DOCSLIB.ORG

Oligodeoxynucleotide Dendritic Cells to the TLR9 Agonist Cpg Distinct

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Oligodeoxynucleotide Dendritic Cells to the TLR9 Agonist Cpg Distinct Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide This information is current as Li Chen, Meenakshi Arora, Manohar Yarlagadda, Timothy of September 24, 2021. B. Oriss, Nandini Krishnamoorthy, Anuradha Ray and Prabir Ray J Immunol 2006; 177:2373-2383; ; doi: 10.4049/jimmunol.177.4.2373 http://www.jimmunol.org/content/177/4/2373 Downloaded from References This article cites 62 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/177/4/2373.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide1 Li Chen,* Meenakshi Arora,* Manohar Yarlagadda,* Timothy B. Oriss,* Nandini Krishnamoorthy,* Anuradha Ray,*† and Prabir Ray2*† Dendritic cells (DCs) sense various components of invading pathogens via pattern recognition receptors such as TLRs. CpG oligodeoxynucleotides (ODNs), which mimic bacterial DNA, inhibit allergic airways disease and promote responses in the spleen to bacterial components. Because many TLR agonists are currently being tested for potential therapeutic effects, it is important to characterize the expression and function of TLRs in different tissues. We show that both myeloid and plasmacytoid DCs in the spleen express TLR9, the receptor for CpG ODNs, but lung DCs show no detectable expression in either subset. TLR4 expression in contrast was detected on both lung and spleen DCs. LPS was superior to CpG ODN in increasing the allostimulatory potential of lung DCs and their expression of CD40. However, both agonists efficiently stimulated spleen DCs. CpG ODNs administered to Downloaded from mice efficiently inhibited Th2 cytokine production both in the lung draining lymph node and in the spleen. Surprisingly, inhibition of Th2 cytokine production was evident despite high levels of expression of GATA-3 and additional transcription factors that regulate Th2 responses. Although in the spleen CpG ODNs induced IL-6, a key cytokine induced via TLR9-MyD88 signaling, no IL-6 was detectable in lung LN cells. These studies show for the first time that lung DCs lack TLR9 expression, but, despite this deficiency, CpG ODNs induce potent inhibitory effects on Th2 cytokine production in the lung without inducing expression of the proinflammatory cytokine, IL-6, which has been linked to chronic diseases in the lung and the gut. The Journal of Immunology, http://www.jimmunol.org/ 2006, 177: 2373–2383. endritic cells (DCs)3 play an important role in Ag pre- tegic distribution, and their ability to capture and process Ag, and sentation in different tissues (1, 2), including the lung (3, present them to T cells in the LNs make DCs the key APCs in the D 4). Research since the late 1980s has shown an impor- lung and in other mucosal surfaces. tant role for DCs in pulmonary immune responses (3, 5–13). DCs Lung DCs are constantly exposed to a myriad of inhaled agents. are present in high density in the proximal airways and are well However, the lung maintains homeostasis in the face of constant positioned to capture Ags. Overall, pulmonary DCs are immature provocation by these multiple stimuli. Interestingly, although LPS by guest on September 24, 2021 in that they express low levels of costimulatory molecules (CD80, and CpG oligodeoxynucleotides (ODNs) are both bacterial com- CD86, and CD40). During inflammation, increased numbers of ponents, LPS induces severe inflammation in the lung precipitating DCs are rapidly recruited from bone marrow progenitors to the sepsis (20, 21), while CpG ODNs suppress allergic airway inflam- airway epithelium, where these immature DCs efficiently capture mation (22–25) and also growth of Mycobacterium tuberculosis in Ags due to their high phagocytic ability (6, 12, 14). Subsequent to the lungs (25). Like the lung, the spleen also encounters pathogens Ag capture, the DCs undergo maturation, which is influenced by being the principal filter unit for pathogens that enter the blood- the microenvironment, and the mature DCs traffic to local draining stream. Administration of CpG ODNs to mice has been shown to lymph nodes (LNs). The transition from immature to mature state cause transient splenomegaly (26), and CpG ODNs potentiate ef- is accompanied by the production of various cytokines and che- fects of TLR agonists in the spleen (27, 28). Bacterial CpG motifs mokines by the DCs that regulate their ability to interact with naive have been