Publications by authors named "Mai Zhang"

17 Publications

  • Page 1 of 1

CRISPR/Cas12a-Assisted Ligation-Initiated Loop-Mediated Isothermal Amplification (CAL-LAMP) for Highly Specific Detection of microRNAs.

Anal Chem 2021 Jun 26;93(22):7942-7948. Epub 2021 May 26.

Beijing Key Laboratory for Bioengineering and Sensing Technology, School of Chemistry and Biological Engineering, University of Science and Technology Beijing, 30 Xueyuan Road, Haidian District, Beijing 100083, China.

Loop-mediated isothermal amplification (LAMP) has been increasingly applied in nucleic acid detection for clinical diagnosis and monitoring pathogenic microorganisms due to its isothermal nature and high sensitivity. However, the false-positive signal resulting from the non-specific amplification and the complexity of primer design are still technically challenging for wide applications. In this paper, we developed the CRISPR/Cas12a-assisted sequence-specific detection of LAMP products to eliminate the effect of non-specific amplification from primer dimers and spurious amplicons. Moreover, by designing a pair of target-specific stem-loop DNA probes, we greatly simplified the primer design for LAMP. The DNA probes could be ligated to form a double-stem-loop DNA template by the detected target, which initiated LAMP reaction and achieved one-nucleotide resolution due to the highly specific ligase reaction. Using microRNAs (miRNAs) as the model targets, the CRISPR/Cas12a-assisted ligation-initiated loop-mediated isothermal amplification (CAL-LAMP) can sensitively detect as low as 0.1 fM miRNAs with high specificity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.analchem.1c00686DOI Listing
June 2021

Comparative analyses of copy number variations between Bos taurus and Bos indicus.

BMC Genomics 2020 Oct 1;21(1):682. Epub 2020 Oct 1.

Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, 430070, China.

Background: Bos taurus and Bos indicus are two main sub-species of cattle. However, the differential copy number variations (CNVs) between them are not yet well studied.

Results: Based on the new high-quality cattle reference genome ARS-UCD1.2, we identified 13,234 non-redundant CNV regions (CNVRs) from 73 animals of 10 cattle breeds (4 Bos taurus and 6 Bos indicus), by integrating three detection strategies. While 6990 CNVRs (52.82%) were shared by Bos taurus and Bos indicus, large CNV differences were discovered between them and these differences could be used to successfully separate animals into two subspecies. We found that 2212 and 538 genes uniquely overlapped with either indicine-specific CNVRs and or taurine-specific CNVRs, respectively. Based on F, we detected 16 candidate lineage-differential CNV segments (top 0.1%) under selection, which overlapped with eight genes (CTNNA1, ENSBTAG00000004415, PKN2, BMPER, PDE1C, DNAJC18, MUSK, and PLCXD3). Moreover, we obtained 1.74 Mbp indicine-specific sequences, which could only be mapped on the Bos indicus reference genome UOA_Brahman_1. We found these sequences and their associated genes were related to heat resistance, lipid and ATP metabolic process, and muscle development under selection. We further analyzed and validated the top significant lineage-differential CNV. This CNV overlapped genes related to muscle cell differentiation, which might be generated from a retropseudogene of CTH but was deleted along Bos indicus lineage.

Conclusions: This study presents a genome wide CNV comparison between Bos taurus and Bos indicus. It supplied essential genome diversity information for understanding of adaptation and phenotype differences between the Bos taurus and Bos indicus populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12864-020-07097-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528262PMC
October 2020

Pseudoprogression and hyperprogression in lung cancer: a comprehensive review of literature.

J Cancer Res Clin Oncol 2020 Dec 28;146(12):3269-3279. Epub 2020 Aug 28.

Department of Thoracic Cancer, Cancer Center, West China Hospital, West China School of Clinical Medicine, Sichuan University, Chengdu, 610041, China.

