Value through Innovation17 January 2013

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Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

25 publications regarding Immunology
  • Author:
    Moss N; Xiong Z; Burke M; Cogan D; Gao DA; Haverty K; Heim-Riether A; Hickey ER; Nagaraja R; Netherton M; O'Shea K; Ramsden P; Schwartz R; Shih D-T; Ward Y; Young E; Zhang Q
    Title:
    Exploration of cathepsin S inhibitors characterized by a triazole P1-P2 amide replacement.
    Source:
    Bioorg Med Chem Lett 22 (23), 7189-7193 (2012)
  • Author:
    Jenh C-H; Cox MA; Cui L; Reich E-P; Sullivan L; Chen S-C; Kinsley D; Qian S; Kim SH; Rosenblum S; Kozlowski J; Fine JS; Zavodny PJ; Lundell D
    Title:
    A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection.
    Source:
    BMC Immunol 13 art.no.2 (2012)
    Abstract:
    Background: The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738.Results: In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC 50ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC 90about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.Conclusions: SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.
  • Author:
    Uto-Konomi A; Miyauchi K; Ozaki N; Motomura Y; Suzuki Y; Yoshimura A; Suzuki S; Cua D; Kubo M
    Title:
    Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines
    Source:
    PLoS ONE 7 (7) art.no.e40343 (2012)
    Abstract:
    Homeostatic regulation of epidermal keratinocytes is controlled by the local cytokine milieu. However, a role for suppressor of cytokine signaling (SOCS), a negative feedback regulator of cytokine networks, in skin homeostasis remains unclear. Keratinocyte specific deletion of Socs3 (Socs3 cKO) caused severe skin inflammation with hyper-production of IgE, epidermal hyperplasia, and S100A8/9 expression, although Socs1 deletion caused no inflammation. The inflamed skin showed constitutive STAT3 activation and up-regulation of IL-6 and IL-20 receptor (IL-20R) related cytokines, IL-19, IL-20 and IL-24. Disease development was rescued by deletion of the Il6 gene, but not by the deletion of Il23, Il4r, or Rag1 genes. The expression of IL-6 in Socs3 cKO keratinocytes increased expression of IL-20R-related cytokines that further facilitated STAT3 hyperactivation, epidermal hyperplasia and neutrophilia. These results demonstrate that skin homeostasis is strictly regulated by the IL-6-STAT3-SOCS3 axis. Moreover, the SOCS3-mediated negative feedback loop in keratinocytes has a critical mechanistic role in the prevention of skin inflammation caused by hyperactivation of STAT3. © 2012 Uto-Konomi et al.
  • Author:
    Horvath C; Andrews L; Baumann A; Black L; Blanset D; Cavagnano J; Hastings K L; Hutto D L; MacLachlan T K; Milton M; Reynolds T; Robert S; Rogge M; Sims J; Treacy G; Warner G; Green J D
    Title:
    Storm forecasting: Additional lessons from the CD28 superagonist TGN1412 trial
    Source:
    Nat Rev Immunol 12 (10), 740 (2012)
    Abstract:
    no Abstract available
  • Author:
    Fu W; Ergun A; Lu T; Hill J A; Haxhinasto S; Fassett M S; Gazit R; Adoro S; Glimcher L; Chan S; Kastner P; Rossi D; Collins J J; Mathis D; Benoist C
    Title:
    A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells
    Source:
    Nature Immunol 13 (10), 972-980 (2012)
    Abstract:
    The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3 + CD4 + regulatory T cells (T reg cells) but is neither strictly necessary nor sufficient to determine the characteristic T reg cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the T reg cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the T reg cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the T reg cell phenotype, a model that would account for several aspects of T reg cell physiology, differentiation and stability. © 2012 Nature America, Inc. All rights reserved.
  • Author:
    Wagner C L; Visvanathan S; Elashoff M; Mcinnes I B; Mease P J; Krueger G G; Murphy F T; Papp K; Gomez-Reino JJ; Mack M; Beutler A; Gladman D; Kavanaugh A
    Title:
    Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab
    Source:
    Ann Rheum Dis 72 (1), 83-88 (2013)
    Abstract:
    Objective: To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA). Methods: GO-REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14. Results: Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1?) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor ?). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone. Conclusions: This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment. Copyright Article author (or their employer) 2012.