shown to promote chronic intestinal inflammation via T cells to direct T cell differentiation (1, 2, 6, 15–19). Their stra- secretion of proinflammatory cytokines such as IL-6 and IFN-␥ (29). CpG ODNs are increasingly being used in various clinical trials (30). Therefore, it is important to better understand the effects *Department of Medicine, Pulmonary, Allergy, and Critical Care Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and †Department of Immu- of CpG ODNs in different tissues and the expression characteris- nology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 tics of TLR9, which is the best-studied receptor for CpG ODNs. Received for publication November 17, 2005. Accepted for publication May Because little is known about TLR expression in lung DCs, which 26, 2006. are the key APCs in the lung, we investigated whether CpG ODNs The costs of publication of this article were defrayed in part by the payment of page exert similar or differential effects on DCs from the lung vs the charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. spleen, which serve distinct functions in the body. 1 This work was supported by Grants HL 60207 (to P.R.) and HL 77430 (to A.R.) We show that while LPS had similar effects on lung and spleen from the National Institutes of Health. DCs and the DCs in turn stimulated CD4ϩ T cells in a comparable 2 Address correspondence and reprint requests to Dr. Prabir Ray, Department of Med- fashion, CpG ODNs exerted differential effects on lung and spleen icine, Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh DCs both in in vitro assays as well as when administered to mice. School of Medicine, 3459 Fifth Avenue, MUH 628 NW, Pittsburgh, PA 15213. E- mail address: [email protected] Studies of the expression profile of the two TLRs at the two lo- 3 Abbreviations used in this paper: DC, dendritic cell; alum, aluminum hydroxide; cations showed that while TLR4 expression is comparable be- cRPMI, complete RPMI; CT, cholera toxin; GUS, ␤-glucuronidase; IDO, indoleam- tween lung and spleen DCs, only the latter express TLR9 with no ine 2,3-dioxygenese; i.n., intranasal; LN, lymph node; pDC, plasmacytoid DC; mDC, myeloid DC; ODN, oligodeoxynucleotide; TRIF, Toll/IL-1 receptor domain-contain- detectable expression in lung DCs. Despite the lack of TLR9 ex- ing adapter-inducing IFN-␤; wt, wild type. pression in lung DCs, CpG ODN administration caused potent Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 2374 DISTINCT RESPONSES OF LUNG AND SPLEEN DCs TO CpG ODN inhibition of allergen-induced Th2 cytokine production in both the Flow cytometry spleen and the lung LN. However, only in the spleen, production Cells were first incubated for 5 min with Fc block (10 ␮g/ml; BD Bio- of IL-6, a key cytokine downstream of TLR9 (31–33) and MyD88 sciences) to minimize nonspecific Ab binding and were then incubated (34), was noted. Interestingly, this inhibition of cytokine produc- with saturating concentrations of appropriate Abs for 5 min on ice in 2% tion was evident in the presence of high levels of expression of FBS/PBS, after which the cells were washed in the same buffer. Before GATA-3, which we and others (35, 36) previously demonstrated to be intracellular TLR9 staining, DCs were stained with dye-conjugated Abs against the cell surface molecules CD11c, MHC class II, and B220. The the master regulator of Th2 differentiation. With the recent identifi- cells were washed, fixed for 30 min using freshly prepared Fix/Perm so- cation of TLR9-independent mechanisms of CpG action (37, 38), our lution (eBioscience), and were washed in PBS and 1ϫ permeabilization data suggest that CpG ODNs can exert both TLR9-dependent (IL-6) buffer (eBioscience) successively to permeabilize the cells. The cells were and -independent effects to regulate immune responses. incubated with biotinylated mAb against murine TLR9 (clone 5G5) or with isotype control (mouse IgG2a), as described (41). Streptavidin-PerCP (BD Biosciences) was used for detection. TLR9 staining was also investigated Materials and Methods using another anti-TLR9 Ab IMG-431 (Imgenex). All samples were ana- Mice lyzed using a FACSCalibur flow cytometer and CellQuest software (BD Biosciences). Dead cells were excluded using forward and side light scatter Ϫ/Ϫ BALB/cByJ, CD40 mice (backcrossed to BALB/c background), and properties. Cell sorting was conducted using a FACSAria cell sorter and C57BL/6 male mice, obtained from The Jackson Laboratory, and DO11.10 FACS Diva software (BD Biosciences).
