This proposal seeks support to conduct mechanistic studies on immune-modulating effects of daclizumab, a humanized antibody that prevents binding of IL-2 to its high-affinity receptor. Psoriasis is the most prevalent T cell mediated disease in humans, affecting 2-3 percent of people in the United States. New, less toxic therapies are urgently needed for patients with extensive disease involvement. The pathogenic role of T cells in psoriasis is a recent discovery, and this finding has led to clinical testing of T cell activation antagonists such as daclizumab. CD25 is the a-subunit of the IL-2R that is expressed selectively on activated T cells and dendritic antigen presenting cells. Daclizumab (anti-CD25) prevents cell activation signals delivered by the IL-2 receptor and, in preliminary experiments, has been shown to reduce T cell mediated inflammation in psoriatic skin lesions. Daclizumab is also used to suppress T cell mediated rejection responses in human transplants, but, as little is known about its mechanism of action in humans, we are proposing experiments to determine how antibody mediated blockade of the IL-2 receptor affects a complex array of inflammation regulating cytokines and activated leukocytes which sustain disease activity in psoriasis. Information on immune mechanisms in psoriasis is likely to be relevant to use of daclizumab in transplants or other autoimmune diseases, since immune activation in psoriasis is similar to these conditions.
The specific aims are 1) Using a quantitative RT-PCR, determine how CD25 blockade modulates the inflammatory cytokine network in psoriatic skin lesions, including expression of other IL-2 family cytokines that potentially antagonize therapeutic actions of daclizumab. 2. Using gene expression arrays, determine how CD25 blockade influences expression of 110 disease-related genes that have been identified in preliminary experiments using Affymetrix Hu5600 chips. 3. Relate changes in gene expression to overall disease activity and pathologic cellular activation, as measured by quantitative histologic assessments and disease-related immunohistochemical probes. We will also measure the impact of daclizumab on T cell activation/deviation towards Type 2 T cells by sensitive flow cytometry based assays.
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|Zaba, Lisa C; Krueger, James G; Lowes, Michelle A (2009) Resident and ""inflammatory"" dendritic cells in human skin. J Invest Dermatol 129:302-8|
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|Chamian, Francesca; Lowes, Michelle A; Lin, Shao-Lee et al. (2005) Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris. Proc Natl Acad Sci U S A 102:2075-80|
|Kumar, Lalit; Feske, Stefan; Rao, Anjana et al. (2005) A 10-aa-long sequence in SLP-76 upstream of the Gads binding site is essential for T cell development and function. Proc Natl Acad Sci U S A 102:19063-8|
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