Purpose: Immune checkpoint inhibitors are associated with clinical benefit in lung cancer. However, response patterns to immunotherapy, including pseudoprogression and hyperprogression, are difficult to diagnose, and their mechanisms remain unclear. This review aimed to describe two response patterns observed in lung cancer, namely pseudoprogression and hyperprogression, including their epidemiology, diagnostic characteristics, and plausible mechanisms.

Methods: We performed a comprehensive literature search in the PubMed database, using keywords "pseudoprogression", "hyperprogression", and "lung cancer", among others. The literature was examined for pseudoprogression and hyperprogression characteristics and plausible mechanisms.

Results: Pseudoprogression manifests in multiple forms; however, the immune system-related response criteria and biopsy data are helpful to make accurate diagnosis. Serological biomarkers, such as neutrophil-to-lymphocyte ratio (NLR) and circulating tumor DNA (ctDNA), might help distinguish pseudoprogression from true progression. The incidence of hyperprogression ranges within 5-19.2%, depending on definition. The unique response pattern of rapid progression is observed not only with immunotherapy, but also with other treatment regimens. Molecular mutations and amplifications may result in hyperprogression; however, the exact mechanism remains unclear.

Conclusion: Atypical response patterns, such as pseudoprogression and hyperprogression, are increasingly common in clinical practice. Immune-related response criteria can help diagnose pseudoprogression. Molecular mechanisms of hyperprogression remain unclear. Biomarkers for pseudoprogression and hyperprogression are required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-020-03360-1DOI Listing
December 2020

Construction of Functionally Compartmental Inorganic Photocatalyst-Enzyme System via Imitating Chloroplast for Efficient Photoreduction of CO to Formic Acid.

ACS Appl Mater Interfaces 2020 Aug 27;12(31):34795-34805. Epub 2020 Jul 27.

Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China.

Inorganic photocatalyst-enzyme systems are a prominent platform for the photoreduction of CO to value-added chemicals and fuels. However, poor electron transfer kinetics and enzyme deactivation by reactive oxygen species in the photoexcitation process severely limit catalytic efficiency. In chloroplast, enzymatic CO reduction and photoexcitation are compartmentalized by the thylakoid membrane, which protects enzymes from photodamage, while the tightly integrated photosystem facilitates electron transfer, promoting photocatalysis. By mimicking this strategy, we constructed a novel functionally compartmental inorganic photocatalyst-enzyme system for CO reduction to formate. To accomplish efficient electron transfer, we first synthesized an integrated artificial photosystem by conjugation of the cocatalyst (a Rh complex) onto thiophene-modified CN (TPE-CN), demonstrating an NADH regeneration rate of 9.33 μM·min, 2.33 times higher than that of a homogeneous counterpart. The enhanced NADH regeneration activity was caused by the tightly conjugated structure of the artificial photosystem, enabling rapid electron transfer from TPE-CN to the Rh complex. To protect formate dehydrogenase (FDH) from photoinduced deactivation, FDH was encapsulated into MAF-7, a metal-organic framework (MOF) material, to compartmentalize FDH from the toxic photoexcitation process, similar to the function of the thylakoid membrane. Moreover, the triazole linkers of MAF-7 possess both hydrophilicity and pH-buffering capacity providing a stable microenvironment for FDH, which could enhance enzyme stability in photosynthesis. The synergy between the enhanced electron transfer of TPE-CN for NADH cofactor regeneration and MOF-protection of the redox enzyme enables the construction of a functionally compartmental inorganic photocatalyst-enzyme association system, promoting CO photoconversion to formic acid with a yield of 16.75 mM after 9 h of illumination, 3.24 times greater than that of the homogeneous reaction counterpart.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.0c06684DOI Listing
August 2020

Visual Detection of Fusion Genes by Ligation-Triggered Isothermal Exponential Amplification: A Point-of-Care Testing Method for Highly Specific and Sensitive Quantitation of Fusion Genes with a Smartphone.

Anal Chem 2019 10 10;91(19):12428-12434. Epub 2019 Sep 10.

School of Chemistry and Biological Engineering , University of Science and Technology Beijing , 30 Xueyuan Road , Haidian District, Beijing 100083 , P. R. China.

