Abstract 1599: Grape seed proanthocyanidins inhibit UV-induced tolerogenic T-cell response through DNA repair-dependent functional activation of Langerhans cells

Abstract

Abstract It is well documented that ultraviolet (UV) radiation-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPD) diminishes the antigen presenting capacity of epidermal Langerhans cells (LCs) and this leads to the suppression of immune system. Previously, we have shown that dietary grape seed proanthocyanidins (GSPs) inhibit UVB-induced immunosuppression in mice via activation of CD8+ T cells. However, it is not understood whether (1) GSPs target LCs while exerting its immunomodulatory effects on T cells in response to the application of cutaneous contact sensitizer, 2,4-dinitrofluorobenzene (DNFB) onto the UV-exposed skin, and whether (2) the ability of GSPs to activate dendritic cells/LCs correlates with their DNA repair properties. To understand this mechanism, we first determined DNA repair ability of GSPs in UV-exposed dendritic cells for which CD11c+ cells were prepared from bone marrow of xeroderma pigmentosum complementation group A-knockout (XPA-KO) mice which are deficient in DNA repair, and their wild-type (WT) counterparts. CD11c+ cells were exposed to UVB radiation with or without pretreatment with GSPs. Treatment of GSPs resulted in significant reduction in the number of CPD-positive cells in CD11c+ cells from WT mice, but this DNA repair effect of GSPs was not seen in the CD11c+ cells from XPA-KO mice. We then analyzed effects of dietary GSPs (0.5%, w/w) on secretion of cytokines by CD11c+ cells that were isolated from lymph nodes and spleens of mice (WT and XPA-KO) that were exposed to UVB [150 mJ/cm2 (WT), 20 mJ/cm2 (XPA-KO)]. Our results showed that in comparison to CD11c+ cells isolated from WT control mice (GSP-untreated), CD11c+ cells isolated from mice that received GSPs in diet secreted a significantly higher level of Th1 cytokines (IL-12, IFNα), while the levels of Th2 cytokines (IL-4, IL-10) were significantly lower, but this effect of GSPs was not observed in CD11c+ cells isolated from XPA-KO mice. Finally, we used an adoptive transfer approach, wherein draining lymph nodes were harvested from mice that were exposed to UVB with and without GSPs supplementation in diet and sensitized by DNFB onto the UVB-exposed skin. CD11c+ cells were positively selected and transferred into naïve mice that were subsequently challenged by application of DNFB on the ear skin. Naïve recipients that received CD11c+ cells from WT, GSPs-treated, UVB-irradiated donors exhibited full contact hypersensitivity (CHS) response, whereas no significant CHS was observed in XPA-KO mice. These data suggest that dietary GSPs inhibit UVB-induced immunosuppression in mice by improving the ability of LCs to mount an immune response via activation of T cells in a manner which correlates with its capacity to enhance repair of UVB-induced DNA damage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1599. doi:1538-7445.AM2012-1599