Abstract
Diphencyprone (DPCP) is a hapten that causes delayed-type hypersensitivity (DTH) reactions in human skin, and is used as a topical therapeutic for alopecia areata, warts, and cutaneous melanoma metastases. We examined peak DTH reactions induced by DPCP (3 days post-challenge) by comprehensive gene expression and histological analysis. To better understand how these DTH reactions naturally resolve, we compared our DPCP biopsies to those from patients with psoriasis vulgaris, a chronic inflammatory disease that does not resolve. By both microarray and qRT-PCR, we found that psoriasis lesional skin has significantly lower expression of many negative immune regulators compared to peak DPCP reactions. These regulators include: interleukin-10, cytotoxic T lymphocyte-associated 4 (CTLA4), programmed cell death 1 (PD1), programmed cell death 1 ligand 1 (PDL1), programmed cell death 1 ligand 2 (PDL2), and indoleamine 2,3-dioxygenase (IDO1). Their decreased expression was confirmed at the protein level by immunohistochemistry. To more completely determine the balance of positive vs. negative immune regulators in both DPCP reactions and psoriasis, we developed one comprehensive gene list for positive regulatory (inflammatory) genes, and another for negative regulatory (immunosuppressive) genes, through Gene Ontology terms and literature review. With this approach, we found that DPCP reactions have a higher ratio of negative to positive regulatory genes (both in terms of quantity and expression levels) than psoriasis lesional skin. These data suggest that the disease chronicity that distinguishes psoriasis from transient DTH reactions may be related to absence of negative immune regulatory pathways, and induction of these is therefore of therapeutic interest. Further study of these negative regulatory mechanisms that are present in DPCP reactions, but not in psoriasis, could reveal novel players in the pathogenesis of chronic inflammation. The DPCP system used here thus provides a tractable model for primary discovery of pathways potentially involved in immune regulation in peripheral tissues.
Highlights
Diphencyprone (DPCP) is a hapten that induces delayed-type hypersensitivity (DTH) reactions in human skin, and is used therapeutically for alopecia areata[1], warts[2], and cutaneous melanoma metastases[3]
DPCP has been shown to alter the cytokine profile in treated alopecic scalp, in particular increasing interleukin (IL)-2 and IL-10 expression[4]. This increased IL-10 expression has been hypothesized to inhibit the lesional T cells of alopecia areata, but a comprehensive evaluation of other negative immune regulators induced by DPCP is lacking
We have previously shown that human skin responses to DPCP evolve from an inflammatory/effector peak at 3 days post-challenge to a more regulated immune response, with diminished markers of T cell activation, at 14 days
Summary
Diphencyprone (DPCP) is a hapten that induces delayed-type hypersensitivity (DTH) reactions in human skin, and is used therapeutically for alopecia areata[1], warts[2], and cutaneous melanoma metastases[3]. This study included comprehensive gene expression profiling, by microarray and qRT-PCR approaches, of biopsies from DPCP-challenged healthy volunteer skin at 3 days (peak reaction), 14 days (actively resolving reaction), and 120 days (4–8 months; fully resolved reaction) compared to placebo-treated skin[5].
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