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Daniel Geh, Caroline Gordon
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease. There are three drugs licensed for the treatment of lupus: corticosteroids, hydroxychloroquine and belimumab. Immunosuppressants such as azathioprine, methotrexate and mycophenolate are also used. Despite these treatments there is still considerable morbidity. New treatments are needed for the management of active lupus. Epratuzumab a humanized IgG1 monoclonal antibody that targets CD22 resulting in selective B cell modulation that has been considered a potential treatment for SLE...
March 15, 2018: Expert Review of Clinical Immunology
Dongfen Yuan, Frederik Rode, Yanguang Cao
We proposed here a minimal physiologically based pharmacokinetic (mPBPK) model for a group of novel engineered antibodies in mice and humans. These antibodies are designed with altered binding properties of their Fc domain with neonatal Fc receptor (FcRn) or the Fab domain with their cognate targets (recycling antibodies) in acidic endosomes. To enable simulations of such binding features in the change of antibody pharmacokinetics and its target suppression, we nested an endothelial endosome compartment in parallel with plasma compartment based on our previously established mPBPK model...
March 14, 2018: AAPS Journal
Jing Wang, Sichen Liu, Baidong Hou, Meixiang Yang, Zhongjun Dong, Hai Qi, Wanli Liu
Class-switch recombination (CSR) and somatic hypermutation (SHM) occur during the differentiation of germinal center B cells (GCBs). Activation-induced cytidine deaminase (AID) is responsible for both CSR and SHM in GCBs. Here, we show that ablation of PTEN through the Cγ1-Cre mediated recombination significantly influences the CSR and SHM responses. The GCs fail to produce the IgG1 B cells, the high affinity antibodies and nearly lost the dark zone (DZ) in Ptenfl/fl Cγ1Cre/+ mice after immunization, suggesting the impaired GC structure...
2018: Frontiers in Immunology
Laura Aragoneses-Fenoll, Gloria Ojeda, María Montes-Casado, Yeny Acosta-Ampudia, Umberto Dianzani, Pilar Portolés, José M Rojo
Class IA phosphatidylinositol 3-kinase (PI3K) catalytic subunits p110α and p110δ are targets in cancer therapy expressed at high levels in T lymphocytes. The role of p110δ PI3K in normal or pathological immune responses is well established, yet the importance of p110α subunits in T cell-dependent immune responses is not clear. To address this problem, mice with p110α conditionally deleted in CD4+ and CD8+ T lymphocytes (p110α-/- ΔT) were used. p110α-/- ΔT mice show normal development of T cell subsets, but slightly reduced numbers of CD4+ T cells in the spleen...
2018: Frontiers in Immunology
Rolf Spirig, Ian K Campbell, Sandra Koernig, Chao-Guang Chen, Bonnie J B Lewis, Rebecca Butcher, Ineke Muir, Shirley Taylor, Jenny Chia, David Leong, Jason Simmonds, Pierre Scotney, Peter Schmidt, Louis Fabri, Andreas Hofmann, Monika Jordi, Martin O Spycher, Susann Cattepoel, Jennifer Brasseit, Con Panousis, Tony Rowe, Donald R Branch, Adriana Baz Morelli, Fabian Käsermann, Adrian W Zuercher
Activation of Fc receptors and complement by immune complexes is a common important pathogenic trigger in many autoimmune diseases and so blockade of these innate immune pathways may be an attractive target for treatment of immune complex-mediated pathomechanisms. High-dose IVIG is used to treat autoimmune and inflammatory diseases, and several studies demonstrate that the therapeutic effects of IVIG can be recapitulated with the Fc portion. Further, recent data indicate that recombinant multimerized Fc molecules exhibit potent anti-inflammatory properties...
March 12, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Ariel L Raybuck, Sung Hoon Cho, Jingxin Li, Meredith C Rogers, Keunwook Lee, Christopher L Williams, Mark Shlomchik, James W Thomas, Jin Chen, John V Williams, Mark R Boothby
B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes...
March 12, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Jamie Jennings-Gee, Sally Quataert, Tridib Ganguly, Ralph D'Agostino, Rajendar Deora, Purnima Dubey
The reemergence of pertussis or whooping cough in several countries highlights the need for better vaccines. Acellular pertussis vaccines (aPV) contain alum as the adjuvant and elicit Th2 biased immune responses that are less effective in protecting against infection than the reactogenic whole cell pertussis vaccines (wPV), which elicit primarily a Th1/Th17 response. An important goal for the field is to devise aPVs that will induce immune responses similar to wPV. We show that Bordetella Colonization Factor A (BcfA), an outer membrane protein from B...
March 12, 2018: Infection and Immunity
Toni K Choueiri, James Larkin, Mototsugu Oya, Fiona Thistlethwaite, Marcella Martignoni, Paul Nathan, Thomas Powles, David McDermott, Paul B Robbins, David D Chism, Daniel Cho, Michael B Atkins, Michael S Gordon, Sumati Gupta, Hirotsugu Uemura, Yoshihiko Tomita, Anna Compagnoni, Camilla Fowst, Alessandra di Pietro, Brian I Rini
BACKGROUND: The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma...
