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1.
Tumor-specific CD4+ T lymphocytes from cancer patients are required for optimal induction of cytotoxic T cells against the autologous tumor 总被引:7,自引:0,他引:7
Baxevanis CN Voutsas IF Tsitsilonis OE Gritzapis AD Sotiriadou R Papamichail M 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(7):3902-3912
This study focuses on the specific CD4+ T cell requirement for optimal induction of cytotoxicity against MHC class II negative autologous tumors (AuTu) collected from patients with various types of cancer at advanced stages. CD4+ T cells were induced in cultures of cancer patients' malignant effusion-associated mononuclear cells with irradiated AuTu (mixed lymphocyte tumor cultures (MLTC)) in the presence of recombinant IL-2 and recombinant IL-7. Tumor-specific CD4+ T cells did not directly recognize the AuTu cells, but there was an MHC class II-restricted cross-priming by autologous dendritic cells (DCs), used as APC. CD8+ CTL, also induced during the MLTC, lysed specifically AuTu cells or DCs pulsed with AuTu peptide extracts (acid wash extracts (AWE)) in an MHC class I-restricted manner. Removal of CD4+ T cells or DCs from the MLTC drastically reduced the CD8+ CTL-mediated cytotoxic response against the AuTu. AWE-pulsed DCs preincubated with autologous CD4+ T cells were able, in the absence of CD4+ T cells, to stimulate CD8+ T cells to lyse autologous tumor targets. Such activated CD8+ T cells produced IL-2, IFN-gamma, TNF-alpha, and GM-CSF. The process of the activation of AWE-pulsed DCs by CD4+ T cells could be inhibited with anti-CD40 ligand mAb. Moreover, the role of CD4+ T cells in activating AWE-pulsed DCs was undertaken by anti-CD40 mAb. Our data demonstrate for the first time in patients with metastatic cancer the essential role of CD4+ Th cell-activated DCs for optimal CD8+ T cell-mediated killing of autologous tumors and provide the basis for the design of novel protocols in cellular adoptive immunotherapy of cancer, utilizing synthetic peptides capable of inducing T cell help in vivo. 相似文献
2.
Valakos ED Kourkouli A Skopeliti M Pafilis P Poulakakis N Voutsas IF Lymberakis P Simou C Voelter W Tsitsilonis OE 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2007,147(1):1-10
Most recent molecular studies revealed the phylogeny of Greek Podarcis species, which for years remained elusive, due to discordant data produced from various chromosomal, complement fixation and protein studies. In this report, we analyzed cellular immune responses of spleen-derived lymphocytes from six allopatric Podarcis species encountered in Greece, by assessing two-way mixed lymphocyte reaction (MLR)-induced proliferation. On the basis of stimulation indices (S.I.) as determined from cultures set up from xenogeneic splenocytes coincubated in pairs, we generated a phylogenetic tree, fully consistent with the phylogenetic relationships of Podarcis as determined by parallel analyses based on partial mitochondrial (mt) DNA sequences. Although the exact mechanisms triggering lymphocyte responses in lizard two-way xenogeneic MLR are not fully understood, our results show the potential use of cell-mediated immune responses as an additional approach to mtDNA analysis, for species delimitation within specific lizard taxa. 相似文献
3.
Disrupting tumor-mediated mechanisms suppressing host immunity represents a novel approach to tumor immunotherapy. Depletion
of regulatory T cells (Tregs) increases endogenous anti-tumor immunity and the efficacy of active immunotherapy in experimental
tumor models. HLA-A2.1/HLA-DR1 (A2.1/DR1) × BALB- neuT
+ (neuT
+) triple transgenic mice represent an improvement over neuT
+ mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. We questioned whether depletion of Tregs with Denileukin diftitox (Ontak) enhances the efficacy of a therapeutic vaccine
consisting of HER-2(85–94) (p85) CTL and HER-2(776–790) (p776) Th peptides against the growth of TUBO.A2 transplantable tumor
in male A2.1/DR1 × neuT
+ Tg mice. While the therapeutic vaccine primed the tumor-reactive CD8+ CTLs and CD4+ effector T lymphocytes (Teffs) compartment, inducing activation, tumor infiltration, and tumor rejection or delay in tumor
growth, treatment with Ontak 1 day prior to vaccination resulted in enhanced CD4+ and CD8+ T-cell-mediated vaccine-specific immune responses in the periphery. This was closely associated with greater infiltration
and a striking change in the intratumor balance of Tregs and vaccine-specific CTLs/Teffs that directly correlated with markedly
enhanced antitumor activity. The data suggest that Tregs control both CD4+ and CD8+ T-cell activity within the tumor, emphasize the importance of the intratumor ratio of vaccine-specific lymphocytes to Tregs,
and demonstrate significant inversion of this ratio and correlation with tumor rejection during Ontak/vaccine immunotherapy. 相似文献
4.
5.