Fusion genes, playing a causal role in human tumorigenesis and developments, are deemed as gold standard molecular biomarkers in cancer diagnosis, therapy, and prognosis. A rapid, robust, and sensitive method of detection of fusion genes for point-of-care (POC) diagnosis is urgently needed. Here, taking the advantages of the superior specificity of the ligation reaction and the highly amplified efficiency of isothermal exponential amplification with a pH indicator, we developed a colorimetric method for visual detection of fusion genes with high sensitivity and specificity by the naked eye. More importantly, we first found that fusion genes can be accurately quantified in a wide dynamic range (2 zmol to 2 fmol) by an open-source app with a smartphone-assisted RGB (red, green, and blue value) reading mode. The proposed method for Visual detection of Fusion genes by Ligation-triggered Isothermal Exponential Amplification is termed Vis-Fusion LIEXA. We have demonstrated that the Vis-Fusion LIEXA is a practical and reliable method for accurate quantitative detection of the fusion gene in a complex biological sample at zmol level in 40 min only with a smartphone, thereby providing a user-friendly and point-of-care testing (POCT) tool for molecular diagnostics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.analchem.9b03061DOI Listing
October 2019

Novel anti-Sialyl-Tn monoclonal antibodies and antibody-drug conjugates demonstrate tumor specificity and anti-tumor activity.

MAbs 2017 May/Jun;9(4):615-627. Epub 2017 Feb 22.

c Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology , Massachusetts General Hospital , Boston , MA , USA.

Targeted therapeutics that can differentiate between normal and malignant tumor cells represent the ideal standard for the development of a successful anti-cancer strategy. The Sialyl-Thomsen-nouveau antigen (STn or Sialyl-Tn, also known as CD175s) is rarely seen in normal adult tissues, but it is abundantly expressed in many types of human epithelial cancers. We have identified novel antibodies that specifically target with high affinity the STn glycan independent of its carrier protein, affording the potential to recognize a wider array of cancer-specific sialylated proteins. A panel of murine monoclonal anti-STn therapeutic antibodies were generated and their binding specificity and efficacy were characterized in vitro and in in vivo murine cancer models. A subset of these antibodies were conjugated to monomethyl auristatin E (MMAE) to generate antibody-drug conjugates (ADCs). These ADCs demonstrated in vitro efficacy in STn-expressing cell lines and significant tumor growth inhibition in STn-expressing tumor xenograft cancer models with no evidence of overt toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/19420862.2017.1290752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419082PMC
February 2018

The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis.

Ann Rheum Dis 2014 Mar 14;73(3):600-8. Epub 2013 Oct 14.

Department of Immunology, Janssen Research & Development, , San Diego, California, USA.

Objective: The histamine H4 receptor (H4R) has been shown to drive inflammatory responses in models of asthma, colitis and dermatitis, and in these models it appears to affect both innate and adaptive immune responses. In this study, we used both H4R-deficient mice and a specific H4R antagonist, JNJ 28307474, to investigate the involvement of the H4R in mouse arthritis models.

Methods: H4R-deficient mice and wild-type mice administered the H4R antagonist were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The impact on Th17 cells was assessed by restimulation of inguinal lymphocytes in the disease or immunisation models and with in vitro stimulation of whole blood.

Results: Both H4R-deficient mice and mice treated with the H4R antagonist exhibited reduced arthritis disease severity in both CAIA and CIA models. This was evident from the reduction in disease score and in joint histology. In the CIA model, treatment with the H4R antagonist reduced the number of interleukin (IL)-17 positive cells in the lymph node and the total production of IL-17. Th17 cell development in vivo was reduced in H4R-deficient mice or in mice treated with an H4R antagonist. Finally, treatment of both mouse and human blood with an H4R antagonist reduced the production of IL-17 when cells were stimulated in vitro.

