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.
|Zaba, Lisa C; Fuentes-Duculan, Judilyn; Eungdamrong, Narat John et al. (2009) Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells. J Invest Dermatol 129:79-88|
|Zaba, Lisa C; Krueger, James G; Lowes, Michelle A (2009) Resident and ""inflammatory"" dendritic cells in human skin. J Invest Dermatol 129:302-8|
|Guttman-Yassky, Emma; Vugmeyster, Yulia; Lowes, Michelle A et al. (2008) Blockade of CD11a by efalizumab in psoriasis patients induces a unique state of T-cell hyporesponsiveness. J Invest Dermatol 128:1182-91|
|Haider, Asifa S; Cohen, Jules; Fei, Ji et al. (2008) Insights into gene modulation by therapeutic TNF and IFNgamma antibodies: TNF regulates IFNgamma production by T cells and TNF-regulated genes linked to psoriasis transcriptome. J Invest Dermatol 128:655-66|
|Lowes, Michelle A; Chamian, Francesca; Abello, Maria V et al. (2007) Eruptive papules during efalizumab (anti-CD11a) therapy of psoriasis vulgaris: a case series. BMC Dermatol 7:2|
|Zaba, Lisa C; Fuentes-Duculan, Judilyn; Steinman, Ralph M et al. (2007) Normal human dermis contains distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages. J Clin Invest 117:2517-25|
|Haider, Asifa S; Lowes, Michelle A; Gardner, Humphrey et al. (2007) Novel insight into the agonistic mechanism of alefacept in vivo: differentially expressed genes may serve as biomarkers of response in psoriasis patients. J Immunol 178:7442-9|
|Wang, Frank; Lee, Edmund; Lowes, Michelle A et al. (2006) Prominent production of IL-20 by CD68+/CD11c+ myeloid-derived cells in psoriasis: Gene regulation and cellular effects. J Invest Dermatol 126:1590-9|
|Lowes, Michelle A; Turton, James A; Krueger, James G et al. (2005) Psoriasis vulgaris flare during efalizumab therapy does not preclude future use: a case series. BMC Dermatol 5:9|
|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|
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