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 2

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Activation and expansion of CTLs by oral OVA requires CD40L. B6 recipien...
Activation and expansion of CTLs by oral OVA requires CD40L. B6 recipient mice congenic for Ly5.1 were adoptively transferred with 3 × 106 transgenic OT-I cells (Ly5.2) and then given control mAb 6C8 or anti-CD40L mAb MR1 (250 μg, intraperitoneally). Mice from each treatment group were then divided into two groups and fed either PBS or 20 mg OVA in PBS on three alternating days. mAb treatment was repeated before the third feeding. Mice were killed 14 days from the start of feeding, and the numbers and phenotype of OT-I cells in their spleens were analyzed by flow cytometry. (a) Dot plots of individual mice show CD44 (left) and CD62L (L-selectin) (right) expression on OT-I cells. The percentage of cells expressing a high level of CD44 or a low level of CD62L is shown in the corresponding quadrant. The number of OT-I cells per spleen (b), CD44 expression as mean fluorescence intensity (MFI) (c), and % CD62Llo OT-I cells (d) in individual recipient mice treated with 6C8 (squares) or MR1 (circles) and then fed PBS (open symbols) or OVA (filled symbols). Data on individual mice are pooled from two experiments.