Conclusions: These results implicate the H4R in disease progression in arthritis and in the production of IL-17 from Th17 cells. This work supports future clinical exploration of H4R antagonists for the treatment of rheumatoid arthritis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2013-203832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151522PMC
March 2014

Antagonism of the histamine H4 receptor reduces LPS-induced TNF production in vivo.

Inflamm Res 2013 Jun 27;62(6):599-607. Epub 2013 Mar 27.

Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Objective: Antagonism of the histamine H4 receptor (H4R) has been shown to be anti-inflammatory in a number of preclinical disease models, however the exact mechanisms behind this are still being uncovered. In vitro, the receptor interacts with TLR and impacts inflammatory mediator production from a number of different cell types. Here it is shown that this interaction also occurs in vivo.

Materials And Methods: Wild-type and H4R deficient BALB/c mice received an i.p. injection of LPS in PBS in conjunction with p.o. JNJ 7777120 or JNJ 28307474 (H4R antagonists). Two hours later blood was collected and TNF was measured.

Results: Two different H4R antagonists inhibited LPS-induced TNF production in mice and this production was also reduced in H4R-deficient mice. The TNF mRNA analysis showed that the major source of the cytokine was the liver and not blood, and that the H4R antagonist only reduced the expression levels in the liver. Depletion or inactivation of macrophages reduced the TNF levels and eliminated the H4R sensitivity. Treatment with an H4R antagonist also reduced LPS-induced liver injury and blocked LPS-enhanced lung inflammation in mice.

Conclusion: The data support an interaction between H4R and TLR activation in vivo that can drive inflammatory responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00011-013-0612-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654183PMC
June 2013

Production platforms for biotherapeutic glycoproteins. Occurrence, impact, and challenges of non-human sialylation.

Biotechnol Genet Eng Rev 2012 ;28:147-75

Sialix, Inc. 1396 Poinsettia Ave. Vista, CA 92081-8504, USA.

One of the fastest growing fields in the pharmaceutical industry is the market for therapeutic glycoproteins. Today, these molecules play a major role in the treatment of various diseases, and include several protein classes, i.e., clotting factors, hormones, cytokines, antisera, enzymes, enzyme inhibitors, Ig-Fc-Fusion proteins, and monoclonal antibodies. Optimal glycosylation is critical for therapeutic glycoproteins, as glycans can influence their yield, immunogenicity and efficacy, which impact the costs and success of such treatments. While several mammalian cell expression systems currently used can produce therapeutic glycoproteins that are mostly decorated with human-like glycans, they can differ from human glycans by presenting two structures at the terminal and therefore most exposed position. First, natural human N-glycans are lacking the terminal Gal 1-3Gal (alpha-Gal) modification; and second, they do not contain the non-human sialic acid N-glycolylneuraminic acid (Neu5Gc). All humans spontaneously express antibodies against both of these glycan structures, risking increased immunogenicity of biotherapeutics carrying such non-human glycan epitopes. However, in striking contrast to the alpha-Gal epitope, exogenous Neu5Gc can be metabolically incorporated into human cells and presented on expressed glycoproteins in several possible epitopes. Recent work has demonstrated that this non-human sialic acid is found in widely varying amounts on biotherapeutic glycoproteins approved for treatment of various medical conditions. Neu5Gc on glycans of these medical agents likely originates from the production process involving the non-human mammalian cell lines and/or the addition of animal-derived tissue culture supplements. Further studies are needed to fully understand the impact of Neu5Gc in biotherapeutic agents. Similar concerns apply to human cells prepared for allo- or auto-transplantation, that have been grown in animal-derived tissue culture supplements.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5661/bger-28-147DOI Listing
June 2012

The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation.

J Invest Dermatol 2010 Apr 12;130(4):1023-33. Epub 2009 Nov 12.

Department of Immunology, Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121, USA.

