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Class II Molecules (class + ii_molecule)
Kinds of Class II Molecules Selected AbstractsAn analysis of variability in the manufacturing of dexosomes: Implications for development of an autologous therapy,BIOTECHNOLOGY & BIOENGINEERING, Issue 2 2005Sanjay Patel Abstract Dexosomes are nanometer-size vesicles released by dendritic-cells, possessing much of the cellular machinery required to stimulate an immune response (i.e. MHC Class I and II). The ability of patient-derived dexosomes loaded with tumor antigens to elicit anti-tumor activity is currently being evaluated in clinical trials. Unlike conventional biologics, where variability between lots of product arises mostly from the manufacturing process, an autologous product has inherent variability in the starting material due to heterogeneity in the human population. In an effort to assess the variability arising from the dexosome manufacturing process versus the human starting material, 144 dexosome preparations from normal donors (111) and cancer patients (33) from two Phase I clinical trials were analyzed. A large variability in the quantity of dexosomes (measured as the number of MHC Class II molecules) produced between individual lots was observed (,>,50-fold). An analysis of intra-lot variability shows that the manufacturing process introduces relatively little of this variability. To identify the source(s) of variability arising from the human starting material, distributions of the key parameters involved in dexosome production were established, and a model created. Computer simulations using this model were performed, and compared to the actual data observed. The main conclusion from these simulations is that the number of cells collected per individual and the productivity of these cells of are the principal sources of variability in the production of Class II. The approach described here can be extended to other autologous therapies in general to evaluate control of manufacturing processes. Moreover, this analysis of process variability is directly applicable to production at a commercial scale, since the large scale manufacture of autologous products entails an exact process replication rather than scale-up in volume, as is the case with traditional drugs or biologics. © 2005 Wiley Periodicals, Inc. [source] Defect of protective immunity to Schistosoma mansoni infection in Mongolian gerbils involves limited recruitment of dendritic cells in the vaccinated skinPARASITE IMMUNOLOGY, Issue 12 2001H. Sato In Mongolian gerbils, Meriones unguiculatus, the attenuated Schistosoma mansoni vaccine, is known to induce marginal or no resistance to a homologous infection. To clarify the base of defective acquisition of the resistance, we have focused on the induction phase of protective immunity to S. mansoni, i.e. cellular responses in the skin and skin-draining lymph nodes (SLN). Percutaneous exposure to normal or ultraviolet (18mJ/cm2)-attenuated cercariae induced comparable increases in SLN leucocyte counts, in contrast to other attenuated schistosome vaccine models in rodents where attenuated parasites induce more notable increases in SLN leucocyte counts than normal ones. Using serial sections, it was demonstrated that greater numbers of attenuated larvae remained for a longer period in the exposed skin than normal ones. Correlated with cellular responses in the SLN, attenuated and normal schistosomes elicited a comparable degree of response of epidermal Langerhans' cells/putative dermal dendritic cells that were visualized by immunohistochemistry using a monoclonal antibody to a gerbil major histocompatibility complex class II molecule (HUSM-M.g.30). It is speculated that in Mongolian gerbils limited recruitment of dendritic cells around attenuated S. mansoni larvae, at least partially, contribute to defective induction of protective immunity by the attenuated vaccine. [source] Immunoglobulin IgG Fc-receptor polymorphisms and HLA class II molecules in Guillain,Barré syndromeACTA NEUROLOGICA SCANDINAVICA, Issue 1 2010S. Sinha Sinha S, Prasad KN, Jain D, Nyati KK, Pradhan S, Agrawal S. Immunoglobulin IgG Fc-receptor polymorphisms and HLA class II molecules in Guillain,Barré syndrome. Acta Neurol Scand: 2010: 122: 21,26. © 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objective,,, To analyze host genetic factors immunoglobulin G Fc receptors (Fc,Rs) and human leukocyte antigen (HLA) class II in GBS patients. Methods,,, Fc,RIIA, IIIA and IIIB polymorphisms were studied in 80 each GBS patients and healthy controls by allele specific PCR. HLA class II DR,1 and DQ,1 typing was performed at the two-digit level by PCR in randomly selected 54 GBS patients and 202 controls. Results,,, Fc,RIIA-H/H (56% vs 9%; P < 0.0001) and Fc,RIIIA-V/V (40% vs 13%; P < 0.0001) genotypes, H131 allele frequencies (0.73 vs 0.26, P < 0.0001) and HLA DQ,1*060x (OR, 1.96; 95% CI, 1.26,3.04; P < 0.01) were significantly increased in GBS than controls. DR,1*0701 alone (OR, 10; 95% CI, 45.90,2.25; P < 0.001) and together with Fc,RIIA-H/H (OR, 11.03; 95% CI, 2.63,46.20; P < 0.001) was significantly associated with GBS patients having microbiological evidence of recent infection. Conclusions,,, The study indicates that homozygous Fc,RIIA and Fc,RIIIA genotypes and Fc,RIIA H131 allele are associated