Andrew Blauvelt, M.D.
Andrew Blauvelt, M.D.
Professor of Dermatology, Microbiology and Immunology
Chief, Dermatology Service, Portland VA Medical Center
Laboratory:
Dr. Blauvelt's lab
The unifying central hypothesis for the studies being performed in the Blauvelt laboratory is that IL-23 produced by activated DC is an early step in development of psoriasis, and that this cytokine subsequently triggers activation of Th17 cells, which in turn activate KC and endothelial cells. In one project, we have recently shown that Th17 cytokines stimulate KC to produce CCL20, a chemokine that attracts additional Th17 cells into skin. This is important because it suggests that Th17 cells, which express the CCL20 receptor CCR6, help to maintain their continual presence in psoriatic skin by secreting cytokines that promote their own chemotaxis. In other words, CCR6+ Th17 cells promote a positive chemotactic feedback loop in skin by making KC produce CCL20. In a second project, we are now characterizing two types of novel transgenic mice that over-express IL-23 within resident skin cells (either in basal keratinocytes or in epidermal Langerhans cells). We will test the ability of anti-IL-23 approaches to ameliorate inflammatory skin disease in these mice. The specific hypothesis for this project is that transgenic mice that over-express IL-23 within resident skin cells develop inflammatory skin disease containing Th17 cells that resembles human psoriasis, and that these mice will respond therapeutically to antibody targeting of either the p19 or p40 subunit of IL-23. In a third project, we are quantifying IL-23 producing DC, Th17 cells, and Th17 cytokine expression in both lesional skin and blood of patients with psoriasis (untreated patients as well as those undergoing treatment). The specific hypothesis for this project is that psoriasis is a Th17-mediated autoimmune inflammatory skin disease, and that blocking this pathway will help ameliorate psoriasis.
We have also recently begun to determine the role of the IL-23/Th17 inflammatory pathway in normal skin function. We hypothesize that this pathway is critically involved in anti-tumor and anti-microbial responses that are present and active in skin.
Dr. Blauvelt's curriculum vitae (June 2009 - pdf document)
Chief, Dermatology Service, Portland VA Medical Center
- Specialties/Interests:
- Psoriasis
- Clinical research
Dr. Blauvelt's research statement
Psoriasis is a common chronic inflammatory skin disease that causes significant impact
on quality of life for those afflicted. The cause of psoriasis is unknown, but T cells and
dendritic cells (DC) within affected skin are believed to mediate disease. IL-23, a recently
discovered cytokine that consists of p19 and p40 subunits, is now believed to be critical in
the development of several classic autoimmune inflammatory diseases in mice. In these diseases,
IL-23 stimulates a specific set of unique T cells that produce IL-17A and IL-22, T cells that
have recently been named "Th17 cells." In humans, recent reports indicate that IL-23 produced
by keratinocytes (KC) and activated DC as well as IL-17A and IL-22 produced by Th17 cells are
increased in psoriatic skin. Furthermore, monoclonal antibodies that target p40 (a protein
subunit of IL-23) have shown marked clinical efficacy in psoriasis patients in phase I-III studies.
These background data suggest that IL-23, IL-17A, and IL-22 are playing critical roles in psoriasis
pathogenesis. The unifying central hypothesis for the studies being performed in the Blauvelt laboratory is that IL-23 produced by activated DC is an early step in development of psoriasis, and that this cytokine subsequently triggers activation of Th17 cells, which in turn activate KC and endothelial cells. In one project, we have recently shown that Th17 cytokines stimulate KC to produce CCL20, a chemokine that attracts additional Th17 cells into skin. This is important because it suggests that Th17 cells, which express the CCL20 receptor CCR6, help to maintain their continual presence in psoriatic skin by secreting cytokines that promote their own chemotaxis. In other words, CCR6+ Th17 cells promote a positive chemotactic feedback loop in skin by making KC produce CCL20. In a second project, we are now characterizing two types of novel transgenic mice that over-express IL-23 within resident skin cells (either in basal keratinocytes or in epidermal Langerhans cells). We will test the ability of anti-IL-23 approaches to ameliorate inflammatory skin disease in these mice. The specific hypothesis for this project is that transgenic mice that over-express IL-23 within resident skin cells develop inflammatory skin disease containing Th17 cells that resembles human psoriasis, and that these mice will respond therapeutically to antibody targeting of either the p19 or p40 subunit of IL-23. In a third project, we are quantifying IL-23 producing DC, Th17 cells, and Th17 cytokine expression in both lesional skin and blood of patients with psoriasis (untreated patients as well as those undergoing treatment). The specific hypothesis for this project is that psoriasis is a Th17-mediated autoimmune inflammatory skin disease, and that blocking this pathway will help ameliorate psoriasis.
We have also recently begun to determine the role of the IL-23/Th17 inflammatory pathway in normal skin function. We hypothesize that this pathway is critically involved in anti-tumor and anti-microbial responses that are present and active in skin.
Dr. Blauvelt's curriculum vitae (June 2009 - pdf document)
Please refer to Dr. Blauvelt's
recent papers in:
Journal of Investigative Dermatology on psoriasis and Th17 cells
Copy of article (pdf format)
Expert Review in Dermatology on the pathogenesis of psoriasis
Copy of article (pdf format)
Psoriatic Arthritis on the pathophysiology of psoriasis
Copy of article (pdf format)