The role of histamine H(4) receptor (H(4)R) was investigated in a T-helper type 2 (Th2)-cell-mediated mouse skin inflammation model that mimics several of the features of atopic dermatitis. Treatment with two specific H(4)R antagonists before challenge with FITC led to a significant reduction in ear edema, inflammation, mast cell, and eosinophil infiltration. This was accompanied by a reduction in the levels of several cytokines and chemokines in the ear tissue. Upon ex vivo antigen stimulation of lymph nodes, H(4)R antagonism reduced lymphocyte proliferation and IL-4, IL-5, and IL-17 levels. One explanation for this finding is that lymph nodes from animals dosed with the H(4)R antagonist, JNJ 7777120, contained a lower number of FITC-positive dendritic cells. The effect of H(4)R antagonism on dendritic cell migration in vivo may be an indirect result of the reduction in tissue cytokines and chemokines or a direct effect on chemotaxis. In addition to anti-inflammatory effects, JNJ 7777120 also significantly inhibited the pruritus shown in the model. Therefore, the dual effects of H(4)R antagonists on pruritus and Th2-cell-mediated inflammation point to their therapeutic potential for the treatment of Th2-mediated skin disorders, including atopic dermatitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/jid.2009.358DOI Listing
April 2010

Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling.

J Immunol 2009 Oct 25;183(8):5333-41. Epub 2009 Sep 25.

Department of Medicine, University of California San Diego, San Diego, CA 92093, USA.

Siglec-F is a sialic acid-binding Ig superfamily receptor that is highly expressed on eosinophils. We have investigated whether administration of an anti-Siglec-F Ab to OVA-challenged wild-type mice would reduce levels of eosinophilic inflammation and levels of airway remodeling. Mice sensitized to OVA and challenged repetitively with OVA for 1 mo who were administered an anti-Siglec-F Ab had significantly reduced levels of peribronchial eosinophilic inflammation and significantly reduced levels of subepithelial fibrosis as assessed by either trichrome staining or lung collagen levels. The anti-Siglec-F Ab reduced the number of bone marrow, blood, and tissue eosinophils, suggesting that the anti-Siglec-F Ab was reducing the production of eosinophils. Administration of a F(ab')(2) fragment of an anti-Siglec-F Ab also significantly reduced levels of eosinophilic inflammation in the lung and blood. FACS analysis demonstrated increased numbers of apoptotic cells (annexin V(+)/CCR3(+) bronchoalveolar lavage and bone marrow cells) in anti-Siglec-F Ab-treated mice challenged with OVA. The anti-Siglec-F Ab significantly reduced the number of peribronchial major basic protein(+)/TGF-beta(+) cells, suggesting that reduced levels of eosinophil-derived TGF-beta in anti-Siglec-F Ab-treated mice contributed to reduced levels of peribronchial fibrosis. Administration of the anti-Siglec-F Ab modestly reduced levels of periodic acid-Schiff-positive mucus cells and the thickness of the smooth muscle layer. Overall, these studies suggest that administration of an anti-Siglec-F Ab can significantly reduce levels of allergen-induced eosinophilic airway inflammation and features of airway remodeling, in particular subepithelial fibrosis, by reducing the production of eosinophils and increasing the number of apoptotic eosinophils in lung and bone marrow.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.0801421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788790PMC
October 2009

Anti-Siglec-F antibody inhibits oral egg allergen induced intestinal eosinophilic inflammation in a mouse model.

Clin Immunol 2009 Apr 8;131(1):157-69. Epub 2009 Jan 8.

Department of Medicine, University of California San Diego, San Diego, CA, USA.

Siglec-F is a sialic acid binding immunoglobulin-superfamily receptor that is highly expressed on eosinophils. We have used a mouse model of oral egg ovalbumin (OVA)-induced eosinophilic inflammation of the gastro-intestinal mucosa associated with diarrhea and weight loss to determine whether administering an anti-Siglec-F antibody would reduce levels of intestinal mucosal eosinophilic inflammation. Mice administered the anti-Siglec-F antibody had significantly lower levels of intestinal eosinophilic inflammation, and this was associated with reduced intestinal permeability changes, normalization of intestinal villous crypt height, and restoration of weight gain. The reduced numbers of intestinal eosinophils in anti-Siglec-F antibody treated mice was associated with significantly reduced numbers of bone marrow and peripheral blood eosinophils, but was not associated with significant changes in the numbers of proliferating or apoptotic jejunal eosinophils. In addition, the anti-Siglec-F Ab reduced Th2 cytokines and IgE levels. Overall, these studies demonstrate that administration of an anti-Siglec-F antibody significantly reduces levels of eosinophilic inflammation in the intestinal mucosa and that this was associated with reduced intestinal permeability changes, normalization of intestinal villous crypt height, and restoration of weight gain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clim.2008.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683248PMC
April 2009