with GBS. HLA class II molecule DR,1*0701 is identified as novel genetic risk factor for development of GBS in patients with preceding infection. [source] Processing and presentation of (pro)-insulin in the MHC class II pathway: the generation of antigen-based immunomodulators in the context of type 1 diabetes mellitusDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2010Timo Burster Abstract Both CD4+ and CD8+ T lymphocytes play a crucial role in the autoimmune process leading to T1D. Dendritic cells take up foreign antigens and autoantigens; within their endocytic compartments, proteases degrade exogenous antigens for subsequent presentation to CD4+ T cells via MHC class II molecules. A detailed understanding of autoantigen processing and the identification of autoantigenic T cell epitopes are crucial for the development of antigen-based specific immunomodulators. APL are peptide analogues of auto-immunodominant T cell epitopes that bind to MHC class II molecules and can mediate T cell activation. However, APL can be rapidly degraded by proteases occurring in the extracellular space and inside cells, substantially weakening their efficiency. By contrast, protease-resistant APL function as specific immunomodulators and can be used at low doses to examine the functional plasticity of T cells and to potentially interfere with autoimmune responses. Here, we review the latest achievements in (pro)-insulin processing in the MHC class II pathway and the generation of APL to mitigate autoreactive T cells and to activate Treg cells. Copyright © 2010 John Wiley & Sons, Ltd. [source] Lipid-mediated presentation of MHC class II molecules guides thymocytes to the CD4 lineageEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2009Satoshi Komaniwa Abstract Previous studies on the MHC class-specific differentiation of CD4+CD8+ thymocytes into CD4+ and CD8+ T cells have focused on the role of coreceptor molecules. However, CD4 and CD8 T cells develop according to their MHC class specificities even in these mice lacking coreceptors. This study investigated the possibility that lineage is determined not only by coreceptors, but is also guided by the way how MHC molecules are presented. MHC class II molecules possess a highly conserved Cys in their transmembrane domain, which is palmitoylated and thereby associates with lipid rafts, whereas neither palmitoylation nor raft association was observed with MHC class I molecules. The generation of CD4 T cells was impaired and that of CD8 T cells was augmented when the rafts on the thymic epithelial cells were disrupted. This was due to the conversion of MHC class II-specific thymocytes from the CD4 lineage to CD8. The ability of I-Ad molecule to associate with rafts was lost when its transmembrane Cys was replaced. The development of DO11.10 thymocytes recognizing this mutant I-Adm was converted from CD4 to CD8. These results suggest that the CD4 lineage commitment is directed by the raft-associated presentation of MHC class II molecules. [source] Extensive HLA class I allele promiscuity among viral CTL epitopesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2007Nicole Frahm Abstract Promiscuous binding of T helper epitopes to MHC class II molecules has been well established, but few examples of promiscuous class I-restricted epitopes exist. To address the extent of promiscuity of HLA class I peptides, responses to 242 well-defined viral epitopes were tested in 100 subjects regardless of the individuals' HLA type. Surprisingly, half of all detected responses were seen in the absence of the originally reported restricting HLA class I allele, and only 3% of epitopes were recognized exclusively in the presence of their original allele. Functional assays confirmed the frequent recognition of HLA class I-restricted T cell epitopes on several alternative alleles across HLA class I supertypes and encoded on different class I loci. These data have significant implications for the understanding of MHC class I-restricted antigen presentation and vaccine development. [source] Disease-related epitope spread in a humanized T cell receptor transgenic model of multiple sclerosisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2004Stephan Ellmerich Abstract While EAE has been an invaluable model for the immunopathogenesis of multiple sclerosis, it has sometimes been difficult to bridge the gap between findings and therapies in the rodent models and the cellular and molecular interactions that can be studied in the human disease. Humanized transgenic models offer a means of achieving this, through the expression of disease-implicated HLA class II molecules, co-expressed with a cognate HLA-class II-restricted, myelin-specific TCR derived from a human T cell clone implicated in disease. We have generated such a transgenic line, called line 8, that co-expresses a high level of HLA-DR15 and a human TCR specific for HLA-DR15/MBP 85,99. T cells from the transgenic line are skewed to the CD4 single-positive compartment and produce IFN-, in response to peptide from mylein basic protein. Mice develop a spontaneous disease phenotype, showing poverty of movement, although this rarely develops into paralysis except following immunization with peptide. On induction of paralysis by immunization with peptide, disease correlates with epitope spread to a number