March 9, 2018: Lancet Oncology
Valery I Turobov, Alexey V Danilkovich, Alexei B Shevelev, Yulia K Biryukova, Natalia V Pozdniakova, Viatcheslav N Azev, Arkady N Murashev, Valery M Lipkin, Igor P Udovichenko
Peptide immunocortin sequence corresponds to the amino acid residues 11-20 of the variable part of human immunoglobulin G1 (IgG1) heavy chain. Since immunocortin was shown previously to inhibit phagocytosis in peritoneal macrophages and ConA-induced T-lymphocytes proliferation in culture, we suggested that immunocortin administering may be of use for patients with self-immune syndrome. Immunocortin in concentration 10 μM inhibited proliferation of both antigen (myelin)-induced and ConA-induced LN lymphocytes isolated from the lymph nodes of Dark Agouti (DA) rats immunized with chorda shear...
2018: Frontiers in Pharmacology
Maite Ramírez, Saritza Santos, Osmarie Martínez, Ricardo Rodríguez, Eric Miranda, Willy D Ramos-Perez, Miguel Otero
Poxviruses are complex dsDNA viruses with over 200 genes, many of them with unknown role in the stimulation of immune responses. Among these, the vaccinia virus (VACV) L3L ORF encodes an essential protein for the transcription of the VACV early genes. To the best of our knowledge, the immune response elicited by L3 has not been characterized. In this regard, our data describes a DNA L3-coding plasmid (pL3L) that stimulates both, humoral- and cell-mediated immune responses in a mouse model. Cell-mediated immune responses were measured by IFN-γ and IL-4 ELISPOT assays...
March 7, 2018: Vaccine
Mitsunori Shiroishi, Yuji Ito, Kenta Shimokawa, Jae Man Lee, Takahiro Kusakabe, Tadashi Ueda
Rheumatoid factors (RFs) are autoantibodies against the fragment-crystallizable (Fc) region of immunoglobulin G (IgG). In individuals with hematological diseases such as cryoglobulinemia and certain B-cell lymphoma forms, the RFs derived from specific heavy- and light-chain germline pairs, so-called "stereotypic RFs," are frequently produced in copious amounts and form immune complexes with IgG in serum. Of note, many structural details of the antigen-recognition mechanisms in RFs are unclear. Here, we report the crystal structure of the RF YES8c derived from the IGHV1-69/IGKV3-20 germline pair, the commonest of the stereotypic RFs, in complex with human IgG1-Fc at 2...
March 9, 2018: Journal of Biological Chemistry
Leonardo Silva de Araujo, Nidai de Bárbara Moreira da Silva, Janaina Aparecida Medeiros Leung, Fernanda Carvalho Queiroz Mello, Maria Helena Féres Saad
Despite the reported high heterogeneity of the human immune response to tuberculosis (TB), new studies may contribute to the understanding of Mycobacterium tuberculosis immunopathogenesis. To investigate the patterns of humoral response during latent (LTBI) and active TB, we evaluated specific IgG subclasses' response, by ELISA, to a set of mycobacterial antigens (Rv2029c, Rv2031c, Rv2034, Rv2628, Rv3353c ESAT6:CFP10, and the new chimeric PstS1(285-374) :CFP10) in plasma samples from exposed uninfected controls (ExC, n = 24), LTBI (n = 61), and TB (n = 15) donors...
January 2018: Tuberculosis
Mark Noviski, James L Mueller, Anne Satterthwaite, Lee Ann Garrett-Sinha, Frank Brombacher, Julie Zikherman
Naive B cells co-express two BCR isotypes, IgM and IgD, with identical antigen-binding domains but distinct constant regions. IgM but not IgD is downregulated on autoreactive B cells. Because these isotypes are presumed to be redundant, it is unknown how this could impose tolerance. We introduced the Nur77-eGFP reporter of BCR signaling into mice that express each BCR isotype alone. Despite signaling strongly in vitro , IgD is less sensitive than IgM to endogenous antigen in vivo and developmental fate decisions are skewed accordingly...
March 9, 2018: ELife
Amr S Ali, Ravali Raju, Somak Ray, Rashmi Kshirsagar, Alan Gilbert, Li Zang, Barry L Karger
As the demand for biological therapeutic proteins rises, there is an increasing need for robust and highly efficient bioprocesses, specifically, maximizing protein production by controlling the cellular nutritional and metabolic needs. A comprehensive lipidomics analysis has been performed, for the first time, over the time course of CHO cells producing an IgG1 monoclonal antibody (mAb) with fed batch 5 L bioreactors. The dynamic nature and importance of the CHO lipidome, especially on cellular growth and specific productivity, is demonstrated...
