Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Cancers (Basel) ; 12(10)2020 Oct 05.
Article in English | MEDLINE | ID: mdl-33028033

ABSTRACT

Follicular lymphoma (FL), the most frequent indolent non-Hodgkin's B cell lymphoma, is considered as a prototypical centrocyte-derived lymphoma, dependent on a specific microenvironment mimicking the normal germinal center (GC). In agreement, several FL genetic alterations affect the crosstalk between malignant B cells and surrounding cells, including stromal cells and follicular helper T cells (Tfh). In our study, we sought to deconvolute this complex FL supportive synapse by comparing the transcriptomic profiles of GC B cells, Tfh, and stromal cells, isolated from normal versus FL tissues, in order to identify tumor-specific pathways. In particular, we highlighted a high expression of IL-6 and IL-7 in FL B cells that could favor the activation of FL Tfh overexpressing IFNG, able in turn to stimulate FL B cells without triggering MHC (major histocompatibility) class II expression. Moreover, the glycoprotein clusterin was found up-regulated in FL stromal cells and could promote FL B cell adhesion. Finally, besides its expression on Tfh, CD200 was found overexpressed on tumor B cells and could contribute to the induction of the immunosuppressive enzyme indoleamine-2,3 dioxygenase by CD200R-expressing dendritic cells. Altogether our findings led us to outline the contribution of major signals provided by the FL microenvironment and their interactions with malignant FL B cells.

2.
Cancer Res ; 69(8): 3563-9, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19351841

ABSTRACT

Clinical outcomes of gastrointestinal stromal tumor (GIST)-bearing patients treated with imatinib mesylate (IM) are variable. Other than the site of mutation within the c-kit gene, prognostic features of GIST remain undefined. IM can exhibit off-target effects such as triggering natural killer (NK) cell activity. We addressed whether NK cell functions could predict long term survival with IM. NK cell functions were followed up in 77 GIST patients enrolled onto two phase III trials. "Immunologic responders" were defined as patients whose NK cell IFN-gamma values after 2 months of IM were higher than or equal to the baseline value at entry into the trial. The prognostic effect of IFN-gamma on progression-free survival was assessed by a Wald test in a Cox regression analysis using the landmark method and stratified by trial and on the c-kit mutational status. Fifty-six patients were evaluable for the NK cell IFN-gamma responses at baseline and 2 months. Their median follow-up for progression-free survival was 3.7 years. Thirty-four of 56 patients were immunologic responders to IM. In the Cox regression analysis, immunologic responders possessed a hazard ratio of progression or death equal to 0.29 (95% confidence interval, 0.12-0.70; P = 0.006) compared with nonresponders. Kaplan-Meier 2-year survival estimates were 85% for immunologic responders and 50% for nonresponders. Moreover, the immunologic response added prognostic value to the c-kit mutation. The NK cell IFN-gamma production after 2 months of treatment could be considered an independent predictor of long term survival in advanced GISTs treated with IM.


Subject(s)
Antineoplastic Agents/therapeutic use , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/immunology , Interferon-gamma/immunology , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Benzamides , Dendritic Cells/immunology , Exons , Female , Gastrointestinal Stromal Tumors/genetics , Humans , Imatinib Mesylate , Interleukin-2/pharmacology , Male , Middle Aged , NK Cell Lectin-Like Receptor Subfamily K/immunology , Natural Cytotoxicity Triggering Receptor 3/immunology , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/immunology
3.
J Immunol ; 175(9): 5839-47, 2005 Nov 01.
Article in English | MEDLINE | ID: mdl-16237076

ABSTRACT

A peptide encompassing residues 131-151 of the spliceosomal U1-70K protein and its analog phosphorylated at Ser140 were synthesized as potential candidates for the treatment of patients with lupus. Studies in the MRL/lpr and (NZB x NZW)F1 lupus models have demonstrated that these sequences contain a CD4+ T cell epitope but administration of the phosphorylated peptide only ameliorates the clinical manifestations of treated MRL/lpr mice. Binding assays with soluble HLA class II molecules and molecular modeling experiments indicate that both peptides behave as promiscuous epitopes and bind to a large panel of human DR molecules. In contrast to normal T cells and T cells from non-lupus autoimmune patients, we found that PBMCs from 40% of lupus patients selected randomly and CFSE-labeled CD4+ T cells proliferate in response to peptide 131-151. Remarkably, however, we observed that phosphorylation of Ser140 prevents CD4+ T cells proliferation but not secretion of regulatory cytokines, suggesting a striking immunomodulatory effect of phosphorylated analog on lupus CD4+ T cells that was unique to patients. The analog might act as an activator of regulatory T cells or as a partial agonist of TCR.


Subject(s)
CD4-Positive T-Lymphocytes/drug effects , Lupus Erythematosus, Systemic/immunology , Peptide Fragments/pharmacology , Ribonucleoprotein, U1 Small Nuclear/pharmacology , Amino Acid Sequence , CD4-Positive T-Lymphocytes/immunology , HLA-DR Antigens/metabolism , Humans , Interleukin-10/biosynthesis , Lymphocyte Activation , Molecular Sequence Data , Phosphorylation
4.
J Immunol ; 169(12): 6928-34, 2002 Dec 15.
Article in English | MEDLINE | ID: mdl-12471126

ABSTRACT

Among HLA-DP specificities, HLA-DP4 specificity involves at least two molecules, HLA-DPA1*0103/DPB1*0401 (DP401) and HLA-DPA1*0103/DPB1*0402 (DP402), which differ from each other by only three residues. Together, they are present worldwide at an allelic frequency of 20-60% and are the most abundant human HLA II alleles. Strikingly, the peptide-binding specificities of these molecules have never been investigated. Hence, in this study, we report the peptide-binding motifs of both molecules. We first set up a binding assay specific for the immunopurified HLA-DP4 molecules. Using multiple sets of synthetic peptides, we successfully defined the amino acid preferences of the anchor residues. With these assays, we were also able to identify new peptide ligands from allergens and viral and tumor Ags. DP401 and DP402 exhibit very similar patterns of recognition in agreement with molecular modeling of the complexes. Pockets P1 and P6 accommodate the main anchor residues and interestingly contain only two polymorphic residues, beta86 and beta11, respectively. Both positions are almost dimorphic and thus produce a limited number of pocket combinations. Taken together, our results support the existence of three main binding supertypes among HLA-DP molecules and should significantly contribute to the identification of universal epitopes to be used in peptide-based vaccines for cancer, as well as for allergic or infectious diseases.


Subject(s)
HLA-DP Antigens/immunology , HLA-DP Antigens/metabolism , Histocompatibility Testing , Peptides/immunology , Peptides/metabolism , Amino Acid Motifs/genetics , Amino Acid Motifs/immunology , Amino Acid Sequence , Amino Acid Substitution/genetics , Amino Acid Substitution/immunology , Cell Line , Epitopes/genetics , Epitopes/immunology , Epitopes/metabolism , Gene Frequency/immunology , HLA-DP Antigens/chemistry , HLA-DP Antigens/genetics , HLA-DP beta-Chains , Histocompatibility Testing/methods , Humans , Models, Molecular , Molecular Sequence Data , Mutation/immunology , Polymorphism, Genetic/immunology , Protein Binding/genetics , Protein Binding/immunology , Sequence Alignment
SELECTION OF CITATIONS
SEARCH DETAIL
...