PDF icon Download PDF
Aktuelle Dermatologie 2003; 29(10): 415-418
DOI: 10.1055/s-2003-43492
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Chemokinrezeptor-Antagonisten bei atopischen Erkrankungen

Chemokine Receptor Antagonists in Allergic DiseasesJ.  Elsner 1, 2 , U.  Forssmann2
  • 1Klinik und Poliklinik für Dermatologie und Venerologie der Medizinischen Hochschule Hannover
  • 2IPF PharmaCeuticals GmbH, An-Institut der Medizinischen Hochschule Hannover
Further Information

Publication History

Publication Date:
07 November 2003 (online)

Also available ateRef
  Permissions and Reprints
Preview

Zusammenfassung

Die Inzidenz allergischer Erkrankungen nimmt in den westlichen Industrieländern stetig zu. Hieraus resultieren für die Therapie sehr hohe Kosten (USA jährlich ca. 18 Milliarden Dollar). Aus diesem Grund ist die Forschung darauf ausgerichtet, neue Medikamente zur Therapie allergischer Erkrankungen zu finden. In diesem Übersichtsartikel stellen wir einen neuen Therapieansatz vor: Die Chemokinrezeptor-Antagonisten bei atopischen Erkrankungen.

Abstract

The incidence of allergic diseases increases in the western industrial countries costing the health care system $ 18 billion (USA) annually. Therefore, institutional and industrial research focus on new concepts to find therapies preventing allergies or stopping the symptoms. Herein, we postulate a new concept in the treatment of allergies: Chemokine receptor antagonists for atopic diseases.