of additional, HLA-DR15-restricted myelin epitopes. This model should be valuable for analyzing epitope spread in a humanized immunogenetic environment and for the testing of specific immunotherapies. [source] N-terminal destruction signals lead to rapid degradation of the major histocompatibility complex class II transactivator CIITAEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2003Felix Schnappauf Abstract Major histocompatibility complex (MHC) class II molecules play an essential role for the cellular immune response by presenting peptide antigens to CD4+ T cells. MHC class II molecules and genes show a highly complex expression pattern, which is orchestrated through a master regulatory factor, called CIITA (class II transactivator). CIITA controls MHC class II expression not only qualitatively, but also quantitatively, and has therefore a direct influence on the CD4 T cell-dependent immune response. CIITA is itself tightly regulated not only on the transcriptional level, but as we show here also on the protein level. CIITA is subjected to a very rapid protein turnover and shows a half-life of about 30,min. Inhibition of degradation by proteasome inhibitors and the identification of ubiquitylated CIITA intermediates indicate that the degradation of CIITA is mediated by the ubiquitin-proteasome system. We identified two regions mediating degradation within the N-terminal domain of CIITA. N-terminal fusions or deletions stabilized CIITA, indicating that the N termini contribute to degradation. Several non-functional CIITA mutants are partially stabilized, but we provide evidence that transcriptional activity of CIITA is not directly linked to degradation. [source] B-lymphocyte subpopulations are equally susceptible to Epstein,Barr virus infection, irrespective of immunoglobulin isotype expressionIMMUNOLOGY, Issue 4 2003Barbro Ehlin-Henriksson Summary While Epstein,Barr virus (EBV) is known to establish latency in the memory B-cell compartment, there is controversy as to whether the memory or the naïve B cell is the initial target for infection. Here we have explored the infectability of the B-cell subsets contained in peripheral blood and tonsils, as distinguished by their surface expression of the immunoglobulin isotypes that help to define naïve and memory pools. First we show that both CD21 and major histocompatibility complex (MHC) class II molecules , respectively, the major receptor and co-receptor for EBV on B cells , are expressed at similar levels on blood and tonsillar B cells, irrespective of surface immunoglobulin class, indicating that each of the subsets demonstrate an equal potential, at least for infection. Then, following in vitro infection of total tonsillar B cells, we found that the relative frequencies of immunoglobulin (Ig)M-, IgG- and IgA-positive cells containing EBV-encoded Epstein,Barr virus nuclear antigen 5 (EBNA5) protein at 48 hr were similar to those of the starting population. However, IgD expression was uniformly decreased, probably as a consequence of cellular activation. These data indicate that recirculating B cells have both the potential for, and susceptibility to, initial infection by EBV, irrespective of the immunoglobulin isotype expressed. [source] Major histocompatibility complex class II, fetal skin dendritic cells are potent accessory cells of polyclonal T-cell responsesIMMUNOLOGY, Issue 2 2000A. Elbe-Bürger Summary Whereas dendritic cells (DC) and Langerhans cells (LC) isolated from organs of adult individuals express surface major histocompatibility complex (MHC) class II antigens, DC lines generated from fetal murine skin, while capable of activating naive, allogeneic CD8+ T cells in a MHC class I-restricted fashion, do not exhibit anti-MHC class II surface reactivity and fail to stimulate the proliferation of naive, allogeneic CD4+ T cells. To test whether the CD45+ MHC class I+ CD80+ DC line 80/1 expresses incompetent, or fails to transcribe, MHC class II molecules, we performed biochemical and molecular studies using Western blot and polymerase chain reaction analysis. We found that 80/1 DC express MHC class II molecules neither at the protein nor at the transcriptional level. Ultrastructural examination of these cells revealed the presence of a LC-like morphology with indented nuclei, active cytoplasm, intermediate filaments and dendritic processes. In contrast to adult LC, no LC-specific cytoplasmic organelles (Birbeck granules) were present. Functionally, 80/1 DC in the presence, but not in the absence, of concanavalin A and anti-T-cell receptor monoclonal antibodies stimulated a vigorous proliferative response of naive CD4+ and CD8+ T cells. Furthermore, we found that the anti-CD3-induced stimulation of naive CD4+ and CD8+ T cells was critically dependent on the expression of Fc,R on 80/1 DC and that the requirement for co-stimulation depends on the intensity of T-cell receptor signalling. [source] Diversification in MHC class II invariant chain-like proteins among fishesJOURNAL OF APPLIED ICHTHYOLOGY, Issue 4 2004M. Sakai Summary The major histocompatibility complex (MHC) class II invariant chains are important for an efficient and complete presentation of antigens by MHC class II molecules. Invariant chain-like proteins (Iclp) 1 and 2 were identified by expressed sequence tag analysis from cDNA library of