This proposal seeks support to conduct mechanistic studies on immune-modulating effects of humanized antibodies to CD11a (anti-CD11a) in psoriasis patients during ongoing clinical trials. 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 has led to extensive (but empiric) clinical testing of new immune-directed approaches. CD11a is an integrin subunit expressed on the surface of T-cells and dendritic cells (DCs) that potentially regulates cell activation, trafficking, and effector immunity. However it is not understood how anti-CD11a modulates chronic cellular activation in any human immune disease. It would be extremely helpful to have this information to elucidate pathogenic and therapeutic immune targets in psoriasis (and, by extension, in other human diseases mediated by type 1 T-cells). Hence, the overall goal of proposed research is to determine how anti-CD11a reduces molecular and cellular inflammatory pathways in diseased skin in relationship to (variable) therapeutic improvements induced by this antibody.
The specific aims are 1. Quantify mRNA levels for pro-inflammatory gene transcripts in psoriatic skin lesions following CD11 a blockade using real-time RT-PCR and relate altered gene expression to the degree of pathologic improvement in disease activity, as assessed by quantitative immunohistology measures. 2. Determine whether antiCD11a affects the organization of DC/T-cell aggregates and the presence of functionally mature DCs in skin lesions. Relate potential changes in DC & T-cell organization to overall disease activity. 3. Detemmine how anti-CD11a affects trafficking and adhesion-related phenotype/function of CLA+(skin homing) T-cells. 4.Ascertain the relationship between CD11a blockade, T-cell activation and persistence of pathogenic or antigen-reactive T-cell populations. Following anti-CD1la we will look for reductions in 1) disease-associated T-cell activation, 2) Type 1 T-cells, and 3) abundance of specific, antigen-reactive T-cells in the peripheral circulation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SSS-J (01))
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Rothermel, Annette L
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Rockefeller University
Other Domestic Higher Education
New York
United States
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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
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