Load more

Recommended publications
  • United States Patent (10) Patent No.: US 7,935,351 B2 Klinman Et Al
    US007935351B2 (12) United States Patent (10) Patent No.: US 7,935,351 B2 Klinman et al. (45) Date of Patent: *May 3, 2011 (54) USE OF CPG OLIGODEOXYNUCLEOTIDES 35. A 3. 2. RS:udolph s et alal. TO INDUCE ANGOGENESIS 5,288,509 A 2f1994 Potman et al. 5.488,039 A 1, 1996 M tal. (75) Inventors: Dennis M. Klinman, Potomac, MD 5.492.899 A 2, 1996 NE al. (US); Mei Zheng, Augusta, GA (US); 5,585,479 A 12/1996 Hoke et al. Barry T. Rouse, Knoxville, TN (US) 5,602,1095,591,721 A 2/19971/1997 MasorAgrawal et etal. al. 5,612,060 A 3, 1997 A1 d (73) Assignees: The United States of America as 5,614,191 A 3, 1997 al represented by the Department of 5,650,156 A 7/1997 Grinstaffet al. Health and Human Services, 5,663,153 A 9, 1997 Hutcerson et al. Washington, DC (US); University of 3. A RE SEE, Tennessee Research Foundation, 5,700,590 A 12/1997 Masoretal Knoxville, TN (US) 5,712.256 A 1/1998 Kulkarni et al. 5,723,335 A 3, 1998 Hutcerson et al. (*) Notice: Subject to any disclaimer, the term of this 3. 2. A 38. El cal patent is extended or adjusted under 35 5.840,705 A 11/1998 Tsukuda U.S.C. 154(b) by 761 days. 5,849,719 A 12, 1998 Carson et al. This patent is Subject to a terminal dis- 33: A 23: SEE claimer. 5,922,766 A 7/1999 Acosta et al.
    [Show full text]
  • Human Naive B Cells Cells by Cpg Oligodeoxynucleotide-Primed T+
    Presentation of Soluble Antigens to CD8+ T Cells by CpG Oligodeoxynucleotide-Primed Human Naive B Cells This information is current as Wei Jiang, Michael M. Lederman, Clifford V. Harding and of September 27, 2021. Scott F. Sieg J Immunol 2011; 186:2080-2086; Prepublished online 14 January 2011; doi: 10.4049/jimmunol.1001869 http://www.jimmunol.org/content/186/4/2080 Downloaded from References This article cites 36 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/186/4/2080.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Presentation of Soluble Antigens to CD8+ T Cells by CpG Oligodeoxynucleotide-Primed Human Naive B Cells Wei Jiang,*,† Michael M. Lederman,*,† Clifford V. Harding,†,‡ and Scott F. Sieg*,† Naive B lymphocytes are generally thought to be poor APCs, and there is limited knowledge of their role in activation of CD8+ T cells.