Increased generation of autologous tumor-reactive lymphocytes by anti-CD3 monoclonal antibody and prothymosin α 总被引:3,自引:0,他引:3
6.
Skopeliti M Voutsas IF Klimentzou P Tsiatas ML Beck A Bamias A Moraki M Livaniou E Neagu M Voelter W Tsitsilonis OE 《Cancer immunology, immunotherapy : CII》2006,55(10):1247-1257
Prothymosin α (proTα) is a 109 amino acid long polypeptide presenting distinct immunoenhancing activity in vitro and in vivo. Recent reports suggest that in apoptotic cells, proTα is cleaved by caspases at its carboxy(C)-terminus generating potentially bioactive fragments. In this study, we identified the peptide segment of proTα presenting maximum immunomodulatory activity. Calf thymus proTα was trypsinised, and the five fragments produced (spanning residues 1–14, 21–30, 31–87, 89–102 and 103–109) were tested for their ability to stimulate healthy donor- and cancer patient-derived peripheral blood mononuclear cell (PBMC) proliferation in autologous mixed lymphocyte reaction (AMLR), natural killer and lymphokine-activated killer cell activity, intracellular production of perforin, upregulation of adhesion molecules and CD25 expression. ProTα(89–102) and proTα(103–109) significantly fortified healthy donor-lymphocytes’ immune responses to levels comparable to those induced by intact proTα. These effects were more pronounced in cancer patients, where peptides proTα(89–102) and proTα(103–109) partly, however significantly, restored the depressed AMLR and cytolytic ability of PBMC, by simulating the biological activity exerted by intact proTα. ProTα(1–14), proTα(21–30) and proTα(31–87) marginally upregulated lymphocyte activation. This is the first report showing that proTα’s immunomodulating activity can be substituted by its C-terminal peptide(s). Whether generation and externalization of such immunoactive proTα fragments occurs in vivo, needs further investigation. However, if these peptides can trigger immune responses, they may eventually be used therapeutically to improve some PBMC functions of cancer patients. 相似文献
7.
Randi T Garmo Steinar Waage Ståle Sviland Britt IF Henriksen Olav Østerås Olav Reksen 《Acta veterinaria Scandinavica》2010,52(1):11
Background
The objectives of this study were to investigate whether there were differences between Norwegian Red cows in conventional and organic farming with respect to reproductive performance, udder health, and antibiotic resistance in udder pathogens. 相似文献8.
Pramod Kumar Yadav Gurmit Singh Satendra Singh Budhayash Gautam Esmaiel IF Saad 《Bioinformation》2012,8(14):664-672
The emergence of multidrug-resistant strain of community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA) strain
has highlighted the urgent need for the alternative and effective therapeutic approach to combat the menace of this nosocomial
pathogen. In the present work novel potential therapeutic drug targets have been identified through the metabolic pathways
analysis. All the gene products involved in different metabolic pathways of CA-MRSA in KEGG database were searched against
the proteome of Homo sapiens using the BLASTp program and the threshold of E-value was set to as 0.001. After database
searching, 152 putative targets were identified. Among all 152 putative targets, 39 genes encoding for putative targets were
identified as the essential genes from the DEG database which are indispensable for the survival of CA-MRSA. After extensive
literature review, 7 targets were identified as potential therapeutic drug target. These targets are Fructose-bisphosphate aldolase,
Phosphoglyceromutase, Purine nucleoside phosphorylase, Uridylate kinase, Tryptophan synthase subunit beta, Acetate kinase and
UDP-N-acetylglucosamine 1-carboxyvinyltransferase. Except Uridylate kinase all the identified targets were involved in more than
one metabolic pathways of CA-MRSA which underlines the importance of drug targets. These potential therapeutic drug targets
can be exploited for the discovery of novel inhibitors for CA-MRSA using the structure based drug design (SBDD) strategy. 相似文献
9.
In the development of multicellularity, signaling proteins has played a very important role. Among them, RAS family is one of the
most widely studied protein family. However, evolutionary analysis has been carried out mainly on super family level leaving sub
family information in scanty. Thus, a subfamily evolutionary study on RAS evolutionary expansion is imperative as it will aid in
better drug designing against dreadful diseases like Cancer and other developmental diseases. The present study was aimed to
understand RAS evolution on both holistic as well as reductive level. All human RAS family genes and protein were subjected to
BLAST tools to find orthologs and paralogs with different parameters followed by phylogenetic tree generation. Our results clearly
showed that H-RAS is the most primitive RAS in higher eukaryotes and then diverged into other RAS family members due to
different gene modification events. Furthermore, a site specific selection pressure analysis was carried out using SELECTON server
which showed that H-RAS, M-RAS and N-RAS are evolving faster than K-RAS and R-RAS. Thus, the results ascertain a new
ground to cancer biologists to exploit negatively selected K-RAS and R-RAS as potent drug targets in cancer therapeutics. 相似文献
10.