The overall goal of this research is to identify the structural basis for protein-protein interactions that modulate interleukin 10 (IL-10) biological activities by elucidating crystal structures of IL-10 complexed with its cell surface receptors, and several Fab fragments of neutralizing antibodies using X-ray diffraction techniques. These data will be used to design IL-10 mutants that enhance or prevent IL-10/IL-10 receptor interactions as well as mutants that change the geometry and/or the stoichiometry of the IL-10 receptor-ligand complex. Formation of a complex consisting of IL-10, a high affinity receptor (IL-10Ralpha), and a signal transducing receptor (IL-10Rbeta) is required for the generation of IL-10 biological activities that suppress TH1-dependent, cell-mediated immune responses. As a result of these activities, IL-10 is a very promising protein therapeutic for the treatment of chronic inflammatory diseases. IL-10 is currently in phase III clinical trials for Crohn's disease and phase II trials for rheumatoid arthritis that affects 40 million people and costs the country over 65 billion dollars annually in work disability. In addition to its immunosuppressive role, IL-10 has been implicated as an autocrine growth factor responsible in the pathogenesis of several B-cell malignancies. Thus, antagonists of IL-10 have potential therapeutic applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047300-05
Application #
6837091
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Rathbun, Gary
Project Start
2001-01-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2006-12-31
Support Year
5
Fiscal Year
2005
Total Cost
$287,000
Indirect Cost
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Eberhardt, Meghan K; Deshpande, Ashlesha; Fike, Joseph et al. (2016) Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection. J Virol 90:9920-9930
Walter, Mark R (2014) The molecular basis of IL-10 function: from receptor structure to the onset of signaling. Curr Top Microbiol Immunol 380:191-212
Deshpande, Ashlesha; Putcha, Balananda-Dhurjati Kumar; Kuruganti, Srilalitha et al. (2013) Kinetic analysis of cytokine-mediated receptor assembly using engineered FC heterodimers. Protein Sci 22:1100-8
Eberhardt, Meghan K; Deshpande, Ashlesha; Chang, W L William et al. (2013) Vaccination against a virus-encoded cytokine significantly restricts viral challenge. J Virol 87:11323-31
Logsdon, Naomi J; Deshpande, Ashlesha; Harris, Bethany D et al. (2012) Structural basis for receptor sharing and activation by interleukin-20 receptor-2 (IL-20R2) binding cytokines. Proc Natl Acad Sci U S A 109:12704-9
Logsdon, Naomi J; Allen, Christopher E; Rajashankar, Kanagalaghatta R et al. (2012) Purification, crystallization and preliminary X-ray diffraction analysis of the IL-20-IL-20R1-IL-20R2 complex. Acta Crystallogr Sect F Struct Biol Cryst Commun 68:89-92
Yoon, Sung Il; Jones, Brandi C; Logsdon, Naomi J et al. (2012) Epstein-Barr virus IL-10 engages IL-10R1 by a two-step mechanism leading to altered signaling properties. J Biol Chem 287:26586-95
Eberhardt, Meghan K; Chang, W L William; Logsdon, Naomi J et al. (2012) Host immune responses to a viral immune modulating protein: immunogenicity of viral interleukin-10 in rhesus cytomegalovirus-infected rhesus macaques. PLoS One 7:e37931
Logsdon, Naomi J; Eberhardt, Meghan K; Allen, Christopher E et al. (2011) Design and analysis of rhesus cytomegalovirus IL-10 mutants as a model for novel vaccines against human cytomegalovirus. PLoS One 6:e28127
Yoon, Sung-Il; Jones, Brandi C; Logsdon, Naomi J et al. (2010) Structure and mechanism of receptor sharing by the IL-10R2 common chain. Structure 18:638-48

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