  • Author:
    Horvath C; Andrews L; Baumann A; Black L; Blanset D; Cavagnaro J; Hastings K L; Hutto D L; MarLachlan T K; Milton M; Reynolds T; Roberts S; Roge M; Sims J; Treacy G; Warner G; Green J D
    Title:
    Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial
    Source:
    Nat Rev Immunol Article in Press (2012)
    Abstract:
    -
  • Author:
    Nakatsuji Y; Okuno T; Moriya M; Sugimoto T; Kinoshita M; Takamatsu H; Nojima S; Kimura T; Kanbg S; Ito D; Nakagawa Y; Toyofuku T; Takata K; Nakano M; Kubo M; Suzuki S; Mantsui-Hasumi A; Uto-Konomi A; Ogata A; Mochizuki H; Sakoda S; Kumangoh A
    Title:
    Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-beta therapy in multiple skerosis.
    Source:
    J Immunol 188 (10), 4858-4865 (2012)
  • Author:
    Fu W; Ergun A; Lu T; Hill J A; Haxhinasto S; Fassett M S; Gazit R; Adoro S; Glimcher L; Chan S; Kastner P; Rossi D; Collins J J; Mathis D; Benoist C
    Title:
    A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells
    Source:
    Nat Immun Article in Press (2012)
    Abstract:
    The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3 +CD4 + regulatory T cells (T reg cells) but is neither strictly necessary nor sufficient to determine the characteristic T reg cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the T reg cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the T reg cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the T reg cell phenotype, a model that would account for several aspects of T reg cell physiology, differentiation and stability.
  • Author:
    Dey AK; Burke B; Sun Y; Sirokman K; Nandi A; Hartog K; Lian Y; Geonnotti AR; Montefiori D; Franti M; Martin G; Carfi A; Kessler P; Martin L; Srivastava IK; Barnett SW
    Title:
    Elicitation of neutralizing antibidies directed against CD4-induced epitope(s) using a CD4 mimetic cross-linked to a HIV-1 envelope gllycoprotein.
    Source:
    PLoS ONE 7 (1) art. no. e30233 (2012)
    Abstract:
    The identification of HIV-1 envelope glycoprotein (Env) structures that can generate broadly neutralizing antibodies (BNAbs) is pivotal to the development of a successful vaccine against HIV-1 aimed at eliciting effective humoral immune responses. To that end, the production of novel Env structure(s) that might induce BNAbs by presentation of conserved epitopes, which are otherwise occluded, is critical. Here, we focus on a structure that stabilizes Env in a conformation representative of its primary (CD4) receptor-bound state, thereby exposing highly conserved "CD4 induced" (CD4i) epitope(s) known to be important for co-receptor binding and subsequent virus infection. A CD4-mimetic miniprotein, miniCD4 (M64U1-SH), was produced and covalently complexed to recombinant, trimeric gp140 envelope glycoprotein (gp140) using site-specific disulfide linkages. The resulting gp140-miniCD4 (gp140-S-S-M64U1) complex was recognized by CD4i antibodies and the HIV-1 co-receptor, CCR5. The gp140-miniCD4 complex elicited the highest titers of CD4i binding antibodies as well as enhanced neutralizing antibodies against Tier 1 viruses as compared to gp140 protein alone following immunization of rabbits. Neutralization against HIV-2 7312/V434M and additional serum mapping confirm the specific elicitation of antibodies directed to the CD4i epitope(s). These results demonstrate the utility of structure-based approach in improving immunogenic response against specific region, such as the CD4i epitope(s) here, and its potential role in vaccine application.
  • Author:
    Yi T; Fogal B; Hao Z; Tobiasova Z; Wang C; Rao DA; Al-Lamki RS; Kinkiles-Smith NC; Kulkami S; Bradley JR; Bothwell ALM; Sassa WC; Tellides G; Pober JS
    Title:
    Reperfusion injury intensifies the adaptive human T cell alloresponse in a human mouse chimeric artery model.
