Specific and general HLA-DR binding motifs: comparison of algorithms

Using panels of peptides well characterized for their ability to bind to HLA DR1, DRB1*1101, or DRB1*0401 molecules, algorithms were deduced to predict binding to these molecules. These algorithms consist of blocks of 8 amino acids containing an amino acid anchor (Tyr, Phe, Trp, Leu, Ile, or Val) at position i and different amino acid combinations at positions i+2 to i+7 depending on the class II molecule. The sensitivity (% of correctly predicted binder peptides) and specificity (% of correctly predicted non-binder peptides) of these algorithms, were tested against different independent panels of peptides and compared to other algorithms reported in the literature. Similarly, using a panel of 232 peptides able to bind to one or more HLA molecules as well as 43 non-binder peptides, we deduced a general motif for the prediction of binding to HLA-DR molecules. The sensitivity and specificity of this general motif was dependent on the threshold score used for the predictions. For a score of 0.1, the sensitivity and specificity were 84.7% and 69.8%, respectively. This motif was validated against several panels of binder and non-binder peptides reported in the literature, as well as against 35, 15-mer peptides from hepatitis C virus core protein, that were synthesized and tested in a binding assay against a panel of 19 HLA-DR molecules. The sensitivities and specificities against these panels of peptides were similar to those attained against the panels used to deduce the algorithm. These results show that comparison of binder and non-binder peptides, as well as correcting for the relative abundance of amino acids in proteins, is a useful approach to deduce performing algorithms to predict binding to HLA molecules

Viremia after one month of interferon therapy predicts treatment outcome in patients with chronic hepatitis C

BACKGROUND &#38; AIMS: In chronic hepatitis C, interferon alfa induces sustained remission in less than 30% of treated patients. The aim of this study is to analyze viral status early after initiation interferon therapy as a predictor of treatment outcome. METHODS: One hundred eighty-one patients with chronic hepatitis C who had been treated with interferon alfa for 12 months (median follow-up, 49 months) were studied. Viremia and aminotransferase levels at the first and third months of therapy as well as 10 pretreatment variables were assessed as potential independent predictors of sustained response to treatment. RESULTS: Sustained response occurred in 51 patients (28%). At month 1 of treatment, viral persistence accurately predicted nonresponse (predictive value, 95.3; 95% confidence interval, 86.0-98.8; P < 0.0001). Independent predictors of sustained response were undetectable viremia at the first month of therapy (P < 0.001), undetectable viremia at the third month (P < 0.001), younger age (P = 0.006), nonsporadic infection (P = 0.012), and higher pretreatment aspartate aminotransferase levels (P = 0.032). In patients who cleared HCV RNA at month 1 of therapy, the predicted probability of sustained response averaged 70% for those younger than 30 years and diminished by 10% for each decade of age. CONCLUSIONS: Failure to clear HCV RNA at month 1 of treatment is strongly and independently associated with a very low probability of a sustained response to interferon

Transmission of hepatitis C virus infection to tree shrews

Although hepatitis C virus (HCV) infection can be reproduced in chimpanzees, these animals are rare and expensive. Tree shrews (tupaias) are small animals, closely related to primates, which adapt easily to a laboratory environment. In this work we have investigated the susceptibility of Tupaia belangeri chinensis to HCV infection. Tupaias caught in the wild in Yunnan (China) were inoculated in China with HCV genotype 1b (study A) and in Spain with a mixture of genotypes 1b, 1a, and 3 (study B). In study B tupaias were divided into three groups: group I was inoculated without previous manipulation, group II received 750 cGy of X-ray whole-body irradiation before inoculation, and group III was used as control. Transient or intermittent viremia occurred in 34.8% (8/23) and anti-HCV in 30.4% (7/23) of tupaias in study A. In study B a transient viremia was detected in 20% (2/10) in group I and in 50% (2/4) in group II. Anti-HCV was found in 1 tupaia from group I and in 3 from group II: Viremia lasted for longer and anti-HCV tended to reach higher titers in animals which received total body irradiation. ALT elevations and nonspecific pathological changes occurred in inoculated tupaias; however, the wild nature of the animals precludes the interpretation of these changes as solely due to HCV infection. In summary our results show that T.b. chinensis are susceptible to HCV and that whole-body irradiation may possibly increase the efficiency of the infection. These animals may serve as an in vivo system for culturing HCV and addressing pathophysiological and therapeutic issues of HCV infection

Atrapamiento o choque femoroacetabular

Hasta no hace muchos años, el atrapamiento o choque femoroacetabular (AFA) ha sido un gran desconocido en la especialidad de Cirugía Ortopédica y Traumatología y ha sido recientemente cuando ha sido dado a conocer y publicado en la comunidad médica. Se conoce en la literatura anglosajonacomo femoroacetabular impingement (FAI), síndrome de Atrapamiento Femoroacetabular (AFA) o Choque Femoroacetabular (CFA) en español, comose acordó en el VI Congreso de la Sociedad Española de Cirugía de la Cadera, (SECCA) celebrado en Burgos los días 17 y 18 de junio de 2004. En este tema de actualización hemos realizado una revisión de nuestra serie de 15 casos, realizados de enero de 2010 a julio de 2012