    [Show full text]
  • Toll-Like Receptor 9 and 21 Have Different Ligand Recognition Profiles
    Toll-like receptor 9 and 21 have different ligand recognition profiles and cooperatively mediate activity of CpG-oligodeoxynucleotides in zebrafish Da-Wei Yeha,b,1, Yi-Ling Liua,1, Yin-Chiu Loc, Chiou-Hwa Yuhd, Guann-Yi Yuc, Jeng-Fan Loe, Yunping Luof, Rong Xiangg, and Tsung-Hsien Chuanga,h,2 aImmunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; bInstitute of Molecular Medicine, National Tsing-Hua University, HsinChu 30013, Taiwan; cNational Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 35053, Taiwan; dInstitute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 35053, Taiwan; eInstitute of Oral Biology, National Yang-Ming University, Taipei 11221, Taiwan; fDepartment of Immunology, School of Basic Medicine, Peking Union Medical College, Beijing 100005, People’s Republic of China; gSchool of Medicine, University of Nankai, Tianjin 300071, People’s Republic of China; and hProgram in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan Edited by Ken J. Ishii, National Institute of Biomedical Innovation, Ibaraki, Japan, and accepted by the Editorial Board October 29, 2013 (received for review March 21, 2013) CpG-oligodeoxynucleotides (CpG-ODNs) are potent immune stim- containing a GTCGTT motif. In contrast, the GTCGTT motif uli currently under investigation as antimicrobial agents for containing CpG-ODN generates stronger immune responses in different species. Toll-like receptor (TLR) 9 and TLR21 are the humans and various domestic animals (8, 9). cellular receptors of CpG-ODN in mammals and chickens, respec- Toll-like receptors (TLRs) are pattern recognition recep- tively. The avian genomes lack TLR9, whereas mammalian tors that play crucial roles in the initiation of host defense genomes lack TLR21.
    [Show full text]
  • Oligodeoxynucleotide in Murine Asthma Anti-Inflammatory Effects Of
    In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma This information is current as of September 23, 2021. Barun K. Choudhury, James S. Wild, Rafeul Alam, Dennis M. Klinman, Istvan Boldogh, Nilesh Dharajiya, William J. Mileski and Sanjiv Sur J Immunol 2002; 169:5955-5961; ; doi: 10.4049/jimmunol.169.10.5955 Downloaded from http://www.jimmunol.org/content/169/10/5955 References This article cites 37 articles, 21 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/169/10/5955.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 23, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma1 Barun K.
    [Show full text]
  • P020210615609549638679.Pdf
    The Journal of Immunology SCARB2/LIMP-2 Regulates IFN Production of Plasmacytoid Dendritic Cells by Mediating Endosomal Translocation of TLR9 and Nuclear Translocation of IRF7 Hao Guo,*,† Jialong Zhang,* Xuyuan Zhang,*,† Yanbing Wang,* Haisheng Yu,*,† Xiangyun Yin,*,† Jingyun Li,*,† Peishuang Du,* Joel Plumas,‡ Laurence Chaperot,‡ ,x,{ ,‖,# , Jianzhu Chen,* Lishan Su,* Yongjun Liu,* ** and Liguo Zhang* Downloaded from Scavenger receptor class B, member 2 (SCARB2) is essential for endosome biogenesis and reorganization and serves as a receptor for both b-glucocerebrosidase and enterovirus 71. However, little is known about its function in innate immune cells. In this study, we show that, among human peripheral blood cells, SCARB2 is most highly expressed in plasmacytoid dendritic cells (pDCs), and its expression is further upregulated by CpG oligodeoxynucleotide stimulation. Knockdown of SCARB2 in pDC cell line GEN2.2 dramatically reduces CpG-induced type I IFN production. Detailed studies reveal that SCARB2 localizes in late endosome/ http://www.jimmunol.org/ lysosome of pDCs, and knockdown of SCARB2 does not affect CpG oligodeoxynucleotide uptake but results in the retention of TLR9 in the endoplasmic reticulum and an impaired nuclear translocation of IFN regulatory factor 7. The IFN-I production by TLR7 ligand stimulation is also impaired by SCARB2 knockdown. However, SCARB2 is not essential for influenza virus or HSV-induced IFN-I production. These findings suggest that SCARB2 regulates TLR9-dependent IFN-I production of pDCs by mediating endosomal translocation of TLR9 and nuclear translocation of IFN regulatory factor 7. The Journal of Immunology, 2015, 194: 4737–4749. ysosomes are ubiquitous acid membrane-bound organelles which also includes scavenger receptor class B, member 1 involved in the degradation of molecules, complexes, and (SCARB1), and CD36 (5).