    Source:
    Arterioscler Thromb Vasc Biol 32 (2), 353-360 (2012)
  • Author:
    Qin H; Nakata M; Chikuma S; Izumi N; Thi Hong L; Honjo T; Nagaoka H; Suzuki K; Maruya M; Fagarasan S; Busslinger M
    Title:
    Activation-induced cytidine deaminase expression in CD4+ T cells is associated with a unique IL-10-producing subset that increases with age.
    Source:
    PLOS ONE 6 (12) arn. e29141 (2011)
  • Author:
    Cattoli G; Fusaro A; Monne I; Coven F; Joannis T; El-Hamid HSA; Hussein AA; Cornelius C; Amarin NM; Mancin M; Holmes EC; Capua I
    Title:
    Evidence for differing evolutionary dynamics of A/H5N1 viruses among countries applying or not applying avian influenza vaccination in poultry.
    Source:
    Vaccine 29 (50), 9368-9375 (2011)
  • Author:
    Gurtner K; Hessel F; Eicheler W; Doerfler A; Zips D; Heider K-H; Krause M; Baumann M
    Title:
    Combined treatment of the immunoconjgate bivatuzumab mertansine and fractionated irradiation improves local tumour control in vivo.
    Source:
    Radiother Oncol 102 (3), 444-449 (2012)
    Abstract:
    Background and purpose: To test whether BIWI 1 (bivatuzumab mertansine), an immunoconjugate of the humanized anti-CD44v6 monoclonal antibody BIWA 4 and the maytansinoid DM1, given simultaneously to fractionated irradiation improves local tumour control in vivo compared with irradiation alone. Material and methods: For growth delay, FaDu tumours were treated with 5 intravenous injections (daily) of phosphate buffered saline (PBS, control), BIWA 4 (monoclonal antibody against CD44v6) or BIWI 1 (bivatuzumab mertansine) at two different dose levels (50 ?g/kg DM1 and 100 ?g/kg DM1). For local tumour control, FaDu tumours received fractionated irradiation (5f/5d) with simultaneous PBS, BIWA 4 or BIWI 1 (two dose levels). Results: BIWI 1 significantly improved local tumour control after irradiation with 5 fractions already in the lower concentration. The dose modifying factor of 1.9 is substantial compared to the majority of other modifiers of radiation response. Conclusion: Because of the magnitude of the curative effect, this approach is highly promising and should be further evaluated using similar combinations with improved tumour-specificity.
  • Author:
    Mechtcheriakova D; Sobanov Y; Bajna E; Svoboda M; Jensen-Jarolim E; Holtappels G; Bachert C; Jaritz M
    Title:
    Activation-induced cytidine deaminase (AID)-associated multigene signature to assess impact of AID in etiology of diseases withh inflammatory component.
    Source:
    Plos One 6 (10) (2011)
  • Author:
    Wex E; Bouyssou T; Duechs MJ; Erb KJ; Gantner F; Sanderson MP; Schnapp A; Stierstorfer BE; Wollin L
    Title:
    Induced Syk deletion leads to suppressed allergic responses but has no effect on neutrophil or monocyte migration in vivo.
    Source:
    Eur J Immunol 41 (11), 3208-3218 (2011)
    Abstract:
    The spleen tyrosine kinase (Syk) is a key mediator of immunoreceptor signaling in immune cells. Thus, interfering with the function of Syk by genetic deletion or pharmacological inhibition might influence a variety of allergic and autoimmune processes. Since conventional Syk knockout mice are not viable, studies addressing the effect of Syk deletion in adult animals have been limited. To further explore functions of Syk in animal models of allergy and to shed light on the role of Syk in the in vivo migration of neutrophils and monocytes, we generated inducible Syk knockout mice. These mice harbor a floxed Syk gene and a tamoxifen-inducible Cre recombinase under the control of the ubiquitously active Rosa26-promoter. Thus, treatment of mice with tamoxifen leads to the deletion of Syk in all organs. Syk-deleted mice were analyzed in mast cell-dependent models and in models focusing on neutrophil and monocyte migration. We show that Syk deletion in adult mice reduces inflammatory responses in mast cell-driven animal models of allergy and asthma but has no effect on the migration of neutrophils and monocytes. Therefore, the inducible Syk knockout mice presented here provide a valuable tool to further explore the role of Syk in disease-related animal models.
