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Research ArticleArticle

N,N′-Diacetyl-l-cystine—the Disulfide Dimer of N-acetylcysteine—Is a Potent Modulator of Contact Sensitivity/Delayed Type Hypersensitivity Reactions in Rodents

Bengt Särnstrand, Anne-Helene Jansson, Giedre Matuseviciene, Annika Scheynius, Stefan Pierrou and Håkan Bergstrand
Journal of Pharmacology and Experimental Therapeutics March 1999, 288 (3) 1174-1184;
Bengt Särnstrand
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Anne-Helene Jansson
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Giedre Matuseviciene
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Annika Scheynius
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Stefan Pierrou
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Håkan Bergstrand
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Abstract

Oral N-acetyl-l-cysteine (NAC) is used clinically for treatment of chronic obstructive pulmonary disease. NAC is easily oxidized to its disulfide. We show here that N,N′-diacetyl-l-cystine (DiNAC) is a potent modulator of contact sensitivity (CS)/delayed type hypersensitivity (DTH) reactions in rodents. Oral treatment of BALB/c mice with 0.003 to 30 μmol/kg DiNAC leads toenhancement of a CS reaction to oxazolone; DiNAC is 100 to 1000 times more potent than NAC in this respect, indicating that it does not act as a prodrug of NAC. Structure-activity studies suggest that a stereochemically-defined disulfide element is needed for activity. The DiNAC-induced enhancement of the CS reaction is counteracted by simultaneous NAC-treatment; in contrast, the CS reaction is even more enhanced in animals treated with DiNAC together with the glutathione-depleting agent buthionine sulfoximine. These data suggest that DiNAC acts via redox processes. Immunohistochemically, ear specimens from oxazolone-sensitized and -challenged BALB/c mice treated with DiNAC display increased numbers of CD8+ cells. DiNAC treatmentaugments the CS reaction also when fluorescein isothiocyanate is used as a sensitizer in BALB/c mice; this is a purported TH2 type of response. However, when dinitrofluorobenzene is used as a sensitizer, inducing a purported TH1 type of response, DiNAC treatment reduces the reaction. Treatment with DiNAC also reduces a DTH footpad-swelling reaction to methylated BSA. Collectively, these data indicate that DiNAC in vivo acts as a potent and effective immunomodulator that can either enhance or reduce the CS or DTH response depending on the experimental conditions.

Footnotes

  • Send reprint requests to: Håkan Bergstrand, Department of Cell & Molecular Biology, Astra Draco, P.O. Box 34, S-22100, Lund, Sweden. E-mail:hakan.bergstrand{at}draco.se.astra.com

  • ↵1 This work was supported in part by Grant 7924 from the Swedish Medical Research Council, and grants from the Swedish Council for Work Life Sciences and the Swedish Foundation for Health Care Sciences and Allergy Research.

  • ↵2 Current address: Department of Human Pharmacology, Box 34, S 22100 Lund, Sweden.

  • ↵3 Current address: Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Hospital and Institute, S 171 76, Stockholm, Sweden.

  • ↵4 Current address: Department of Cell & Molecular Biology, Astra Draco AB, Box 34, S 221 00 Lund, Sweden.

  • Abbreviations:
    ADA 202–718
    ethylene-2,2′-bis(dithio)-bis(ethanol)
    AMG
    aminoguanidine
    BSO
    l-buthionine-[S, R]-sulfoximine
    CS
    contact (hyper)sensitivity
    CSA
    cyclosporin A
    DDTC
    diethyldithiocarbamate
    DiNAC
    N,N′-diacetyl-l-cystine
    DNFB
    2,4-dinitrofluorobenzene
    DTH
    delayed type hypersensitivity
    FITC
    fluorescein isothiocyanate
    HEDS
    bis-(2-hydroxyethyl)-disulfide
    mAbs
    monoclonal antibodies
    mBSA
    methylated BSA
    l-NAME
    Nω-nitro-l-arginine methyl ester
    NAC
    N-acetyl-l-cysteine
    NO
    nitric oxide
    Oxazolone
    4-ethoxymethylene-2-phenyl-2-oxazolin-5-one
    RPA
    RNase protection assay
    • Received May 22, 1998.
    • Accepted October 16, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 3
1 Mar 1999
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Research ArticleArticle

N,N′-Diacetyl-l-cystine—the Disulfide Dimer of N-acetylcysteine—Is a Potent Modulator of Contact Sensitivity/Delayed Type Hypersensitivity Reactions in Rodents

Bengt Särnstrand, Anne-Helene Jansson, Giedre Matuseviciene, Annika Scheynius, Stefan Pierrou and Håkan Bergstrand
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1174-1184;

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Research ArticleArticle

N,N′-Diacetyl-l-cystine—the Disulfide Dimer of N-acetylcysteine—Is a Potent Modulator of Contact Sensitivity/Delayed Type Hypersensitivity Reactions in Rodents

Bengt Särnstrand, Anne-Helene Jansson, Giedre Matuseviciene, Annika Scheynius, Stefan Pierrou and Håkan Bergstrand
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1174-1184;
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