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HLA Molecules (hla + molecule)
Selected AbstractsReliable prediction of T-cell epitopes using neural networks with novel sequence representationsPROTEIN SCIENCE, Issue 5 2003Morten Nielsen Abstract In this paper we describe an improved neural network method to predict T-cell class I epitopes. A novel input representation has been developed consisting of a combination of sparse encoding, Blosum encoding, and input derived from hidden Markov models. We demonstrate that the combination of several neural networks derived using different sequence-encoding schemes has a performance superior to neural networks derived using a single sequence-encoding scheme. The new method is shown to have a performance that is substantially higher than that of other methods. By use of mutual information calculations we show that peptides that bind to the HLA A*0204 complex display signal of higher order sequence correlations. Neural networks are ideally suited to integrate such higher order correlations when predicting the binding affinity. It is this feature combined with the use of several neural networks derived from different and novel sequence-encoding schemes and the ability of the neural network to be trained on data consisting of continuous binding affinities that gives the new method an improved performance. The difference in predictive performance between the neural network methods and that of the matrix-driven methods is found to be most significant for peptides that bind strongly to the HLA molecule, confirming that the signal of higher order sequence correlation is most strongly present in high-binding peptides. Finally, we use the method to predict T-cell epitopes for the genome of hepatitis C virus and discuss possible applications of the prediction method to guide the process of rational vaccine design. [source] Loss of heterozygosity on chromosome 6 in HPV-16 positive cervical carcinomas carrying the DRB1*1501-DQB1*0602 haplotypeGENES, CHROMOSOMES AND CANCER, Issue 4 2004Hugo Arias-Pulido High-risk human papillomaviruses (HPVs), specifically HPV-16 and -18, have been associated with the development of carcinoma in situ (CIS) and of invasive cervical cancer (CC). However, only a small fraction of HPV-infected women will show signs of disease progression, suggesting that other factors in the carcinogenic pathway are needed. We previously demonstrated that human leukocyte antigen (HLA) DRB1*1501-DQB1*0602 (high risk) was associated with the development of CIS and CC tumors in HPV-16-positive patients. To characterize the molecular changes that could be relevant to tumor progression, we compared the extent of loss of heterozygosity (LOH) on chromosome 6 in HPV-16-positive CIS patients who were carriers of high-risk and neutral HLA haplotypes. CIS and CC cases demonstrated similar LOH patterns. A wide range of LOH frequencies was found at 6p (10,53%) and 6q (5,28%) in CIS cases, suggesting that LOH is an early event in the carcinogenic process. A comparative analysis of LOH frequencies in the high-risk versus the neutral HLA haplotypes showed a statistically significant difference in the extent of LOH at 6p24,p25 (58.6% versus 25.8%; P = 0.018) and at 6p21.3 (79.3% versus 35.5%; P = 0.001), a region that contains the HLA complex. LOH at this region could affect genes encoding HLA class I,II molecules, as well as factors responsible for the assembly, transport, and stable expression of HLA molecules. These losses may be a reflection of both an abnormal immune response and a general genome-wide instability resulting from virus persistence. © 2004 Wiley-Liss, Inc. [source] Identification of therapeutically relevant mHags and strategies for mHag-based immunotherapy after allogeneic HSCT: where do we stand?ISBT SCIENCE SERIES: THE INTERNATIONAL JOURNAL OF INTRACELLULAR TRANSPORT, Issue n1 2010B. Eiz-Vesper Minor histocompatibility antigens (mHags) play a major role in graft-versus-host disease (GvHD) and graft-versus-leukaemia (GvL) effect following human leucocyte antigen (HLA)-matched hematopoietic stem cell transplantation (HSCT). These antigens are defined as immunogenic peptides derived from polymorphic proteins and can be recognized by allogeneic cytotoxic T cells (CTLs) in the context of HLA molecules. The tissue distribution of mHags and HLA molecules influences the clinical outcome of T-cell responses to these antigens. Differential T-cell recognition of mHags