Literatur

  • 1 Elsner J, Forssmann U. Another renaissance of eosinophils in allergic diseases.  ACI International. 2002;  14 151-155
    PubMedSearch in Google Scholar
  • 2 Loetscher P, Clark-Lewis I. Agonistic and antagonistic activities of chemokines.  J Leukoc Biol. 2001;  69 881-884
    PubMedSearch in Google Scholar
  • 3 Ponath P D, Qin S, Post T W, Wang J, Wu L, Gerard N P, Newman W, Gerard C, Mackay C R. Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils.  J Exp Med. 1996;  183 2437-2448
    CrossrefPubMedSearch in Google Scholar
  • 4 Uguccioni M, Mackay C R, Ochensberger B, Loetscher P, Rhis S, LaRosa G J, Rao P, Ponath P D, Baggiolini M, Dahinden C A. High expression of the chemokine receptor CCR3 in human blood basophils. Role in activation by eotaxin, mcp-4, and other chemokines.  J Clin Invest. 1997;  100 1137-1143
    PubMedSearch in Google Scholar
  • 5 Ochi H, Hirani W M, Yuan Q, Friend D S, Austen K F, Boyce J A. T helper cell type 2 cytokine-mediated comitogenic responses and CCR3 expression during differentiation of human mast cells in vitro.  J Exp Med. 1999;  190 267-280
    CrossrefPubMedSearch in Google Scholar
  • 6 Sallusto F, Mackay C R, Lanzavecchia A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells.  Science. 1997;  277 2005-2007
    CrossrefPubMedSearch in Google Scholar
  • 7 Humbles A A, Lu B, Friend D S, Okinaga S, Lora J, Al Garawi A, Martin T R, Gerard N P, Gerard C. The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness.  Proc Natl Acad Sci USA. 2002;  99 1479-1484
    PubMedSearch in Google Scholar
  • 8 Ma W, Bryce P J, Humbles A A, Laouini D, Yalcindag A, Alenius H, Friend D S, Oettgen H C, Gerard C, Geha R S. CCR3 is essential for skin eosinophilia and airway hyperresponsiveness in a murine model of allergic skin inflammation.  J Clin Invest. 2002;  109 621-628
    CrossrefPubMedSearch in Google Scholar
  • 9 Owen C. Chemokine receptors in airway disease: which receptors to target?.  Pulm Pharmacol Ther. 2001;  14 193-202
    PubMedSearch in Google Scholar
  • 10 Bertrand C P, Ponath P D. CCR3 blockade as a new therapy for asthma.  Expert Opin Investig Drugs. 2000;  9 43-52
    CrossrefPubMedSearch in Google Scholar
  • 11 Gong J H, Clark-Lewis I. Antagonists of monocyte chemoattractant protein 1 identified by modification of functionally critical NH2-terminall residues.  J Exp Med. 1995;  181 631-640
    CrossrefPubMedSearch in Google Scholar
  • 12 Weber M, Uguccioni M, Baggiolini M, Clark Lewis I, Dahinden C A. Deletion of the NH2-terminal residue converts monocyte chemotactic protein 1 from an activator of basophil mediator release to an eosinophil chemoattractant.  J Exp Med. 1996;  183 681-685
    CrossrefPubMedSearch in Google Scholar
  • 13 Wells T NC, Power C A, Lusti-Narasimhan M, Hoogewerf A J, Cooke R M, Chung C, Peitsch M C, Proudfoot A EI. Selectivity and antagonism of chemokine receptors.  J Leukoc Biol. 1996;  59 53-60
    PubMedSearch in Google Scholar
  • 14 Baggiolini M, Moser B. Blocking chemokine receptors.  J Exp Med. 1997;  186 1189-1191
    CrossrefPubMedSearch in Google Scholar
  • 15 Proudfoot A E, Power C A, Hoogewerf A J, Montjovent M O, Borlat F, Offord R E, Wells T N. Extension of recombinant human RANTES by the retention of the initiating methionine produces a potent antagonist.  J Biol Chem. 1996;  271 2599-2603
    CrossrefPubMedSearch in Google Scholar
  • 16 Teixeira M M, Wells T N, Lukacs N W, Proudfoot A E, Kunkel S L, Williams T J, Hellewell P G. Chemokine-induced eosinophil recruitment. Evidence of a role for endogenous eotaxin in an in vivo allergy model in mouse skin.  J Clin Invest. 1997;  100 1657-1666
    PubMedSearch in Google Scholar
  • 17 Simmons G, Clapham P R, Picard L, Offord R E, Rosenkilde M M, Schwartz T W, Buser R, Wells T NC, Proudfoot A E. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist.  Science. 1997;  276 276-279
    CrossrefPubMedSearch in Google Scholar
  • 18 Mack M, Luckow B, Nelson P J, Cihak J, Simmons G, Clapham P R, Signoret N, Marsh M, Stangassinger M, Borlat F, Wells T NC, Schlondorff D, Proudfoot A EI. Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: A novel inhibitory mechanism of HIV infectivity.  J Exp Med. 1998;  187 1215-1224
    CrossrefPubMedSearch in Google Scholar
  • 19 Struyf S, De Meester I, Scharpe S, Lenaerts J P, Menten P, Wang J M, Proost P, van Damme J. Natural truncation of RANTES abolishes signaling through the CC chemokine receptors CCR1 and CCR3, impairs its chemotactic potency and generates a CC chemokine inhibitor.  Eur J Immunol. 1998;  28 1262-1271
    PubMedSearch in Google Scholar
  • 20 Proost P, Struyf S, Couvreur M, Lenaerts J P, Conings R, Menten P, Verhaert P, Wuyts A, van Damme J. Posttranslational modifications affect the activity of the human monocyte chemotactic proteins MCP-1 and MCP-2: identification of MCP- 2(6 - 76) as a natural chemokine inhibitor.  J Immunol. 1998;  160 4034-4041
    PubMedSearch in Google Scholar
  • 21 Oravecz T, Pall M, Roderiquez G, Gorrell M D, Ditto M, Nguyen N Y, Boykins R, Unsworth E, Norcross M A. Regulation of the receptor specificity and function of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted) by dipeptidyl peptidase IV (CD26)- mediated cleavage.  J Exp Med. 1997;  186 1865-1872
