Lymphatic Dysfunction Impairs Antigen-Specific Immunization, but Augments Tissue Swelling Following Contact with Allergens

Abstract

The lymph transports tissue-resident dendritic cells (DCs) to regional lymph nodes (LNs), having important roles in immune function. The biological effects on tissue inflammation following lymphatic flow obstruction in vivo, however, are not fully known. In this study, we investigated the role of the lymphatic system in contact hypersensitivity (CHS) responses using k-cyclin transgenic (kCYC(+/-)) mice, which demonstrate severe lymphatic dysfunction. kCYC(+/-) mice showed enhanced ear swelling to both DNFB and FITC, as well as stronger irritant responses to croton oil compared with wild-type littermates. Consistently, challenged ears of kCYC(+/-) mice exhibited massive infiltrates of inflammatory cells. In contrast, DC migration to regional LNs, drainage of cell-free antigen to LNs, antigen-specific IFN-γ production, and lymphocyte proliferation were impaired during the sensitization phase of CHS in kCYC(+/-) mice. Transfer experiments using lymphocytes from sensitized mice and real-time PCR analysis of cytokine expression using challenged ear revealed that ear swelling was enhanced because of impaired lymphatic flow. Collectively, we conclude that insufficient lymphatic drainage augments apparent inflammation to topically applied allergens and irritants. The findings add insight into the clinical problem of allergic and irritant contact dermatitis that commonly occurs in humans with peripheral edema of the lower legs.