common carp head kidney (HK) stimulated with concanavalin A and lipopolysaccharide. The sequences were 1043 and 1016 bp in length encoding 234 and 198 amino acid proteins, respectively. Based on their predicted structure, the genes harboured transmembrane domain (TMD) and Tg (thyroglobulin) type 1 domains. Expression analysis revealed that both genes were expressed in normal tissues of HK, intestine, brain and gill. By database search, similar homologues were found in Atlantic salmon, fugu and catfish. Phylogenetic and alignment analysis indicate diversity among fish Iclps. [source] Rationally designed mutations convert complexes of human recombinant T cell receptor ligands into monomers that retain biological activityJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 1 2005Jianya Y Huan Abstract Single-chain human recombinant T cell receptor ligands derived from the peptide binding/TCR recognition domain of human HLA-DR2b (DRA*0101/DRB1*1501) produced in Escherichia coli with and without amino-terminal extensions containing antigenic peptides have been described previously. While molecules with the native sequence retained biological activity, they formed higher order aggregates in solution. In this study, we used site-directed mutagenesis to modify the ,-sheet platform of the DR2-derived RTLs, obtaining two variants that were monomeric in solution by replacing hydrophobic residues with polar (serine) or charged (aspartic acid) residues. Size exclusion chromatography and dynamic light scattering demonstrated that the modified RTLs were monomeric in solution, and structural characterization using circular dichroism demonstrated the highly ordered secondary structure of the RTLs. Peptide binding to the ,empty' RTLs was quantified using biotinylated peptides, and functional studies showed that the modified RTLs containing covalently tethered peptides were able to inhibit antigen-specific T cell proliferation in vitro, as well as suppress experimental autoimmune encephalomyelitis in vivo. These studies demonstrated that RTLs encoding the Ag-binding/TCR recognition domain of MHC class II molecules are innately very robust structures, capable of retaining potent biological activity separate from the Ig-fold domains of the progenitor class II structure, with prevention of aggregation accomplished by modification of an exposed surface that was buried in the progenitor structure. Copyright © 2004 Society of Chemical Industry [source] Human leukocyte antigen-DRB1*1101 correlates with less severe hepatitis in Taiwanese male carriers of hepatitis B virus,JOURNAL OF MEDICAL VIROLOGY, Issue 4 2009Yi-Wen Huang Abstract Human leukocyte antigen (HLA) class II molecules are associated with host immune responses against hepatitis B virus infection. Male gender is the apparent host factor when someone encounters with the severity of hepatitis. The aim of this study was to investigate the association of the most polymorphic HLA class II allele, human leukocyte antigen,DRB1, with the severity of hepatitis in male carriers of hepatitis B virus. In this prospective cohort study, a total of 204 carriers of hepatitis B virus (131 men and 73 women) who have been followed-up for more than 1 year at the outpatient clinic of a university hospital were collected consecutively. Fifty carriers of hepatitis B virus (group I) with alanine aminotransferase <2× upper limit of normal (mean follow-up 83.6 months) were compared with 154 chronic hepatitis B patients (group II) with alanine aminotransferase ,2× upper limit of normal (mean follow-up 81.3 months). Alleles of HLA-DRB1 were typed by the polymerase chain reaction,sequence specific oligonucleotide probe hybridization and genotypes of hepatitis B virus by melting curve analysis. HLA-DRB1*1101 was found in 18% of group I versus 8% of group II in male carriers (OR 0.23, P,=,0.020, after adjustment for age) and 4% versus 9.4% in female carriers (P,=,0.094). In male carriers harboring DRB1*1101, the distribution of hepatitis B viral genotype was comparable between the two groups. HLA-DRB1*1101 correlates with less severe hepatitis in Taiwanese male carriers of hepatitis B virus. J. Med. Virol. 81:588,593, 2009 © 2009 Wiley-Liss, Inc. [source] Focal adhesion kinase mediates human leukocyte histocompatibility antigen class II-induced signaling in gingival fibroblastsJOURNAL OF PERIODONTAL RESEARCH, Issue 6 2007S. Yoshizawa Background and Objective:, The role of human leukocyte antigen class II molecules on nonantigen-presenting cells has been a matter of controversy. We previously reported that human leukocyte antigen class II molecules on human gingival fibroblasts do not present antigens, but transduce signals into the cells by making a complex with antigenic peptide T-cell receptor or by stimulating cell surface human leukocyte antigen-DR molecules with human leukocyte antigen-DR antibody (L243), which mimics the formation of the human leukocyte antigen class II,antigenic peptide T-cell receptor complex, resulting in the expression of several cytokines. The aim of this study was to detect human leukocyte antigen class II-associated molecules mediating human leukocyte antigen class II-induced signals into the cells. Material and Methods:, Antibody-based protein-microarray analysis was performed to detect activated signaling molecules in gingival