    [Show full text]
  • Screening of Novel Immunostimulatory Cpg Odns and Their Anti-Leukemic Effects As Immunoadjuvants of Tumor Vaccines in Murine Acute Lymphoblastic Leukemia
    519-529.qxd 20/12/2010 01:05 ÌÌ ™ÂÏ›‰·519 ONCOLOGY REPORTS 25: 519-529, 2011 519 Screening of novel immunostimulatory CpG ODNs and their anti-leukemic effects as immunoadjuvants of tumor vaccines in murine acute lymphoblastic leukemia JIN WANG, WANGGANG ZHANG, AILI HE, WANHONG ZHAO and XINGMEI CAO Department of Hematology, Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, P.R. China Received July 29, 2010; Accepted October 11, 2010 DOI: 10.3892/or.2010.1093 Abstract. Acute lymphoblastic leukemia (ALL) is a common Additional therapeutic strategies are required in order to malignant disease and a major cause of mortality due to further prolong remission duration and eradicate minimal recurrent disease. Immunotherapy is a promising strategy for residual disease, ideally with less toxicity than conventional eradicating minimal residual disease and thus preventing the chemotherapy. One of the these approaches is active immuno- relapse of leukemia. Apart from stem cell transplantation, therapy with novel vaccination regimens. We previously CpG oligodeoxynucleotides (ODNs) are excellent candidates launched a phase-I clinical trial and evaluated the efficacy for the immunotherapy of leukemia. However, the number of and toxicity of vaccination in patients with relapsed or usable CpG ODNs is limited. In this study, we tested a panel refractory acute leukemia, which proved to be a feasible, of CpG ODNs and obtained three CpG ODN sequences with safe, and capable way of eliciting anti-leukemic responses strong immunostimulatory activity by comparing their in vivo (1). capacity to activate lymphocytes. The data revealed that the As tumor cells are considered to be poorly immunogenic, flanking bases, the spacing of individual CpG motifs and poly- it is difficult to elicit an effective specific anti-tumor activity guanosine ends, contribute to the immunostimulatory activity from these cells alone.
    [Show full text]
  • Oligonucleotide-Ficoll Conjugate Nanoparticle Adjuvant for Enhanced Immunogenicity of Anthrax Protective Antigen † † † † † † Bob Milley,*, Radwan Kiwan, Gary S
    This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Article pubs.acs.org/bc Optimization, Production, and Characterization of a CpG- Oligonucleotide-Ficoll Conjugate Nanoparticle Adjuvant for Enhanced Immunogenicity of Anthrax Protective Antigen † † † † † † Bob Milley,*, Radwan Kiwan, Gary S. Ott, Carlo Calacsan, Melissa Kachura, John D. Campbell, ‡ † Holger Kanzler, and Robert L. Coffman † Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, United States ‡ MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland 20878, United States ABSTRACT: We have synthesized and characterized a novel phosphorothioate CpG oligodeoxynucleotide (CpG ODN)-Ficoll conjugated nanoparticulate adjuvant, termed DV230-Ficoll. This adjuvant was constructed from an amine-functionalized-Ficoll, a heterobifunctional linker (succinimidyl-[(N-maleimidopropionamido)- hexaethylene glycol] ester) and the CpG-ODN DV230. Herein, we describe the evaluation of the purity and reactivity of linkers of different lengths for CpG-ODN-Ficoll conjugation, optimization of linker coupling, and conjugation of thiol-functionalized CpG to maleimide- functionalized Ficoll and process scale-up. Physicochemical character- ization of independently produced lots of DV230-Ficoll reveal a bioconjugate with a particle size of approximately 50 nm and covalent attachment of more than 100 molecules of CpG per Ficoll. Solutions of purified DV230-Ficoll were stable for at least 12 months at frozen and refrigerated temperatures and stability was further enhanced in lyophilized form. Compared to nonconjugated monomeric DV230, the DV230-Ficoll conjugate demonstrated improved in vitro potency for induction of IFN-α from human peripheral blood mononuclear cells and induced higher titer neutralizing antibody responses against coadministered anthrax recombinant protective antigen in mice.
