Transient blockade of CD40 ligand dissociates pathogenic from protective mucosal immunity
Arno Hänninen, … , William R. Heath, Leonard C. Harrison
Arno Hänninen, … , William R. Heath, Leonard C. Harrison
Published January 15, 2002
Citation Information: J Clin Invest. 2002;109(2):261-267. https://doi.org/10.1172/JCI13720.
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Article

Transient blockade of CD40 ligand dissociates pathogenic from protective mucosal immunity

Abstract

Antigen administration via oral and other mucosal routes can suppress systemic immunity to the antigen and has been used to prevent experimental autoimmune disease. This approach may prove ineffective or even harmful if it leads to a concomitant induction of cytotoxic T lymphocytes (CTLs), and indeed, mucosal administration of the model antigen ovalbumin (OVA) has been shown to elicit CTL activation while simultaneously inducing oral tolerance. Here we show that induction by oral OVA of CTLs in wild-type mice, and of diabetes in mice expressing OVA transgenically in pancreatic β cells, can be prevented by transiently blocking the CD40 ligand (CD40L). However, CD40L blockade did not diminish oral tolerance, as measured by suppression of systemic OVA-primed T cell proliferation, IFN-γ secretion, and Ab production. Consistent with these findings, mice lacking CD40 expression could be orally tolerized to OVA. Transient CD40L blockade therefore dissociates pathogenic from protective immunity and should enhance the efficacy and safety of oral tolerance for preventing autoimmune disease.

Authors

Arno Hänninen, Nathan R. Martinez, Gayle M. Davey, William R. Heath, Leonard C. Harrison

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Figure 1

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CTL priming by systemic or oral OVA requires CD40L signaling. (a) A sing...
CTL priming by systemic or oral OVA requires CD40L signaling. (a) A single intraperitoneal injection of 250 μg of control mAb 6C8 (squares) or anti-CD40L mAb MR1 (circles) was given to B6 mice (n = 4 in each group), 1 day before challenge with 2 × 107 intravenous OVA-coated H-2Kbm-1 splenocytes to prime CTLs. After 14 days, mice were killed and their splenocytes were tested for CTL activity, expressed as OVA-specific lysis for representative individual mice. Primed splenocytes as effectors (E) were tested against 51Cr-loaded cells as targets (T). (b) The same doses of 6C8 or MR1 were given to mice (n = 12 in each group) that were then fed 20 mg OVA on three alternating days. After 14 days, without further priming, mice were killed and their splenocytes were tested for CTL activity, this time expressed as lytic units per spleen for individual mice.