fibroblasts stimulated via human leukocyte antigen class II molecules. Then, we examined if these molecules structurally associate with human leukocyte antigen class II and actually transduce signals into the cells. Results:, Stimulation of human leukocyte antigen class II on gingival fibroblasts by L243 resulted in enhanced phosphorylation of focal adhesion kinase. Focal adhesion kinase was co-immunoprecipitated with human leukocyte antigen-DR by L243. Stimulation of gingival fibroblasts with L243 induced phosphorylation of focal adhesion kinase. Luteolin, a putative focal adhesion kinase inhibitor, suppressed phosphorylation of focal adhesion kinase and dose dependently inhibited human leukocyte antigen class II-induced cytokine production. Conclusion:, Focal adhesion kinase is structurally associated with human leukocyte antigen-DR and mediates human leukocyte antigen class II-induced signals in gingival fibroblasts. [source] Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-, and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia AJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2009A. PAVLOVA Summary.,Background: Approximately 25% of severe hemophilia A (HA) patients develop antibodies to factor VIII protein. Patients: In the present case-controlled cohort study, 260 severely affected, mutation-type-matched HA patients were studied for association of human leukocyte antigen (HLA) class II molecules and polymorphisms in the genes encoding interleukin-10 (IL-10), tumor necrosis factor-, (TNF-,) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) and development of inhibitors. Results: Our results demonstrate a higher frequency of DRB1*15 and DQB1*0602 alleles as well as of the haplotype DRB1*15/DQB1*0602 in inhibitor patients [odds ratio (OR) 1.9; P < 0.05]. In TNF-,, the A allele of the ,308G>A polymorphism was found with higher frequency in the inhibitor cohort (0.22 vs. 0.13, OR 1.80). This finding was more pronounced for the homozygous A/A genotype (OR 4.7). For IL-10, the ,1082G allele was observed more frequently in patients with inhibitors (0.55 vs. 0.43; P = 0.008). The functional cytokine phenotype was determined for the first time, on the basis of the genetic background, and this showed that 12% of patients with inhibitors were high-TNF-,/high-IL-10 producers, as compared with 3% of non-inhibitor patients (OR 4.4). A trend for a lower frequency of the A allele of the CT60 polymorphism in CTLA-4 was found in inhibitor patients (0.42 vs. 0.50). Conclusions: In conclusion, the reported data clearly highlighted the participation of HLA molecules in inhibitor formation in a large cohort of patients. The higher frequencies of the ,308G>A polymorphism in TNF-, and ,1082A>G in IL-10 in inhibitor patients confirmed the earlier published data. The CT60 single-nucleotide polymorphism in CTLA-4 is of apparently less importance. [source] Oral immunization with Porphyromonas gingivalis outer membrane protein and CpG oligodeoxynucleotides elicits T helper 1 and 2 cytokines for enhanced protective immunityMOLECULAR ORAL MICROBIOLOGY, Issue 3 2010C. Liu Summary The aim of this study was to evaluate the efficacy of an oral vaccine containing the 40-kDa outer membrane protein of Porphyromonas gingivalis (40K-OMP) and synthetic oligodeoxynucleotides containing unmethylated CpG dinucleotides (CpG ODN) to control oral infection by P. gingivalis. Oral immunization with 40K-OMP plus CpG ODN induced significant 40K-OMP-specific serum immunoglobulin G (IgG), IgA, and saliva IgA antibody responses. The 40K-OMP-specific CD4+ T cells induced by oral 40K-OMP plus CpG ODN produced both T helper type 1 (Th1; interferon-,) and Th2 (interleukin-4) cytokines. Furthermore, increased frequencies of CD11c+ B220+ dendritic cells (DCs) and CD11c+ CD11b+ DCs with upregulated expression of CD80, CD86, CD40, and major histocompatibility complex class II molecules were noted in spleen, Peyer's patches, and cervical lymph nodes. Immunized mice were then infected orally with P. gingivalis to determine whether the immune responses induced by oral 40K-OMP plus CpG ODN were capable of suppressing the bone resorption caused by P. gingivalis infection. Mice given 40K-OMP plus CpG ODN showed significantly reduced bone loss associated with oral infection by P. gingivalis. Oral administration of 40K-OMP together with CpG ODN induces Th1-type and Th2-type cells, which provide help for protective immunity against P. gingivalis infection. This may be an important tool for the prevention of chronic periodontitis. [source] Structural features of a zinc binding site in the superantigen strepococcal pyrogenic exotoxin A (SpeA1): Implications for MHC class II recognitionPROTEIN SCIENCE, Issue 6 2001Matthew Baker Abstract Streptococcal pyrogenic exotoxin A (SpeA) is produced by Streptococcus pyogenes, and has been associated with severe infections such as scarlet fever and Streptococcal Toxic Shock Syndrome (STSS). In this study, the crystal structure of SpeA1 (the product of speA allele 1) in the presence of 2.5 mM zinc was determined at 2.8 Å resolution. The protein crystallizes in the orthorhombic space group P21212, with four molecules in the crystallographic asymmetric unit. The final structure has a crystallographic R -factor of 21.4% for 7,031 protein atoms, 143 water molecules, and 4 zinc atoms (one zinc