  • Author:
    Fogal B; Yi T; Wang C; Rao DA; Lebastchi A; Kulkami S; Tellides G; Pober JS
    Title:
    Neutralizing IL-6 reduces human arterial allograft rejection by allowing emergence of CD161+CD+4+ regulatory T cells.
    Source:
    J Immunol 187 (12), 6268-6280 (2011)
    Abstract:
    Perioperative injuries to an allograft exacerbate graft rejection, which in humans is primarily mediated by effector memory T cells. IL-6 transcripts in human coronary artery segments rapidly increase posttransplantation into immunodeficient mouse hosts compared with those of pretransplant specimens and fall dramatically by 30 d. Adoptive transfer of human PBMCs allogeneic to the artery 2 d postoperatively results in T cell infiltrates and intimal expansion 4 wk later. Ab neutralization of human IL-6 reduces the magnitude of intimal expansion and total T cell infiltration but increases the relative expression of CD161 while decreasing other Th17 markers. Coculture of MHC class II-expressing human endothelial cells (ECs) with allogeneic CD4+memory T cells results in T cell activation and EC secretion of IL-6. Neutralizing IL-6 in primary allogeneic T cell-EC cocultures results in enhanced T cell proliferation of CD161+ CD4+ T cells, reduces total T cell proliferation upon restimulation in secondary cultures (an effect dependent on CD161+ T cells), increases expression of FOXP3 in CD161+ T cells, and generates T cells that suppress proliferation of freshly isolated T cells. These data suggest that IL-6 released from injured allograft vessels enhances allogeneic T cell infiltration and intimal expansion in a model of human allograft rejection by inhibiting an increase in CD161 +regulatory T cells.
  • Author:
    Osanya A; Song E-H; Metz K; Shimak RM; Boggiatto PM; Huffman E; Johnson C; Hostetter JM; Pohl NLB; Petersen CA
    Title:
    Pathogen-derived oligosaccharides improve innate immune response to intracellular parasite infection.
    Source:
    Am J Pathol 179 (3), 1329-1337 (2011)
    Abstract:
    Pathogen glycolipids, including Leishmania spp. lipophosphoglycan (LPG) and Mycobacterium tuberculosis mannosylated lipoarabinomannan (ManLAM), modulate essential interactions with host phagocytic cells. Polysaccharide and lipid components promote immunomodulation. Owing to the stereochemistry required to synthesize oligosaccharides, the roles for oligosaccharides in the pathogenesis of infectious diseases have remained largely unknown. Recent advances in carbohydrate chemistry allowed us to synthesize pathogen surface oligosaccharides to discern their immune responsealtering activities. Trimannose cap carbohydrates from ManLAM and LPG altered the production of proinflammatory cytokines via a toll-like receptor (TLR2)mediated mechanism in vitro and in vivo. In vivo treatment with trimannose led to increased Th1-polarizing, IL-12p40producing cells from the draining lymph nodes of treated Leishmania majorinfected mice compared with cells from untreated infected mice. Trimannose treatment increased the production of other Th1 proinflammatory cytokines (ie, interferon-?, IL-6, and tumor necrosis factor-?) critical for a productive immune response to either pathogen. This significant difference in cytokine production between trimannose cap sugartreated and control groups was not observed in draining lymph node cells from TLR2-/- mice. Type of inflammation and rate of bead entry into macrophages and dendritic cells were different for trimannose-coated beads compared with control oligosaccharide- coated beads, indicating selective lectin receptor/oligosaccharide interactions mediating cell entry and cytokine production. These novel findings may prompt the development of targeted oligosaccharide adjuvants against chronic infections.
  • Author:
    Battegay M; Arasteh K; Plettenberg A; Bogner JR; Livrozet JM; Witt MD; Mossdorf E; Yong C-L; Zhang W; Macha S; Berger F; Stern J; Robinson P; Quinson A-M
    Title:
    Bioavailability of extended-release nevirapine 400 and 300 mg in HIV-1: A multicenter, open-label study.
