, at a frequency
similar to the responsiveness to other wt p53 peptides. Interestingly, regardless of their p53 codon 72 genotype, CD8+ T cells
stimulated with either p5372P or p5372R peptide were cross-reactive against T2 cells pulsed with either peptide, as well as HLA-A2+ head and neck cancer (HNC) cell lines presenting p5372P and/or p5372R peptides for T cell recognition. Therefore, the cross-reactivity of CD8+ T cells for the polymorphic wt p5365–73 peptides, irrespective of their p53 codon 72 polymorphism, suggests that employing either peptide in wt p53-based vaccines
can result in efficient targeting of this epitope. 相似文献
18.
Rahma OE Ashtar E Czystowska M Szajnik ME Wieckowski E Bernstein S Herrin VE Shams MA Steinberg SM Merino M Gooding W Visus C Deleo AB Wolf JK Bell JG Berzofsky JA Whiteside TL Khleif SN 《Cancer immunology, immunotherapy : CII》2012,61(3):373-384
Purpose
Peptide antigens have been administered by different approaches as cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by two vaccine approaches using the wild-type (wt) p53 vaccine.Experimental design
Twenty-one HLA-A2.1 patients with stage III, IV, or recurrent ovarian cancer overexpressing the p53 protein with no evidence of disease were treated in two cohorts. Arm A received SC wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells IV. Interleukin-2 (IL-2) was administered to both cohorts in alternative cycles.Results
Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B developed an immunologic response as determined by ELISPOT and tetramer assays. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced the expansion of T regulatory cells. The median overall survival was 40.8 and 29.6?months for arm A and B, respectively; the median progression-free survival was 4.2 and. 8.7?months, respectively.Conclusion
We found that using either vaccination approach generates comparable specific immune responses against the p53 peptide with minimal toxicity. Accordingly, our findings suggest that the use of less demanding SC approach may be as effective. Furthermore, the use of low-dose SC IL-2 as an adjuvant might have interfered with the immune response. Therefore, it may not be needed in future trials. 相似文献19.
Massive infection of memory CD4 T cells is a hallmark of early simian immunodeficiency virus (SIV) infection, with viral infection peaking at day 10 postinfection (p.i.), when a majority of memory CD4 T cells in mucosal and peripheral tissues are infected. It is not clear if mononuclear cells from the monocyte and macrophage lineages are similarly infected during this early phase of explosive HIV and SIV infections. Here we show that, at day 10 p.i., Lin(-) HLA-DR(+) CD11c/123(-) CD13(+) CD14(-) macrophages in the jejunal mucosa were infected, albeit at lower levels than CD4 memory T cells. Interestingly, Lin(-) HLA-DR(+) CD11c/123(-) CD13(+) CD14(-) macrophages in peripheral blood, like their mucosal counterparts, were preferentially infected compared to Lin(-) HLA-DR(+) CD11c/123(-) CD13(+) CD14(+) monocytes, suggesting that differentiated macrophages were selectively infected by SIV. CD13(+) CD14(-) macrophages expressed low levels of CD4 compared to CD4 T cells but expressed similar levels of CCR5 as lymphocytes. Interestingly, CD13(+) CD14(-) macrophages expressed Apobec3G at lower levels than CD13(+) CD14(+) monocytes, suggesting that intracellular restriction may contribute to the differential infection of mononuclear subsets. Taken together, our results suggest that CD13(+) CD14(-) macrophages in mucosal and peripheral tissues are preferentially infected very early during the course of SIV infection. 相似文献
20.
Boots AM Hubers H Kouwijzer M den Hoed-van Zandbrink L Westrek-Esselink BM van Doorn C Stenger R Bos ES van Lierop MJ Verheijden GF Timmers CM van Staveren CJ 《Arthritis research & therapy》2007,9(4):R71
We sought to identify an altered peptide ligand (APL) based on the endogenously expressed synovial auto-epitope of human cartilage glycoprotein-39 (HC gp-39) for modulation of cognate, HLA-DR4-restricted T cells. For this purpose we employed a panel of well-characterized T cell hybridomas generated from HC gp-39-immunized HLA-DR4 transgenic mice. The hybridomas all respond to the HC gp-39(263-275) epitope when bound to HLA-DR4(B1*0401) but differ in their fine specificities. First, the major histocompatibility complex (MHC) and T-cell receptor (TCR) contact residues were identified by analysis of single site substituted analogue peptides for HLA-DR4 binding and cognate T cell recognition using both T hybridomas and polyclonal T cells from peptide-immunized HLA-DR4 transgenic mice. Analysis of single site substituted APL by cognate T cells led to identification of Phe265 as the dominant MHC anchor. The amino acids Ala268, Ser269, Glu271 and Thr272 constituted the major TCR contact residues, as substitution at these positions did not affect HLA-DR4(B1*0401) binding but abrogated T cell responses. A structural model for visualisation of TCR recognition was derived. Second, a set of non-classical APLs, modified at the MHC key anchor position but with unaltered TCR contacts, was developed. When these APLs were analysed, a partial TCR agonist was identified and found to modulate the HC gp-39(263-275)-specific, pro-inflammatory response in HLA-DR4 transgenic mice. We identified a non-classical APL by modification of the p1 MHC anchor in a synovial auto-epitope. This APL may qualify for rheumatoid arthritis immunotherapy. 相似文献