Complement is an important effector system in autoimmune and inflammatory tissue injury. Decay accelerating factor (DAF, CDS5) is a GPI-anchored cell surface protein that restricts complement activation on autologous cells. The objective of this proposal is to define the in vivo biology of DAF, both in preventing end organ injury as a complement inhibitor and as an emerging negative regulator of adaptive immunity. Our overall hypothesis is that DAF not only protects end organs from complement attack but also negatively regulates T/B cell responses to self and foreign antigens.
Two specific aims are proposed: 1. To delineate the in vivo activity of DAF as a complement inhibitor in mouse models of end organ injury. We hypothesize that DAF functions in vivo mainly as a classical pathway (CP) complement regulator, whereas Crry, a widely expressed murine membrane C3 regulator regarded as the functional homologue of the human membrane cofactor protein (MCP, CD46), controls both the CP and the alternative pathways (AP). We postulate that Crry determines tissue sensitivity to AP complement attack, while levels of both DAF and Crry together influence tissue sensitivity to CP complement attack. We will create bone marrow chimeric mice, Crry conditional knockout mice and Crry knock-in (to the DAF locus) mice, which will be used along with the previously generated DAF knockout mice to test our hypothesis in models of complement-mediated tissue injury. These studies may shed light on the in vivo activity and relationship of DAF and MCP on human tissues. 2. To test the hypothesis that DAF is also a negative regulator of adaptive immunity in vivo and to elucidate the mechanism(s) by which DAF exerts this effect. We will use DAF knockout mice, TCR transgenic mice and complement-blocking reagents to test this hypothesis in an ovalbumin immunization and an autoimmune disease (experimental autoimmune encephalomyelitis) model. These experiments may establish a novel and critical link between complement and the adaptive immunity. Collectively, the proposed studies will increase our understanding of DAF and facilitate its therapeutic exploitation in autoimmunity, organ transplantation and vaccine development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044970-10
Application #
7627212
Study Section
Special Emphasis Panel (ZRG1-III (01))
Program Officer
Esch, Thomas R
Project Start
2000-09-15
Project End
2010-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
10
Fiscal Year
2009
Total Cost
$331,721
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gullipalli, Damodar; Zhang, Fengkui; Sato, Sayaka et al. (2018) Antibody Inhibition of Properdin Prevents Complement-Mediated Intravascular and Extravascular Hemolysis. J Immunol 201:1021-1029
Wang, Xiaoxu; Van Lookeren Campagne, Menno; Katschke Jr, Kenneth J et al. (2018) Prevention of Fatal C3 Glomerulopathy by Recombinant Complement Receptor of the Ig Superfamily. J Am Soc Nephrol 29:2053-2059
Williams, Allison Lesher; Gullipalli, Damodar; Ueda, Yoshiyasu et al. (2017) C5 inhibition prevents renal failure in a mouse model of lethal C3 glomerulopathy. Kidney Int 91:1386-1397
Ueda, Yoshiyasu; Mohammed, Imran; Song, Delu et al. (2017) Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation. Blood 129:1184-1196
Zhang, Congcong; Wang, Chunxiao; Li, Yulin et al. (2017) Complement C3a signaling facilitates skeletal muscle regeneration by regulating monocyte function and trafficking. Nat Commun 8:2078
Wang, Yuan; Miwa, Takashi; Ducka-Kokalari, Blerina et al. (2015) Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation. J Immunol 195:1171-81
Ratajczak, Mariusz Z; Borkowska, Sylwia; Mierzejewska, Kasia et al. (2015) Further evidence that paroxysmal nocturnal haemoglobinuria is a disorder of defective cell membrane lipid rafts. J Cell Mol Med 19:2193-201
Miao, Jing; Lesher, Allison M; Miwa, Takashi et al. (2014) Tissue-specific deletion of Crry from mouse proximal tubular epithelial cells increases susceptibility to renal ischemia-reperfusion injury. Kidney Int 86:726-37
Zhang, Congcong; Li, Yulin; Wang, Chunxiao et al. (2014) Complement 5a receptor mediates angiotensin II-induced cardiac inflammation and remodeling. Arterioscler Thromb Vasc Biol 34:1240-8
Lesher, Allison M; Zhou, Lin; Kimura, Yuko et al. (2013) Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis. J Am Soc Nephrol 24:53-65

Showing the most recent 10 out of 45 publications