specifically expressed in hematopoietic cells, including malignant cells from the recipient, may result in a beneficial GvL effect without detrimental GvHD. Furthermore, T-cell responses against proteins solely expressed in hematopoietic cell lineages from which the malignancy is derived may be appropriate mediators of GvL reactivity without GvHD induction. mHags with hematopoiesis-restricted expression may therefore serve as primary targets of the T-cell-mediated GvL/graft-versus-tumour (GvT) effect following HLA-identical HSCT. This paper reviews the recent findings on methods for identification of mHags specifically functioning as GvL/GvT targets and outlines perspectives for the development of novel strategies for mHag-based immunotherapy. [source] Strategies for developing multi-epitope, subunit-based, chemically synthesized anti-malarial vaccinesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 5b 2008M. E. Patarroyo ,,Introduction ,,P. falciparum invasion of RBCs ,,Merozoite proteins involved in invading erythrocytes ,,Erythrocyte proteins involved in merozoite invasion ,,The state of current worldwide anti-malarial vaccine approaches ,,A rational approach towards developing subunit-based synthetic vaccines ,,The immune response elicited by conserved HABPs ,,Structural analysis of native and modified HABPs ,,Secondary structure analysis ,,Native and modified HABP 3D structure explains some immunological phenomena ,,Supporting the haplotype , and allele-conscious TCR concept ,,Modified HABPs' 3D structure revealed a fit into HLA molecules ,,Conclusion Abstract An anti-malarial vaccine against the extremely lethal Plasmodium falciparum is desperately needed. Peptides from this parasite's proteins involved in invasion and having high red blood cell-binding ability were identified; these conserved peptides were not immun genic or protection-inducing when used for immunizing Aotus monkeys. Modifying some critical binding residues in these high-activi binding peptides' (HABPs') attachment to red blood cells (RBC) allowed them to induce immunogenicity and protection against expermental challenge and acquire the ability to bind to specific HLA-DRp1* alleles. These modified HABPs adopted certain characterist structural configurations as determined by circular dichroism (CD) and 1H nuclear magnetic resonance (NMR) associated with certain HLA-DR,1* haplotype binding activities and characteristics, such as a 2-Å-distance difference between amino acids fitting into HLA-DRp1 Pockets 1 to 9, residues participating in binding to HLA-DR pockets and residues making contact with the TCR, suggesting haplotyp and allele-conscious TCR. This has been demonstrated in HLA-DR-like genotyped monkeys and provides the basis for designing high effective, subunit-based, multi-antigen, multi-stage, synthetic vaccines, for immediate human use, malaria being one of them. [source] HLA phenotypes and outcomes of hepatitis B virus infection in Taiwan,JOURNAL OF MEDICAL VIROLOGY, Issue 1 2004Ya-Fang Wu Abstract The relationship of HLA phenotype and outcome of hepatitis B virus (HBV) infection was studied in two ethnic groups of Taiwan: Han Chinese and Taiwanese Aborigines. In Han Chinese, the study groups consisted of 98 persons who tested both hepatitis B surface antigen (HBsAg) and anti-HBs negative (Uninfected Group), 324 persons who tested HBsAg negative and both anti-HBs and anti-HBc positive (Recovered Group), and 98 patients who tested HBsAg positive for at least 6 months (Chronically Infected Group). In Taiwanese Aborigines, the study groups consisted of 34 persons in Uninfected Group, 229 persons in the Recovered Group, and 138 patients in the Chronically Infected Group. All subjects were tested for HLA (A, B, DRB1) phenotypes by sequence-specific oligonucleotide probe hybridization (SSOPH). HLA-DR*0406 was significantly more frequent in the Recovered Group, compared with the Chronically Infected Group (P,<,0.001) in Han Chinese. There was a significant excess of HLA-B*4001 (P,=,0.045) in the Recovered Group, compared with the Chronically Infected Group in Taiwanese Aborigines. The observation that different HLA phenotypes associated with recovery from HBV infection in different racial groups implies that various HLA molecules could present different HBV epitopes to induce effective immune responses. J. Med. Virol. 72:17,25, 2004. © 2004 Wiley-Liss, Inc. [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] | ||||||||||