    Source:
    Clin Ther 33 (9), 1308-1320 (2011)
    Abstract:
    Background: Nevirapine (NVP) is a widely used non-nucleoside reverse transcriptase inhibitor. A once-daily extended-release (XR) formulation would potentially increase adherence and thus efficacy. Objective: The aim of this study was to investigate the steady-state bioavailability of 2 once-daily tablet formulations of NVP XR (containing 25% or 20% hypromellose; NVP XR25 and NVP XR20, respectively) in 400- or 300-mg tablets compared with twice-daily immediate-release (IR) NVP 200-mg tablets. Methods: This Phase Ib multinational, multicenter, open-label trial was conducted in patients aged 18 to 60 years, infected with HIV-1 (viral load, ?50 copies/mL), and treated for ?12 weeks with twice-daily NVP IR 200 mg. Patients were switched to NVP XR25 400 or 300 mg or NVP XR20 400 or 300 mg for 19 days. Plasma samples were collected over 24-hour periods at steady state. Primary end points were AUC0-24,ss, Cmax,ss, and Cmin,ss, analyzed using an ANOVA statistical model on the logarithmic scale and 2-sided 90% CI. Sample size was determined assuming an intrasubject %CV of 20% for Cmax. Adverse events (AEs) and viral loads were monitored. Results: Ninety-two patients were enrolled (NVP XR25 400 mg, 24 patients; NVP XR20 400 mg, 24; NVP XR25 300 mg, 21; NVP XR20 300 mg, 23). Compared with NVP IR, the AUC0-24,ss values of the NVP XR formulations were lower (test/reference ratios: 79.5% [90% CI, 73.0-86.7; P = 0.544], 71.0% [90% CI, 63.3-79.7; P = 0.956], 90.3% [90% CI, 80.4-101.4; P = 0.044], and 83.7% [90% CI, 77.9-89.9; P = 0.148] with NVP XR25 400 mg, NVP XR20 400 mg, NVP XR25 300 mg, and NVP XR20 300 mg, respectively). The relative bioavailability of NVP XR25 was greater compared with that of NVP XR20. Cmax,ss values were lower with all NVP XR formulations compared with NVP IR. For Cmin,ss, NVP XR25 400 and 300 mg were not significantly different from NVP IR, with 90% CIs within the range of 80% to 125% (P = 0.039 and P = 0.017, respectively). All AEs were mild or moderate, with no significant differences between treatment groups. No virologic failures (viral load, >50 copies/mL over 2 consecutive readings) were observed. Conclusions: Extent of bioavailability was lower and tmax,ss was delayed with all NVP XR formulations compared with NVP IR. The bioavailability of the NVP XR25 formulations was greater than that of the NVP XR20 formulations. Cmin,ss with NVP XR25 was similar to that with NVP IR. All of the NVP XR formulations were well tolerated. The 400-mg NVP XR25 formulation was selected for further development.
  • Author:
    Lasaro MO; Sazanovich M; Giles-Davis W; Mrass P; Ertl HCJ; Weninger W; Bunte RM; Sewell DA; Hussain SF; Paterson Y; Fu Y-X
    Title:
    Active immunotherapy combined with blockade of a coinhibitory pathway achieves regression of large tumor masses in cancer-prone mice.
    Source:
    Mol Ther 19 (9), 1727-1736 (2011)
    Abstract:
    Vaccines that aim to expand tumor-specific CD8 T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we here show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8 T-cell responses, which fail to affect the size of the tumors. In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B-and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8 T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.
  • Author:
    Ertl R; Birzele F; Hildebrandt T; Klein D
    Title:
    Viral transcriptome analysis of feline immunodeficiency virus infected cells using second generation sequencing technology.
