Regulation of the Type I Interferon Response to Ultraviolet Light
Abstract
Rationale, Objective, and Aims: Recent studies have classified lupus as one of the top-ten causes of mortality in young women. As a highly complex multi-organ autoimmune disorder, lupus has proven remarkably difficult to understand and treat in terms of the specific immunologic processes. However, the majority of lupus patients have two particular features in common: (I) sensitivity to ultraviolet (UV) sunlight rays, affecting up to about 80% of patients, and (II) a heightened immune response known as interferon signature, reported in about 75% of patients. Interferon signature is a predictor of worse disease and is detected in different cells and organs in SLE patients: e.g., blood, skin, kidney. Recently, we established a direct connection between the two and showed that skin exposure to UV light stimulates a strong and rapid interferon signature in both human and mouse skin. Interestingly, this response was not limited to the skin and was also seen systemically, in the blood and the kidney. In normal skin, the interferon signature disappears after a while. Lupus patients however, have a persistently elevated interferon signature in the skin. What regulatory mechanisms pull the break and prevent excessive/persistent interferon signature in response to UV light is not known. Similarly, what regulatory mechanism fails to control the interferon signature in lupus skin remains a mystery. We propose to investigate the role of a specific molecule called VISTA to suppress the interferon signature in lupus skin and in response to UV light. Studies to date have shown that absence of VISTA leads to worse skin and kidney disease in lupus mouse models and an increase in the interferon signature. In our own studies, we found that treating human cells with an antibody that targets VISTA can suppress the interferon signature. Therefore, we propose that engaging VISTA will pull the break on the interferon signature in response to UV light and in lupus skin cells, using unique mouse models and primary patient samples. Focus Area(s): Our proposal addresses two of the Idea Award focus areas: “understanding lupus disease mechanism” and “determining the pathobiology of lupus disease in target human tissues.” Applicability of the Research: A. What types of patients will it help and how will it help them? Sensitivity to sunlight and the presence of an interferon signature affect the majority of lupus patients. If VISTA engagement can suppress the interferon signature, this novel approach could prevent UV-light triggered interferon response as well as keep the elevated interferon signature in asymptomatic patients under control. This could potentially keep the disease at bay and prevent disease flares in the majority of SLE patients. B. What are the potential clinical applications, benefits, and risks? Thanks to the availability of a mouse model that expresses the human VISTA, we will test the therapeutic potential of targeting this protein in vivo. Moreover, we will test the ability of a VISTA-targeting antibody to modulate interferon response in cells isolated from lupus skin, providing a disease relevant context. The major benefits of our proposal are identification of a new therapeutic target and uncovering new knowledge of interferon regulation. Despite the risk of proposing an entirely novel regulatory pathway, our published and preliminary data strongly suggest that mitigating interferon response to UV light is critical and that VISTA is a promising target. C. What is the projected time it may take to achieve a patient-related outcome? This proposal will take three essential steps in testing the therapeutic potential of a novel target: in vivo studies in the context of a relevant stimulus, i.e., UV light exposure, in vivo testing of a human therapeutic in mice that express the human protein, and testing of the immunomodulatory effects in primary cells obtained from lupus patients. Different routes of administration will
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110889
Entities
People
- Sladjana Skopelja-Gardner
Organizations
- Dartmouth–Hitchcock Medical Center
- United States Army