First let's start by talking about what makes a good preclinical model of psoriasis?
A good pre-clinical psoriasis model should obviously re-capitulate the key features of the clinical disease in humans. Therefore, a plausible model will exhibit the following criteria:
- Epidermal hyperproliferation of keratinocytes (acanthosis) and altered differentiation of the epidermis.
- Papillomatosis (regular and symmetrical extension of rete ridges).
- Infiltration of T cells, dendritic cells, macrophages and neutrophils.
- Functional role for T cells.
- Altered dermal vascularity.
From a commercial viewpoint, other criteria can be added to the list such as the chosen model should also be rapid, convenient and cost effective for screening psoriatic drugs. To date, this has been an aspect that researchers have struggled with and many utilize complex and costly xenograft and trasngenic models.
Topical treatment of skin with Aldara, a cream preparation containing 5% imiquimod (IMQ), results in tumor regression in up to 90% of patients with non-melanoma skin cancer. IMQ is a ligand for the toll-like receptors TLR7 and TLR8. It is a potent immune activator that is commonly used for virus-associated skin abnormalities and cancerous lesions. It exacerbates psoriasis at both the local treated areas as well as distant sites, which has led to the development of a pre-clinical model of psoriasis using topically applied Aldara cream. The anti-tumor and anti-viral effects of IMQ are mostly mediated by activation of TLR7 and TLR8 expressed by monocytes, macrophages and dendritic cells producing pro-inflammatory cytokines and chemokines. Application of Aldara on the ears and back of mice results in the development of psoriasis-like lesions within 5 days of application and is underpinned by an influx of various cells as well as hyperplasia of the epidermis.
How does the IMQ-induced psoriasis-like inflammation model correlate to human psoriasis?
Although it is recognized that mouse skin differs from human skin in several ways, a recent study employing functional genomics methods has revealed many similaries between human psoriais and mouse models across thousands of genes thus supporting the use of preclinical models to screen anti-psoriatic compounds. Over 50,000 transcripts represented on the Affymetrix Human genome were compared to corresponding orthologues in the Affymetric Mouse genome. This comparative study demonstrated that there was high correlation between psoriatic gene expression in human psoriatic skin samples in comparison to the IMQ-induced psoriasis model. In particular, these similarities were related to genes responsible for epidermal development and keratinization.
Benefits of the IMQ-induced psoriasis model compared to other psoriasis models?
The IMQ-induced psoriasis model represents a simply, rapid and cost effective method of inducing psoriasis in mice, which avoids the expense and labor intensive breeding programs, which are required for producing the keratinocyte transgenic mouse lines (e.g. K14-AREG, K5-Stat3C or K5-TGFb1) or the complexity and expertise required for the xenograft models. Furthermore, some of these transgenic mouse lines suffer from shortened life span due to stunted growth and severe psoriatic skin lesions as a result of the genetic modification, thus rendering them less amenable to therapeutic intervention.