atom per molecule). Four protein ligands,Glu 33, Asp 77, His 106, and His 110,form a zinc binding site that is similar to the one observed in a related superantigen, staphylococcoal enterotoxin C2. Mutant toxin forms substituting Ala for each of the zinc binding residues were generated. The affinity of these mutants for zinc ion confirms the composition of this metal binding site. The implications of zinc binding to SpeA1 for MHC class II recognition are explored using a molecular modeling approach. The results indicate that, despite their common overall architecture, superantigens appear to have multiple ways of complex formation with MHC class II molecules. [source] Genetic approaches for the induction of a CD4+ T cell response in cancer immunotherapyTHE JOURNAL OF GENE MEDICINE, Issue 6 2005Aude Bonehill Abstract Recently, it has become more and more obvious that not only CD8+ cytotoxic T lymphocytes, but also CD4+ T helper cells are required for the induction of an optimal, long-lasting anti-tumor immune response. CD4+ T helper cells, and in particular IFN-,-secreting type 1 T helper cells, have been shown to fulfill a critical function in the mounting of a cancer-specific response. Consequently, targeting antigens into MHC class II molecules would greatly enhance the efficacy of an anti-cancer vaccine. The dissection of the MHC class II presentation pathway has paved the way for rational approaches to achieve this goal: novel systems have been developed to genetically manipulate the MHC class II presentation pathway. First, different genetic approaches have been used for the delivery of known epitopes into the MHC class II processing pathway or directly onto the peptide-binding groove of the MHC molecules. Second, several strategies exist for the targeting of whole tumor antigens, containing both MHC class I and class II restricted epitopes, to the MHC class II processing pathway. We review these data and describe how this knowledge is currently applied in vaccine development. Copyright © 2005 John Wiley & Sons, Ltd. [source] Evidence for Humoral Rejection of a Pancreatic Islet Graft and Rescue with Rituximab and IV Immunoglobulin TherapyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009L. Kessler We describe the decline in islet function, in relation to HLA sensitization, in an islet transplant recipient and the recovery of this function after treatment with anti-CD20 monoclonal antibody and IV immunoglobulins. A 51-year-old woman with type 1 diabetes received one intraportal islet infusion. Following this transplantation, she became insulin independent. A search for HLA antibodies by using an ELISA technique remained consistently negative for HLA class I and II. It was only 2 years after the islet transplantation that this search became positive against class II antigens, reaching a peak of reactivity concomitantly with the appearance of a deterioration of glucose control requiring low-dose insulin therapy. Luminex® screening and single-antigen assays then revealed the presence of both nondonor-specific and donor-specific antibodies against HLA class II molecules. This immunization, already present in the pretransplant serum, had increased during the 6 months preceding the clinical deterioration. Since these data nevertheless pointed to antibody-mediated rejection of the islet allograft, treatment with anti-CD20 monoclonal antibody and IV immunoglobulins was initiated. One month later, the search by ELISA for antibodies against HLA class II antigens became negative, the Luminex® tests normalizing more gradually. As the result of an improvement in glucose control, the patient was again insulin-free. [source] Anti-CD28 Antibody-Induced Kidney Allograft Tolerance Related to Tryptophan Degradation and TCR, Class II, B7+ Regulatory CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2005Fabienne Haspot B7/CTLA-4 interactions negatively regulate T-cell responses and are necessary for transplant tolerance induction. Tolerance induction may therefore be facilitated by selectively inhibiting the B7/CD28 pathway without blocking that of B7/CTLA-4. In this study, we selectively inhibited CD28/B7 interactions using a monoclonal antibody modulating CD28 in a rat model of acute kidney graft rejection. A short-term treatment abrogated both acute and chronic rejection. Tolerant recipients presented few alloantibodies against donor MHC class II molecules, whereas untreated rejecting controls developed anti-MHC class I and II alloantibodies. PBMC from tolerant animals were unable to proliferate against donor cells but could proliferate against third-party cells. The depletion of B7+, non-T cells fully restored this reactivity whereas purified T cells were fully reactive. Also, NK cells depletion restored PBMC reactivity in 60% of tolerant recipients. Conversely, NK cells from tolerant recipients dose-dependently inhibited alloreactivity. PBMC anti-donor reactivity could be partially restored in vitro by blocking indoleamine-2,3-dioxygenase (IDO) and iNOS. In vivo, pharmacologic inhibition of these enzymes led to the rejection of the otherwise tolerated transplants. This study demonstrates that an initial selective blockade of CD28 generates B7+ non-T regulatory cells and a kidney transplant tolerance sustained by the activity of IDO and iNOS. [source] Human leukocyte