Cloning and pharmacological characterization of the dog histamine H4 receptor.

Eur J Pharmacol 2008 Sep 2;592(1-3):26-32. Epub 2008 Jul 2.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.

The histamine H4 receptor has been shown to have a role in chemotaxis and mediator release in various types of immune cells and has been implicated in mediating inflammation in vivo. Previous work has shown that there were differences in the histamine H4 receptor sequence of different species and these translated into changes in the pharmacology of the receptors. To help further understand the nature of these differences, we have cloned and expressed the histamine H4 receptor of dog (Canis familiaris). The dog histamine H4 receptor has a 61-71% homology with the receptors from other species, with a 71% homology to the human receptor. The affinity for histamine at the dog histamine H4 receptor is 18 nM and is 3-fold lower than the human ortholog. A number of previously described histamine H4 receptor ligands were tested for affinity at the dog histamine H4 receptor and histamine showed the highest affinity of the ligands tested. In addition, the histamine H4 receptor selective antagonist, JNJ 7777120, had a Ki value of 50 nM and acts as an antagonist at the dog receptor. In general, agonists of the human histamine H4 receptor were also agonists of the dog receptor albeit with different efficacy levels. The cloning and in vitro pharmacological characterization of the dog histamine H4 receptor provide useful information for future studies using dog models as well as in understanding the ligand-receptor interactions of the receptor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2008.06.095DOI Listing
September 2008

The histamine H(4) receptor: a novel modulator of inflammatory and immune disorders.

Pharmacol Ther 2007 Mar 28;113(3):594-606. Epub 2006 Dec 28.

Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

All 4 known histamine receptors (H(1)R, H(2)R, H(3)R and H(4)R) have been used or proposed as therapeutic targets for varied diseases. This article reviews the recent progress in understanding the function of the recently described histamine receptor H(4)R in a variety of immune responses and the potential therapeutic value of H(4)R antagonists. The H(4)R is expressed primarily on cells involved in inflammation and immune response. It has effects on chemotaxis, as well as cytokine and chemokine production of mast cells, eosinophils, dendritic cells, and T cells. H(4)R antagonists, JNJ 7777120 and JNJ 10191584 (also known as VUF 6002) have been developed with excellent affinity and selectivity towards human and rodent H(4)R. These antagonists also demonstrate efficacy as anti-inflammatory agents in vivo. H(4)R antagonists have shown promising activity in down-regulating immune responses in a range of animal disease models including acute inflammation, hapten-mediated colitis, and allergic airway inflammation. Due to its distribution on immune cells and its proven role in inflammatory functions, the H(4)R appears to be a therapeutic target for the treatment of a variety of immune disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pharmthera.2006.11.008DOI Listing
March 2007

Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse eosinophils.

Blood 2007 May 1;109(10):4280-7. Epub 2007 Feb 1.

Glycobiology Research and Training Center, Departments of Medicine and Cellular & Molecular Medicine, and Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093-0687, USA.