    CrossrefPubMedSearch in Google Scholar
  • 22 Struyf S, Proost P, Schols D, De Clercq E, Opdenakker G, Lenaerts J P, Detheux M, Parmentier M, De M, Scharpe I S, Van Damme J. CD26/dipeptidyl-peptidase IV down-regulates the eosinophil chemotactic potency, but not the anti-HIV activity of human eotaxin by affecting its interaction with CC chemokine receptor 3.  J Immunol. 1999;  162 4903-4909
    PubMedSearch in Google Scholar
  • 23 Proost P, De Meester I, Schols D, Struyf S, Lambeir A M, Wuyts A, Opdenakker G, DeClercq E, Scharpe S, Van Damme J. Amino-terminal truncation of chemokines by CD26/dipeptidyl-peptidase IV. Conversion of RANTES into a potent inhibitor of monocyte chemotaxis and HIV-1-infection.  J Biol Chem. 1998;  273 7222-7227
    CrossrefPubMedSearch in Google Scholar
  • 24 Detheux M, Standker L, Vakili J, Munch J, Forssmann U, Adermann K, Pohlmann S, Vassart G, Kirchhoff F, Parmentier M, Forssmann W G. Natural proteolytic processing of hemofiltrate CC chemokine 1 generates a potent CC chemokine receptor (CCR)1 and CCR5 agonist with anti-HIV properties.  J Exp Med. 2000;  192 1501-1508
    CrossrefPubMedSearch in Google Scholar
  • 25 Schulz-Knappe P, Magert H J, Dewald B, Meyer M, Cetin Y, Kubbies M, Tomeczkowski J, Kirchhoff K, Raida M, Adermann K, Kist A, Reinecke M, Sillard R, Pardigol A, Uguccioni M, Baggiolini M, Forssmann W G. HCC-1, a novel chemokine from human plasma.  J Exp Med. 1996;  183 295-299
    CrossrefPubMedSearch in Google Scholar
  • 26 Elsner J, Petering H, Hochstetter R, Kimmig D, Wells T N, Kapp A, Proudfoot A E. The CC chemokine antagonist Met-RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3.  Eur J Immunol. 1997;  27 2892-2898
    PubMedSearch in Google Scholar
  • 27 Elsner J, Mack M, Bruhl H, Dulkys Y, Kimmig D, Simmons G, Clapham P R, Schlondorff D, Kapp A, Wells T N, Proudfoot A E. Differential activation of CC chemokine receptors by AOP-RANTES.  J Biol Chem. 2000;  275 7787-7794
    CrossrefPubMedSearch in Google Scholar
  • 28 Nibbs R J, Salcedo T W, Campbell J D, Yao X T, Li Y, Nardelli B, Olsen H S, Morris T S, Proudfoot A E, Patel V P, Graham G J. C-C chemokine receptor 3 antagonism by the beta-chemokine macrophage inflammatory protein 4, a property strongly enhanced by an amino-terminal alanine-methionine swap.  J Immunol. 2000;  164 1488-1497
    PubMedSearch in Google Scholar
  • 29 Loetscher P, Pellegrino A, Gong J H, Mattioli I, Loetscher M, Bardi G, Baggiolini M, Clark-Lewis I. The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural antagonists for CCR3.  J Biol Chem. 2001;  276 2986-2991
    CrossrefPubMedSearch in Google Scholar
  • 30 Horuk R, Ng H P. Chemokine receptor antagonists.  Med Res Rev. 2000;  20 155-168
    CrossrefPubMedSearch in Google Scholar
  • 31 Schwarz M K, Wells T N. New therapeutics that modulate chemokine networks.  Nat Rev Drug Discov. 2002;  1 347-358
    CrossrefPubMedSearch in Google Scholar
  • 32 Baba M, Nishimura O, Kanzaki N, Okamoto M, Sawada H, Iizawa Y, Shiraishi M, Aramaki Y, Okonogi K, Ogawa Y, Meguro K, Fujino M. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity.  Proc Natl Acad Sci USA. 1999;  96 5698-5703
    CrossrefPubMedSearch in Google Scholar
  • 33 Shiraishi M, Aramaki Y, Seto M, Imoto H, Nishikawa Y, Kanzaki N, Okamoto M, Sawada H, Nishimura O, Baba M, Fujino M. Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety.  J Med Chem. 2000;  43 2049-2063
    CrossrefPubMedSearch in Google Scholar
  • 34 Arakaki R, Tamamura H, Premanathan M, Kanbara K, Ramanan S, Mochizuki K, Baba M, Fujii N, Nakashima H. T134, a small-molecule CXCR4 inhibitor, has no cross-drug resistance with AMD3100, a CXCR4 antagonist with a different structure.  J Virol. 1999;  73 1719-1723
    PubMedSearch in Google Scholar
  • 35 Hesselgesser J, Ng H P, Liang M, Zheng W, May K, Bauman J G, Monahan S, Islam I, Wei G P, Ghannam A, Taub D D, Rosser M, Snider R M, Morrissey M M, Perez H D, Horuk R. Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor.  J Biol Chem. 1998;  273 15 687-15 692
    PubMedSearch in Google Scholar
  • 36 Liang M, Rosser M, Ng H P, May K, Bauman J G, Islam I, Ghannam A, Kretschmer P J, Pu H, Dunning L, Snider R M, Morrissey M M, Hesselgesser J, Perez H D, Horuk R. Species selectivity of a small molecule antagonist for the CCR1 chemokine receptor.  Eur J Pharmacol.. 2000;  389 41-49
    CrossrefPubMedSearch in Google Scholar
  • 37 White J R, Lee J M, Dede K, Imburgia C S, Jurewicz A J, Chan G, Fornwald J A, Dhanak D. Christmann LT, Darcy MG, Widdowson KL, Foley JJ, Schmidt DB, Sarau HM. Identification of potent, selective non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4-induced eosinophil migration.  J Biol Chem. 2000;  275 36 626-36 631
    PubMedSearch in Google Scholar
  • 38 Sabroe I, Peck M J, Van Keulen B J, Jorritsma A, Simmons G, Clapham P R, Williams T J, Pease J E. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry.  J Biol Chem. 2000;  275 25 985-25 992
    PubMedSearch in Google Scholar

Prof. Dr. Jörn Elsner

Klinik und Poliklinik für Dermatologie und Venerologie der Medizinischen Hochschule Hannover

Ricklinger Straße 5 · 30449 Hannover

Email: elsner@htp-tel.de