antigen-DR15, low infant sibling exposure and multiple sclerosis: Gene,environment interactionANNALS OF NEUROLOGY, Issue 2 2010Ingrid A. F. van der Mei The risk for development of multiple sclerosis has been associated with human leukocyte antigen-DRB1*1501-DQB1*0602 (HLA-DR15) genotype, low infant sibling exposure, and high Epstein,Barr nuclear antigen IgG levels. In a population-based case,control study (Tasmania, Australia), we found that the combined effect of HLA-DR15 positivity and low infant sibling exposure on multiple sclerosis (odds ratio, 7.88; 95% confidence interval, 3.43,18.11) was 3.9-fold greater than expected (test for interaction, p = 0.019) This interaction was observed irrespective of Epstein,Barr nuclear antigen IgG levels. This suggests that immune mechanisms involving HLA class II molecules are susceptible to modulation in early life. Ann Neurol 2009;66:261,265 ANN NEUROL 2010;67:259,263 [source] Proinflammatory mediator,induced reversal of CD4+,CD25+ regulatory T cell,mediated suppression in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 3 2007Jocea M. R. van Amelsfort Objective We previously demonstrated that CD4+,CD25+ regulatory T (Treg) cells are present in increased numbers in the synovial fluid (SF) of rheumatoid arthritis (RA) patients and display enhanced suppressive activity as compared with their peripheral blood (PB) counterparts. Despite the presence of these immunoregulatory cells in RA, chronic inflammation persists. The purpose of the present study was to investigate whether particular proinflammatory mediators that are associated with RA could abrogate CD4+,CD25+ Treg,mediated suppression. Methods Monocyte phenotype was determined by flow cytometry and cytokine levels by enzyme-linked immunosorbent assay. Magnetically sorted CD4+,CD25, and CD4+,CD25+ T cells derived from the PB and SF obtained from RA patients were stimulated alone or in coculture with anti-CD3 monoclonal antibody (mAb) and autologous antigen-presenting cells, in the absence or presence of anti-CD28 mAb or the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor , (TNF,), or IL-7. Results Monocytes from the SF of RA patients displayed increased expression of HLA class II molecules, CD80, CD86, and CD40 as compared with PB-derived monocytes, indicating their activated status. Mimicking this increased costimulatory potential, addition of anti-CD28 mAb to cocultures of CD4+,CD25, and CD4+,CD25+ T cells resulted in reduced CD4+,CD25+ Treg,mediated suppression in both PB and SF. Furthermore, IL-7 and, to a limited extent, TNF,, both of which are produced by activated monocytes and were detected in SF, abrogated the CD4+,CD25+ Treg,mediated suppression. In contrast, IL-6 did not influence Treg-mediated suppression. Conclusion Our findings suggest that the interaction of CD4+,CD25+ Treg cells with activated monocytes in the joint might lead to diminished suppressive activity of CD4+,CD25+ Treg cells in vivo, thus contributing to the chronic inflammation in RA. [source] Immunoglobulin IgG Fc-receptor polymorphisms and HLA class II molecules in Guillain,Barré syndromeACTA NEUROLOGICA SCANDINAVICA, Issue 1 2010S. Sinha Sinha S, Prasad KN, Jain D, Nyati KK, Pradhan S, Agrawal S. Immunoglobulin IgG Fc-receptor polymorphisms and HLA class II molecules in Guillain,Barré syndrome. Acta Neurol Scand: 2010: 122: 21,26. © 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objective,,, To analyze host genetic factors immunoglobulin G Fc receptors (Fc,Rs) and human leukocyte antigen (HLA) class II in GBS patients. Methods,,, Fc,RIIA, IIIA and IIIB polymorphisms were studied in 80 each GBS patients and healthy controls by allele specific PCR. HLA class II DR,1 and DQ,1 typing was performed at the two-digit level by PCR in randomly selected 54 GBS patients and 202 controls. Results,,, Fc,RIIA-H/H (56% vs 9%; P < 0.0001) and Fc,RIIIA-V/V (40% vs 13%; P < 0.0001) genotypes, H131 allele frequencies (0.73 vs 0.26, P < 0.0001) and HLA DQ,1*060x (OR, 1.96; 95% CI, 1.26,3.04; P < 0.01) were significantly increased in GBS than controls. DR,1*0701 alone (OR, 10; 95% CI, 45.90,2.25; P < 0.001) and together with Fc,RIIA-H/H (OR, 11.03; 95% CI, 2.63,46.20; P < 0.001) was significantly associated with GBS patients having microbiological evidence of recent infection. Conclusions,,, The study indicates that homozygous Fc,RIIA and Fc,RIIIA genotypes and Fc,RIIA H131 allele are associated with GBS. HLA class II molecule DR,1*0701 is identified as novel genetic risk factor for development of GBS in patients with preceding infection. [source] Interleukin 13 and inflammatory markers in human sepsis,BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 6 2004N. Collighan Background: Interleukin (IL) 13 is an anti-inflammatory cytokine that reduces inflammatory cytokine production, and enhances monocyte survival and MHC class II and CD23 expression. The only report of IL-13 in human sepsis noted no increase in IL-13 concentration, in contrast to animal data. This study further examined the expression of IL-13 in relation to human sepsis. Methods: In a prospective observational study of 31 patients (24 men) with sepsis or septic shock, high-sensitivity enzyme-linked immunoabsorbent assay (ELISA) was used to quantify levels of tumour necrosis factor (TNF) , on admission, and on days 1, 3, 5 and 7 thereafter. IL-13 