CD33-related Siglecs (CD33rSiglecs) are a family of sialic acid-recognizing lectins on immune cells whose biologic functions are unknown. We studied in vivo functions of Siglec-F, the CD33rSiglec expressed on mouse eosinophils, which are prominent in allergic processes. Induction of allergic lung inflammation in mice caused up-regulation of Siglec-F on blood and bone marrow eosinophils, accompanied by newly induced expression on some CD4(+) cells, as well as quantitative up-regulation of endogenous Siglec-F ligands in the lung tissue and airways. Taken together with the tyrosine-based inhibitory motif in the cytosolic tail of Siglec-F, the data suggested a negative feedback loop, controlling allergic responses of eosinophils and helper T cells, via Siglec-F and Siglec-F ligands. To pursue this hypothesis, we created Siglec-F-null mice. Allergen-challenged null mice showed increased lung eosinophil infiltration, enhanced bone marrow and blood eosinophilia, delayed resolution of lung eosinophilia, and reduced peribronchial-cell apoptosis. Anti-Siglec-F antibody cross-linking also enhanced eosinophil apoptosis in vitro. These data support the proposed negative feedback role for Siglec-F, represent the first in vivo demonstration of biologic functions for any CD33rSiglec, and predict a role for human Siglec-8 (the isofunctional paralog of mouse Siglec-F) in regulating the pathogenesis of human eosinophil-mediated disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2006-08-039255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1885492PMC
May 2007

The histamine H4 receptor in autoimmune disease.

Expert Opin Investig Drugs 2006 Nov;15(11):1443-52

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Histamine exerts its actions through four known receptors. The recently cloned histamine receptor, H4R, has been shown to have a role in chemotaxis and mediator release in various types of immune cells including mast cells, eosinophils, dendritic cells and T cells. H4R antagonists have been shown to have anti-inflammatory properties and efficacy in a number of disease models, such as those for asthma and colitis in vivo. Recently, H4R antagonists have been developed with high receptor affinity and specificity, which make them good tools for further characterisation of the receptor in animal models and, eventually, in humans. Histamine and the cells that produce it, such as mast cells and basophils, have long been thought to be involved in allergic conditions but there has recently been recognition that they may also play a role in various autoimmune diseases. Given this and the fact that the H4R has function in mast cells, dendritic cells and T cells, antagonists for the receptor may be useful in treating autoimmune diseases in addition to allergy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1517/13543784.15.11.1443DOI Listing
November 2006

Cell surface sialic acids do not affect primary CD22 interactions with CD45 and surface IgM nor the rate of constitutive CD22 endocytosis.

Glycobiology 2004 Nov 7;14(11):939-49. Epub 2004 Jul 7.

Glycobiology Research and Training Center, Departments of Medicine and Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0687, USA.

CD22/Siglec-2 is a B cell-specific molecule modulating surface IgM (sIgM) signaling via cytosolic tyrosine-based motifs. CD22 recognizes alpha2-6-linked sialic acids (Sias) via an amino-terminal Ig-like domain. This Sia-binding site is typically masked by unknown sialylated ligands on the same cell surface, an interaction required for optimal signaling function. We studied the effect of cell surface Sias on specific interactions of CD22 with other molecules and on its turnover via endocytosis. A novel approach for simultaneous biotinylation and cross-linking showed that CD22 associates with CD45 and sIgM at much higher levels than reported in prior studies, possibly involving cell surface multimers of CD22. Sia removal or mutation of a CD22 arginine residue required for Sia recognition did not affect these associations even in human:mouse heterologous systems, indicating that they are primarily determined by evolutionarily conserved protein-protein interactions. Thus masking of the Sia-binding site of CD22 involves many cell surface sialoglycoproteins, without requiring specific ligand(s) and/or is mediated by secondary interactions with Sias on CD45 and sIgM. Abrogating Sia interactions also does not affect constitutive CD22 endocytosis. Sia removal does enhance the much faster rate of anti-CD22 antibody-triggered endocytosis, as well as killing by an anti-CD22 immunotoxin. In contrast to the unstimulated state, sIgM cross-linking inhibits both antibody-induced endocytosis and immunotoxin killing. Thus the signal- modulating activity of CD22 Sia recognition cannot be explained by mediation of primary interactions with specific molecules, nor by effects on constitutive endocytosis. The effects on antibody-mediated endocytosis could be of relevance to immunotoxin treatment of lymphomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/glycob/cwh126DOI Listing
November 2004