    Source:
    Vet Immunol Immunopathol 143 (3-4), 314-324 (2011)
    Abstract:
    Feline immunodeficiency virus (FIV) is a widespread pathogen causing immunodeficiency in domestic cats and related wild cat species. The virus genome includes the main structural genes common to all retroviruses as well as accessory genes displaying essential functions during the viral life cycle. Expression of viral genes involves transcription of provirus genomes into full-length transcripts, which are partially processed into several spliced mRNA variants for the translation of particular proteins. Among several FIV isolates derived from domestic cats, notable differences in pathogenicity could be observed leading to identification of low and high pathogenic virus isolates. This study investigates the viral transcriptome of two differentially virulent FIV strains using second generation sequencing (SGS) technology. The expression levels of viral genes as detected by SGS were additionally determined by reverse transcription quantitative PCR analysis in order to compare two methods of mRNA quantification. The different properties of both methods, especially regarding normalization between samples, had to be considered when comparing the resulting data. SGS turned out to be a suitable technique for comparing mRNA transcription between both FIV infected cell lines and the identification of spliced viral transcripts. In contrast to this, the quantification of these spliced isoforms using SGS data was impeded by the short length of sequencing reads. In summary, SGS analysis revealed very consistent mRNA levels for the majority of viral genes between the low pathogenic Petaluma and the more highly pathogenic Glasgow 8 isolate. Notable differences among the two FIV strains could be observed in the viral mRNA splicing where Glasgow 8 displays similarities to the transcription pattern seen in the early stages of natural lentivirus infections. Thus, divergences in the regulation of post-transcriptional RNA processing might represent an additional contributor to the diverse pathogenic effects of individual FIV isolates. Taken together, this study aims to investigate the viral transcriptome as one part of the complex network of virus-host interactions, which will contribute to gaining deeper insights into FIV pathogenesis.
  • Author:
    Seclen E; Soriano V; Gonzalez MM; Martin-Carbonero L; Gellermann H; Distel M; Kadus W; Poveda E
    Title:
    Impact of baseline HIV-1 tropism on viral response and CD4 cell count gains in HIV-infected patients receiving first-line antiretroviral therapy.
    Source:
    J Infect Dis 204 (1), 138-144 (2011)
    Abstract:
    Background. Viral tropism influences the natural history of human immunodeficiency type 1 (HIV-1) disease: X4 viruses are associated with faster decreases in CD4 cell count. There is scarce information about the influence of viral tropism on treatment outcomes. Methods. Baseline plasma samples from patients recruited to the ArTEN (Atazanavir/ritnoavir vs. Nevirapine on a background of Tenofovir and Emtricitabine) trial were retrospectively tested for HIV-1 tropism using the genotypic tool geno2phenoFPR55.75%. ArTEN compared nevirapine with atazanavir-ritonavir, both along with tenofovir-emtricitabine, in drug-naïve patients. Results. Of 569 ArTEN patients, 428 completed 48 weeks of therapy; 282 of these received nevirapine and 146 of these received atazanavir-ritonavir. Overall, non-B subtypes of HIV-1 were recognized in 96 patients (22%) and X4 viruses were detected in 55 patients (14%). At baseline, patients with X4 viruses had higher plasma HIV RNA levels (5.4 vs 5.2 log copies/mL, respectively; P 5 .044) and lower CD4 cell counts (145 vs 188 cells/?L, respectively; P < .001) than those with R5 strains. At week 48, virologic responses were lower in patients with X4 viruses than in patients with R5 viruses (77% vs 92%, respectively; P = .009). Multivariate analysis confirmed HIV-1 tropism as an independent predictor of virologic response at week 24 (P = .012). This association was extended to week 48 (P = .007) in clade B viruses. Conversely, CD4 cell count recovery was not influenced by baseline HIV-1 tropism. Conclusions. HIV-1 tropism is an independent predictor of virologic response to first-line antiretroviral therapy. In contrast, it does not seem to influence CD4 cell count recovery. Clinical Trials Registration. NCT00389207. - DERWENT Abstract - This study (NCT00389207) evaluated the impact of baseline HIV-1 tropism on viral response and CD4 cell count gains in 428 HIV-infected patients receiving 1st-line antiretroviral therapy. Overall, non-B subtypes of HIV-1 were recognized in 96 patients and X4 viruses were detected in 55 patients. At baseline, patients with X4 viruses had higher plasma HIV RNA levels and lower CD4 cell counts than those with R5 strains. At wk 48, virologic responses were lower in patients with X4 viruses than in patients with R5 viruses. Multivariate analysis confirmed HIV-1 tropism as an independent predictor of virologic response at wk 24. Thus, HIV-1 tropism is an independent predictor of virologic response to 1st-line antiretroviral therapy.