    [Show full text]
  • Oligodeoxynucleotide Dendritic Cells to the TLR9 Agonist Cpg Distinct
    Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide This information is current as Li Chen, Meenakshi Arora, Manohar Yarlagadda, Timothy of September 23, 2021. B. Oriss, Nandini Krishnamoorthy, Anuradha Ray and Prabir Ray J Immunol 2006; 177:2373-2383; ; doi: 10.4049/jimmunol.177.4.2373 http://www.jimmunol.org/content/177/4/2373 Downloaded from References This article cites 62 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/177/4/2373.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide1 Li Chen,* Meenakshi Arora,* Manohar Yarlagadda,* Timothy B. Oriss,* Nandini Krishnamoorthy,* Anuradha Ray,*† and Prabir Ray2*† Dendritic cells (DCs) sense various components of invading pathogens via pattern recognition receptors such as TLRs.
    [Show full text]
  • Toll-Like Receptors As Potential Therapeutic Targets for Multiple Diseases
    REVIEWS TOLL-LIKE RECEPTORS AS POTENTIAL THERAPEUTIC TARGETS FOR MULTIPLE DISEASES Claudia Zuany-Amorim, John Hastewell and Christoph Walker The family of Toll-like receptors (TLRs) is receiving considerable attention as potential regulators and controllers of the immune response through their ability to recognize pathogen-associated molecular patterns. The discovery that endogenous ligands, as well as microbial components, are recognized by TLRs, and that small-molecular-mass synthetic compounds activate TLRs, raised interest in these receptors as potential targets for the development of new therapies for multiple diseases. In this review, we discuss the current and future use of TLR agonists or antagonists in chronic inflammatory diseases and highlight potential problems that are associated with such approaches. 2 INNATE IMMUNITY The immune system has been divided traditionally into PAMPs . The first report of a mammalian TLR and its The early response of a host to an INNATE and ADAPTIVE component, each of which has involvement in host defence — TLR-4 as a receptor for infections by pathogens, such as different roles and functions in defending the organism LIPOPOLYSACCHARIDE (LPS)3 — was followed rapidly by the bacteria and viruses, before the against foreign agents, such as bacteria or viruses. The discovery that the human genome contains several antigen-specific, adaptive innate immune system has developed a series of con- TLRs — ten have been found so far, TLR-1–TLR-10. immune response is induced. served receptors, known as pattern-recognition recep- Members of the TLR family share characteristic extra- ADAPTIVE IMMUNITY tors (PRRs), that recognize specific pathogen-associated cellular and cytoplasmic domains.
    [Show full text]
  • Toll-Like Receptors and Their Potential Roles in Kidney Disease
    J Am Soc Nephrol 15: 854–867, 2004 Signaling Danger: Toll-Like Receptors and their Potential Roles in Kidney Disease HANS-JOACHIM ANDERS,* BERNHARD BANAS,† and DETLEF SCHLO¨ NDORFF* *Nephrological Center, Medizinische Poliklinik, Klinikum der Universität München-Junenstadt, Germany; and †Klinik u. Poliklinik f. Innere Medizin II, Universität Regensburg, Germany. Abstract. Toll-like receptors (TLR) are an emerging family of cells are among the non-immune cells that express TLR1, -2, receptors that recognize pathogen-associated molecular pat- -3, -4, and -6, suggesting that these TLR might contribute to terns and promote the activation of leukocytes and intrinsic the activation of immune responses in tubulointerstitial injury renal cells. Ligands of the TLR include exogenous microbial (e.g., bacterial pyelonephritis, sepsis, and transplant nephrop- components such as LPS (TLR4), lipoproteins and peptidogly- athy). In addition, TLR9 has been shown to be involved in cans (TLR1, -2, -6), viral RNA (TLR3), bacterial and viral antigen-induced immune complex glomerulonephritis and lu- unmethylated cytosin-guanosin dinucleotide (CpG)-DNA pus nephritis by regulating humoral and cellular immune re- (TLR9), and endogenous molecules including heat-shock pro- sponses. TLR are evolutionary conserved regulators of innnate teins and extracellular matrix molecules. Upon stimulation, and adaptive immune reponses. It is likely that TLR are in- TLR induce expression of inflammatory cytokines or costimu- volved in many if not all types of renal inflammation. Here the latory molecules via the MyD88-dependent and MyD88-inde- authors provide an overview on the biology of TLR, summa- pendent signaling pathways shared with the interleukin-1 re- rize the present data on their expression in the kidney, and ceptors.