March 9, 2018: Biotechnology Journal
Susan L Baldwin, Fan-Chi Hsu, Neal Van Hoeven, Emily Gage, Brian Granger, Jeffrey A Guderian, Sasha E Larsen, Erica C Lorenzo, Laura Haynes, Steven G Reed, Rhea N Coler
Elderly people are at high risk for influenza-related morbidity and mortality due to progressive immunosenescence. While toll-like receptor (TLR) agonist containing adjuvants, and other adjuvants, have been shown to enhance influenza vaccine-induced protective responses, the mechanisms underlying how these adjuvanted vaccines could benefit the elderly remain elusive. Here, we show that a split H1N1 influenza vaccine (sH1N1) combined with a TLR4 agonist, glucopyranosyl lipid adjuvant formulated in a stable oil-in-water emulsion (GLA-SE), boosts IgG2c:IgG1 ratios, enhances hemagglutination inhibition (HAI) titers, and increases protection in aged mice...
2018: Frontiers in Immunology
Fatemeh Askarian, John D Lapek, Mitesh Dongre, Chih-Ming Tsai, Monika Kumaraswamy, Armin Kousha, J Andrés Valderrama, Judith A Ludviksen, Jorunn P Cavanagh, Satoshi Uchiyama, Tom E Mollnes, David J Gonzalez, Sun N Wai, Victor Nizet, Mona Johannessen
Staphylococcus aureus produces membrane-derived vesicles (MVs), which share functional properties to outer membrane vesicles. Atomic force microscopy revealed that S. aureus -derived MVs are associated with the bacterial surface or released into the surrounding environment depending on bacterial growth conditions. By using a comparative proteomic approach, a total of 131 and 617 proteins were identified in MVs isolated from S. aureus grown in Luria-Bertani and brain-heart infusion broth, respectively. Purified S...
2018: Frontiers in Microbiology
Peng Zhang, Henry Kuang, Yanlin He, Sharon O Idiga, Siming Li, Zhimin Chen, Zhao Yang, Xing Cai, Kezhong Zhang, Matthew J Potthoff, Yong Xu, Jiandie D Lin
Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat-enriched secreted factor NRG4 protects mice from high-fat diet-induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling...
March 8, 2018: JCI Insight
Ann J Hessell, Mariya B Shapiro, Rebecca Powell, Delphine C Malherbe, Sean P McBurney, Shilpi Pandey, Tracy Cheever, William F Sutton, Christoph Kahl, Byung Park, Susan Zolla-Pazner, Nancy L Haigwood
A high level of V1V2-specific IgG antibodies in vaccinees' sera was the only independent variable that correlated with a reduced risk of HIV acquisition in the RV144 clinical trial. In contrast, IgG avidity, antibody neutralization, and antibody-dependent cellular cytotoxicity each failed as independent correlates of infection. Extended analyses of RV144 samples demonstrated antiviral activity of V1V2-specific vaccine-induced antibodies. V2-specific antibodies have also been associated with protection from SIV, and the V2i-specific subset of human monoclonal antibodies (mAbs), while poor neutralizers, mediate Fc-dependent antiviral functions in vitro The objective of this study was to determine the protective efficacy of a V2i-specific human mAb 830A against mucosal SHIV challenge...
March 7, 2018: Journal of Virology
Adrián Lázaro-Frías, Sergio Gómez-Medina, Lucas Sánchez-Sampedro, Karl Ljungberg, Mart Ustav, Peter Liljeström, César Muñoz-Fontela, Mariano Esteban, Juan García-Arriaza
Zaire and Sudan ebolavirus species cause a severe disease in humans and non-human primates (NHPs) characterized by high mortality rate. There are no licensed therapies or vaccines against Ebola virus disease (EVD), and the recent 2013-2016 outbreak in West Africa highlighted the need of EVD-specific medical countermeasures. Here, we have generated and characterized head-to-head the immunogenicity and efficacy of five vaccine candidates against Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA), expressing either the virus glycoprotein (GP) or GP together with the virus protein 40 (VP40) forming virus-like particles (VLPs)...
March 7, 2018: Journal of Virology
Pedro Henrique Ferreira Marçal, Lúcia Alves de Oliveira Fraga, Ana Márcia Menezes de Mattos, Laura Menegati, Angélica da Conceição Oliveira Coelho, Roberta Olmo Pinheiro, Euzenir Nunes Sarno, Malcolm S Duthie, Henrique Couto Teixeira
BACKGROUND Leprosy remains a health problem in many countries, with difficulties in diagnosis resulting in delayed treatment and more severe disabilities. Antibodies against several Mycobacterium leprae antigens have, however, shown value as diagnostic and/or prognostic markers. OBJECTIVES The objective of this study was to evaluate serum immunoglobulin (Ig) IgM and IgG subclass reactivity against three M. leprae specific antigens: NDO-HSA, a conjugate formed by natural octyl disaccharide bound to human serum albumin; LID-1, the fusion protein product of the ml0405 and ml2331 genes; and NDO-LID, a combination of LID-1 and NDO...
2018: Memórias do Instituto Oswaldo Cruz
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