Induction of hapten-specific tolerance by interleukin 10 in vivo

Alexander H. Enk, Joachim Salega, Detlef Becker, Mansour Mohamadzadeh, Jüirgen Knop

Research output: Contribution to journalArticlepeer-review

215 Scopus citations

Abstract

Interleukin 10 (IL-10) is released during the induction phase of contact sensitivity and was shown in prior functional studies to convert epidermal Langerhans cells (LC) from potent inducers of primary immune responses to specifically tolerizing cells in vitro. To investigate whether IL-10 also subserves the function of a tolerizing agent in vivo ears of BALB/c or C3H mice were injected intradermally with 1-2 μg of recombinant mouse (rm)IL-10 8 h before epicutaneous application of 3% trinitrochlorobenzene (TNCB; a contact allergen). As a control, mice were injected with phosphate-buffered saline or IL-10 plus neutralizing amounts of anti-IL-10 mAb. 5 d later, mice were challenged with 1% TNCB on contralateral ears and ear swelling response was measured 24 h later. Whereas control-treated mice showed a normal ear swelling response to epicutaneous challenge (Δ mm-2 = 25 ± 5), ear swelling response of IL-10-treated animals was significantly inhibited (Δ mm-2 = 3 ± 2). Coinjection of IL-10-specific mAb together with rmIL-10 completely abrogated this effect. To differentiate between a state of nonresponsiveness and induction of tolerance by IL-10, mice initially treated with IL-10 and TNCB were resensitized with 3% TNCB in the absence of any treatment after 14 d of rest (group 1). Again mice were challenged 5 d later and ear swelling responses were tested. Whereas control mice treated with allergen alone (group 2) showed a good swelling response (Δ mm-2 = 28 ± 6), IL-10-treated mice (group 1) showed a minimal response towards application of allergen (Δ mm-2 = 4 ± 2). To show that anergy induction by IL-10 was antigen-specific, mice initially treated with IL-10 plus TNCB were exposed to 0.5% dinitrofluorobenzene (DNFB) 14 d later (group 1). After challenge with 0.1% DNFB, IL-10-treated mice showed an ear swelling response (Δ mm-2 = 13 ± 3; group 1) similar to that of control mice only sensitized with DNFB (Δ mm-2 = 14 ± 3; group 3). In an attempt to show the induction of antigen-specific tolerance in these mice in vitro, regional lymph nodes of mice initially treated with TNCB plus IL-10 (group 1) and control-treated mice (groups 2 and 3) were prepared and cultured in the presence of TNBS, dinitrobenzene sulfonate (DNBS), or medium to measure antigen-specific proliferation. Lymph node cells from animals sequentially treated with IL-10 plus TNCB and afterwards DNFB in the absence of IL-10 (group 1) showed a low, but significant proliferation (~15,000 cpm) to DNBS, but only background proliferation (~3,000 cpm) to TNBS, or medium. In contrast, lymph node cells from animals treated with TNCB or DNFB in the absence of IL-10 (groups 2 and 3) proliferated to the sensitizing agent, but not control allergens. To elucidate the mechanism of action of IL-10, the epidermal cytokine pattern was analyzed on the mRNA level after injection of IL-10 or controls and application of allergen. Injection of IL-10 (but not controls) significantly impeded the induction of proinflammatory cytokines IL-1β, tumor necrosis factor α and IL-1α. In aggregate our data indicate that in vivo application of IL-10 before allergen treatment induces antigen- specific tolerance in mice and that IL-10 might act via inhibition of proinflammatory cytokines.

Original languageEnglish (US)
Pages (from-to)1397-1402
Number of pages6
JournalJournal of Experimental Medicine
Volume179
Issue number4
StatePublished - Apr 1 1994
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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