    [Show full text]
  • Therapeutic Administration of a Synthetic Cpg Oligodeoxynucleotide Triggers Formation of Anti-Cpg Antibodies
    Published OnlineFirst June 27, 2012; DOI: 10.1158/0008-5472.CAN-12-0257 Cancer Priority Report Research Therapeutic Administration of a Synthetic CpG Oligodeoxynucleotide Triggers Formation of Anti-CpG Antibodies Julia Karbach1, Antje Neumann1, Claudia Wahle1, Kathrin Brand1, Sacha Gnjatic2, and Elke Jager€ 1 Abstract The synthetic oligodeoxynucleotide CpG 7909, which contains unmethylated cytosine/guanine (CpG) motifs, has potent immunostimulatory effects when coadministered with NY-ESO-1 peptides or recombinant NY-ESO-1 protein, resulting in an enhanced cellular and humoral immune response against the vaccine antigen. In this study, we report the development of anti-CpG-ODN antibodies in 21 of 37 patients who received CpG 7909 either alone or as a vaccine adjuvant. Specific anti-CpG immunoglobulin G (IgG) antibody titers ranged from 1:400 to 1:100,000. The anti-CpG antibodies cross-reacted with other synthetic CpG-ODNs but not with the DNA of mixed bacterial vaccine and were shown to be phosphorothioate backbone specific. Vaccine-related severe side effects observed in some patients were most likely not related to the development of anti-CpG antibodies. In addition, anti-CpG antibodies did not have negative effects on the vaccine immune response. These results show that anti- CpG antibodies develop in humans against short unmethylated CpG dinucleotide sequences after administration of CpG 7909. Our data therefore substantiate the potency of CpG 7909 to directly stimulate human B-cells and suggest that anti-CpG antibody monitoring should be a part of ongoing and planned clinical trials with CpG- ODNs. Cancer Res; 72(17); 4304–10. Ó2012 AACR. Introduction act on B-cell and monocyte activation.
    [Show full text]
  • Toll-Like Receptor 9 Agonists for Cancer Therapy
    Biomedicines 2014, 2, 211-228; doi:10.3390/biomedicines2030211 OPEN ACCESS biomedicines ISSN 2227-9059 www.mdpi.com/journal/biomedicines/ Review Toll-Like Receptor 9 Agonists for Cancer Therapy Davide Melisi 1,2,*, Melissa Frizziero 2, Anna Tamburrino 1, Marco Zanotto 1, Carmine Carbone 1, Geny Piro 3 and Giampaolo Tortora 2,3 1 Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 10, Piazzale L.A. Scuro, 37134 Verona, Italy; E-Mails: [email protected] (A.T.); [email protected] (M.Z.); [email protected] (C.C.) 2 Medical Oncology, Azienda Ospedaliera Universitaria Integrata, 10, Piazzale L.A. Scuro, 37134 Verona, Italy; E-Mails: [email protected] (M.F.); [email protected] (G.T.) 3 Laboratory of Oncology and Molecular Therapy, Department of Medicine, University of Verona, 10, Piazzale L.A. Scuro, 37134 Verona, Italy; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +39-45-812-8148; Fax: +39-45-802-7410. Received: 17 April 2014; in revised form: 24 July 2014 / Accepted: 28 July 2014 / Published: 4 August 2014 Abstract: The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs) have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC) and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses.
    [Show full text]