  • Author:
    Rosenstiel Ph; Billmann-Born S; Till A; Lipinski S; Sina Ch; Haesler R; Kerick M; Schreiber St; Latiano A; Annese V; Manke Th; Seegert D; Hanidu A; Li J; van Heel D; Arlt A; Schaefer H
    Title:
    Genome-wide expression profiling identifies an impairment of negative feedback signals in the Crohn's disease-associated NOD2 variant L1007fsinsC.
    Source:
    J Immunol 186 (7), 4027-4038 (2011)
    Abstract:
    NOD2 is an intracellular receptor for the bacterial cell wall component muramyl dipeptide (MDP), and variants of NOD2 are associated with chronic inflammatory diseases of barrier organs (e. g., Crohn's disease, asthma, and atopic eczema). It is known that activation of NOD2 induces a variety of inflammatory and antibacterial factors. The exact transcriptomal signatures that define the cellular programs downstream of NOD2 activation and the influence of the Crohn-associated variant L1007fsinsC are yet to be defined. To describe the MDP-induced activation program, we analyzed the transcriptomal reactions of isogenic HEK293 cells expressing NOD2(wt) or NOD2(L1007fsinsC) to stimulation with MDP. Importantly, a clear loss of function could be observed in the cells carrying the Crohn-associated variant L1007fsinsC, whereas the NOD2(wt) cells showed differential regulation of growth factors, chemokines, and several antagonists of NF-kappa B (e. g., TNFAIP3 [A20] and IER3). This genotype-dependent regulation pattern was confirmed in primary human myelomonocytic cells. The influence of TNFAIP3 and IER3 in the context of NOD2 signaling was characterized, and we could validate the predicted role as inhibitors of NOD2-induced NF-kappa B activation. We show that IER3 impairs the protective effect of NOD2(wt) against bacterial cytoinvasion. These results further our understanding of NOD2 as a first-line defense molecule and emphasize the importance of simultaneous upregulation of counter-regulatory anti-inflammatory factors as an integral part of the NOD2-induced cellular program. Lack of these regulatory events due to the L1007fsinsC variant may pivotally contribute to the induction and perpetuation of chronic inflammation.
  • Author:
    Jabara HH; Angelini F; Brodeur SR; Geha RS
    Title:
    Ligation of CD46 to CD40 inhibits CD40 signaling in B cells.
    Source:
    Int Immunol 23 (3), 215-221 (2011)
    Abstract:
    CD40 induces B cells to switch to IgE in the presence of IL-4 and up-regulates their expression of the low-affinity receptor for IgE, CD23, which promotes the immune response to allergen complexed with IgE antibody. CD40 binds to CD40L and to the C4b-binding protein (C4BP) using distinct sites. CD46 is a receptor for the product of activated complement C4b. Some microbial antigens bind both C4BP and CD46, potentially bridging CD40 to CD46. In addition, immune complexes containing both C4b and C4BP may cross-link CD40 to CD46. We demonstrate that cross-linking CD46 to CD40 on B cells inhibits CD40-mediated up-regulation of surface CD23 expression and induction of IL-4-dependent IgE isotype switching. This was associated with inhibition of induction of C? germ line transcripts and of activation-induced cytidine deaminase mRNA expression. Furthermore, co-ligation of CD46 to CD40 blocked CD40-mediated NF-?B activation. These observations suggest that complement components may play an important role in regulating CD40 activation of B cells and the allergic response.
  • Author:
    den Engelsman´J; Garidel P; Smulders R; Koll H; Smith B; Bassarab S; Seidl A; Hainzl O; Jiskoot W
    Title:
    Strategies for the assessment of protein aggregates in pharmaceutical biotech product development.
    Source:
    Pharm Res 28 (4), 920-933 (2011)
    Abstract:
    Within the European Immunogenicity Platform (EIP) (http://www.e-i-p.eu), the Protein Characterization Subcommittee (EIP-PCS) has been established to discuss and exchange experience of protein characterization in relation to unwanted immunogenicity. In this commentary, we, as representatives of EIP-PCS, review the current state of methods for analysis of protein aggregates. Moreover, we elaborate on why these methods should be used during product development and make recommendations to the biotech community with regard to strategies for their application during the development of protein therapeutics.
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