and IL-2 were assayed by standard ELISA, and HLA-DR on CD14-positive monocytes was measured by flow cytometry. Results: Twenty-three patients developed septic shock. Monocyte HLA-DR levels showed greater depression and a slower recovery in shocked than non-shocked patients. The serum IL-13 concentration was significantly higher in the shocked group from admission to day 3, but subsequently decreased to levels similar to those in the non-shocked group. IL-13 concentrations were higher in non-survivors. The TNF-, concentration was higher in those with septic shock than in those without. The TNF-, level correlated with IL-13 concentration (rS = 0·61, P = 0·002). The IL-13/TNF-, ratio was greater in patients with shock than those with sepsis only (P = 0·017). IL-2 was undetectable. Conclusion: In human sepsis and septic shock, IL-13 correlated with TNF-, expression, but its effect on HLA-DR class II molecules remains unclear. Copyright © 2004 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Coronin is involved in uptake of Mycobacterium bovis BCG in human macrophages but not in phagosome maintenanceCELLULAR MICROBIOLOGY, Issue 12 2001Stephanie Schüller By applying density gradient electrophoresis (DGE) to human macrophages infected with Mycobacterium bovis BCG, we were able to separate three different bacterial fractions representing arrested phagosomes, phagolysosomes and mycobacterial clumps. After further purification of the phagosomal population, we found that isolated phagosomes containing live BCG were arrested in maturation as they exhibited only low amounts of the lysosomal glycoprotein LAMP-1 and processing of the lysosomal hydrolase cathepsin D was blocked. In addition, low amounts of MHC class I and class II molecules and the absence of HLA-DM suggest sequestration of mycobacterial phagosomes from antigen-processing pathways. We further investigated the involvement of the actin-binding protein coronin in intracellular survival of mycobacteria and showed that human coronin, as well as F-actin, were associated with early stages of mycobacterial phagocytosis but not with phagosome maintenance. Therefore, we conclude that the unique DGE migration pattern of arrested phagosomes is not as a result of retention of coronin, but that there are other proteins or lipids responsible for the block in maturation in human macrophages. [source] High-affinity human leucocyte antigen class I binding variola-derived peptides induce CD4+ T cell responses more than 30 years post-vaccinia virus vaccinationCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2009M. Wang Summary Interferon-, secreting T lymphocytes against pox virus-derived synthetic 9-mer peptides were tested by enzyme-linked immunospot in peripheral blood of individuals vaccinated with vaccinia virus more than 30 years ago. The peptides were characterized biochemically as high-affinity human leucocyte antigen (HLA) class I binders (KD , 5 nM). However, five of the individuals tested did not show typical CD8+ T cell-mediated HLA class I-restricted responses. Instead, these donors showed CD4+ T cell-dependent responses against four of a total of eight antigenic 9-mer peptides discovered recently by our group. These latter responses were blocked specifically in the presence of anti-HLA class II antibody. We conclude that long-lived memory responses against pox virus-derived 9-mer peptides, with high binding affinity for HLA class I molecules, are mediated in some cases by CD4+ T cells and apparently restricted by HLA class II molecules. [source] Down-regulation of CXCR1 and CXCR2 expression on human neutrophils upon activation of whole blood by S. aureus is mediated by TNF-,CLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2001I. Tikhonov It was suggested that bacterial products can inhibit the expression of leucocyte chemokine receptors during sepsis and affect leucocyte functions in septic syndrome. Superantigens and toxins produced by Staphylococcus aureus are capable of activating leucocytes via binding to MHC-II antigens on monocytes and T-cell receptor molecules on T lymphocytes. It was recently shown that staphylococcal enterotoxins directly down-regulate the expression of CC chemokine receptors on monocytes through binding to MHC class II molecules. We studied the effects of killed S. aureus on the expression of interleukin-8 receptors, CXCR1 and CXCR2, on polymorphonuclear leucocytes (PMN), which are known to lack the expression of MHC-II antigens. It was shown that S. aureus down-regulated the cell-surface expression of CXCR1 and CXCR2 on PMN in the whole blood and total blood leucocyte fraction containing PMN and monocytes, but did not modulate IL-8 receptor expression in purified PMN suspension. Antibody to TNF-, abrogated down-regulation of IL-8 receptors induced by S. aureus. In contrast, LPS reduced CXCR1 and CXCR2 expression in purified PMN and whole blood in a TNF-,-independent manner. We further showed that TNF-,-induced decrease of CXCR1 and CXCR2 expression was associated with lower IL-8 binding and lower CXCR1 and CXCR2 mRNA levels, and was abrogated by protease inhibitors. We suggest that during septicemia, S. aureus may inhibit neutrophil responsiveness to IL-8 and other CXC chemokines via TNF-,- mediated down-regulation of CXCR1 and CXCR2. [source] | |||||||||||||||||||||||||||||||