Transient blockade of CD40 ligand dissociates pathogenic from protective mucosal immunity
Arno Hänninen, Nathan R. Martinez, Gayle M. Davey, William R. Heath, Leonard C. Harrison
Arno Hänninen, Nathan R. Martinez, Gayle M. Davey, William R. Heath, Leonard C. Harrison
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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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Anti-CD40L treatment does not prevent oral tolerance measured as suppres...
Anti-CD40L treatment does not prevent oral tolerance measured as suppression of systemic priming of (a) T cell proliferation measured as 3H-thymidine (T) incorporation, or (b) IFN-γ production measured as ELIspots. Mice (n = 3 in each group) were injected with control mAb 6C8 or anti-CD40L mAb MR1 (250 μg intraperitoneally), and then fed either PBS or 20 mg OVA in PBS on three alternating days. After 7 days, they were immunized subcutaneously with OVA (0.1 mg) in CFA in the base of tail. Ten days later, spleens and inguinal lymph nodes were harvested for measurement of T cell proliferation (a) and cytokine production (b) in the absence (white bars) or presence (black bars) of 0.1 mg/ml OVA (mean and SD shown for spleen), and sera obtained for measurement of anti-OVA Ab’s (not shown, see text), as described in Methods. 3H-T, 3H-thymidine.