Specific and general HLA-DR binding motifs: comparison of algorithms

Using panels of peptides well characterized for their ability to bind to HLA DR1, DRB1*1101, or DRB1*0401 molecules, algorithms were deduced to predict binding to these molecules. These algorithms consist of blocks of 8 amino acids containing an amino acid anchor (Tyr, Phe, Trp, Leu, Ile, or Val) at position i and different amino acid combinations at positions i+2 to i+7 depending on the class II molecule. The sensitivity (% of correctly predicted binder peptides) and specificity (% of correctly predicted non-binder peptides) of these algorithms, were tested against different independent panels of peptides and compared to other algorithms reported in the literature. Similarly, using a panel of 232 peptides able to bind to one or more HLA molecules as well as 43 non-binder peptides, we deduced a general motif for the prediction of binding to HLA-DR molecules. The sensitivity and specificity of this general motif was dependent on the threshold score used for the predictions. For a score of 0.1, the sensitivity and specificity were 84.7% and 69.8%, respectively. This motif was validated against several panels of binder and non-binder peptides reported in the literature, as well as against 35, 15-mer peptides from hepatitis C virus core protein, that were synthesized and tested in a binding assay against a panel of 19 HLA-DR molecules. The sensitivities and specificities against these panels of peptides were similar to those attained against the panels used to deduce the algorithm. These results show that comparison of binder and non-binder peptides, as well as correcting for the relative abundance of amino acids in proteins, is a useful approach to deduce performing algorithms to predict binding to HLA molecules

Therapeutic effect of a peptide inhibitor of TGF-β on pulmonary fibrosis

Pulmonary fibrosis encompasses several respiratory diseases characterized by epithelial cell injury, inflammation and fibrosis. Transforming growth factor (TGF)-β1 is one of the main profibrogenic cytokines involved in the pathogenesis of lung fibrosis. It induces fibroblast differentiation into myofibroblasts, which produce high levels of collagen and concomitantly loss of lung elasticity and reduction of the respiratory function. In the present study, we have investigated the effects of P17 (a TGF-β inhibitor peptide) on IMR-90 lung fibroblast differentiation in vitro, as well as on the inhibition of the development of bleomycin-induced pulmonary fibrosis in mice. It was found that in IMR-90 cells, P17 inhibited TGF-β1-induced expression of connective tissue growth factor and α-smooth muscle actin. In vivo, treatment of mice with P17 2days after bleomycin administration decreased lung fibrosis, areas of myofibroblast-like cells and lymphocyte infiltrate. P17 also reduced mRNA expression of collagen type I, fibronectin and the fibronectin splice isoform EDA in the lung, and increased the expression of IFN-γ mRNA. Finally, therapeutic treatment with P17 in mice with already established fibrosis was able to significantly attenuate the progression of lung fibrosis. These results suggest that P17 may be useful in the treatment of pulmonary fibrosis

Simple strategy to induce antibodies of distinct specificity: application to the mapping of gp120 and inhibition of HIV-1 infectivity

In this study 96 15-mer peptides encompassing the entire sequence of HIV-1 gp120 were synthesized and used to immunize BALB/c mice (i) alone or (ii) in conjunction with the T helper cell determinant FISEAIIHVLHSR (FIS) from sperm whale myoglobin, which is well recognized by major histocompatibility complex (MHC) class II molecules of BALB/c. Of these peptides 39 were immunogenic per se and 57 were not. Out of the 57 non-immunogenic peptides 53 could be rendered immunogenic with the second immunization protocol. With the exception of 4 cases, the anti-peptide antibody titers induced in (ii) were equal (14 cases) or higher (78 cases) than those induced in (i). From the 96 anti-peptide antibodies tested, 12 were able to recognize recombinant gp120 with good antibody titers, a result in agreement with previously identified B cell epitopes from gp120 by anti-peptide antibodies induced with longer peptides conjugated to a carrier protein. Moreover, 4 of the 12 anti-peptide antisera that recognized gp 120 were able to neutralize HIV-1 infectivity in vitro, showing that the strategy of co-immunization with FIS may afford functional antibodies

Tumor therapy in mice by using a tumor antigen linked to modulin peptides from Staphylococcus epidermidis

Staphylococcus epidermidis releases a complex of at least four peptides, termed phenol-soluble modulins (PSM), which stimulate macrophages to produce proinflammatory cytokines via activation of TLR2 signalling pathway. We demonstrated that covalent linkage of PSM peptides to an antigen facilitate its capture by dendritic cells and, in combination with different TLR ligands, can favour the in vivo induction of strong and persistent antigen-specific immune responses. Treatment of mice grafted with HPV16-E7-expressing tumor cells (TC-1) with poly(I:C) and a peptide containing αMod linked to the H-2D(b)-restricted cytotoxic T-cell epitope E7(49-57) from HPV16-E7 protein allowed complete tumor regression in 100% of the animals. Surprisingly, this immunomodulatory property of modulin-derived peptides was TLR2 independent and partially dependent upon the EGF-receptor signalling pathway. Our results suggest that alpha or gamma modulin peptides may serve as a suitable antigen carrier for the development of anti-tumoral or anti-viral vaccines