Activation of the complement system by immune complexes (IC) leads to an inflammatory response. This occurs through the direct actions of complement proteins as well as indirectly via the stimulation of other mediator systems. Furthermore, complement is necessary for an optimal humoral immune response to naive antigens and effective disposal of circulating ICs. The studies in this application will examine the role of the complement system in the prototypical IC disease, systemic lupus erythematosus (SLE). Here, the NZBNV F, murine model of SLE will be studied. These animals have pathological features similar to those of human SLE, including the development of a wide spectrum of auto-antibodies and diffuse proliferative glomerulonephritis that ultimately is fatal. The roles of complement will be dissected through its inhibition. Because C3 and C5 play pivotal roles in complement actions, the effects of inhibiting each will be compared in these studies. Inhibition of C3 will be achieved with the murine protein Crry (Complement receptor related protein y). Two different strategies of Crry administration will be used: 1) recombinant Crry containing a non-complement activating IgG1 """"""""tail"""""""" (Crry-Ig) will be given chronically to animals; and, 2) transgenic mice constitutively producing endogenous soluble Crry will be studied (Crry-tg). C5 will be inhibited with an anti-mouse C5 monoclonal antibody that blocks the cleavage and activation of C5. As a parallel approach, the role of C3 in experimental SLE will also be determined by using mice made deficient in C3 through gene targeting (C3 -/- mice). Such studies will determine the effects of absolute C3 deficiency in experimental SLE. These studies will carefully evaluate how the complement system is involved in the pathogenesis of experimental SLE. The following variables will be measured: 1 ) clinical outcomes, including mortality and renal functional changes; 2) pathological alterations in kidney, including the progressive fibrogenesis occurring in glomeruli and the tubulointerstitium; 3) proinflammatory cytokines that are up regulated in these models; 4) amount and antigen specificity's of circulating and glomerular bound auto-antibodies; and, 5) the relative state of autoimmune activation of B lymphocytes. Dissecting the pro- and anti-inflammatory actions of the complement system in experimental SLE will provide important insights into the mechanisms of disease in human SLE, as well as in other IC diseases and may lead to viable therapeutic approaches that can be applied in practice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK055357-04S1
Application #
6921653
Study Section
Pathology A Study Section (PTHA)
Program Officer
Flessner, Michael Francis
Project Start
1999-08-15
Project End
2005-03-31
Budget Start
2004-08-15
Budget End
2005-03-31
Support Year
4
Fiscal Year
2004
Total Cost
$32,139
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Cravedi, Paolo; van der Touw, William; Heeger, Peter S (2013) Complement regulation of T-cell alloimmunity. Semin Nephrol 33:565-74
Foxley, Sean; Zamora, Marta; Hack, Bradley et al. (2013) Curcumin aggravates CNS pathology in experimental systemic lupus erythematosus. Brain Res 1504:85-96
Naik, Abhijit; Sharma, Shweta; Quigg, Richard J (2013) Complement regulation in renal disease models. Semin Nephrol 33:575-85
Jacob, Alexander; Chaves, Lee; Eadon, Michael T et al. (2013) Curcumin alleviates immune-complex-mediated glomerulonephritis in factor-H-deficient mice. Immunology 139:328-37
Jacob, Alexander; Hack, Bradley; Chen, Peili et al. (2011) C5a/CD88 signaling alters blood-brain barrier integrity in lupus through nuclear factor-ýýB. J Neurochem 119:1041-51
Bao, Lihua; Haas, Mark; Quigg, Richard J (2011) Complement factor H deficiency accelerates development of lupus nephritis. J Am Soc Nephrol 22:285-95
Jacob, Alexander; Hack, Bradley; Chiang, Eddie et al. (2010) C5a alters blood-brain barrier integrity in experimental lupus. FASEB J 24:1682-8
Jacob, Alexander; Hack, Bradley; Bai, Tao et al. (2010) Inhibition of C5a receptor alleviates experimental CNS lupus. J Neuroimmunol 221:46-52
Puri, Tipu S; Shakaib, Mohammed I; Chang, Anthony et al. (2010) Chronic kidney disease induced in mice by reversible unilateral ureteral obstruction is dependent on genetic background. Am J Physiol Renal Physiol 298:F1024-32
Qiao, G; Li, Z; Minto, A W et al. (2010) Altered thymic selection by overexpressing cellular FLICE inhibitory protein in T cells causes lupus-like syndrome in a BALB/c but not C57BL/6 strain. Cell Death Differ 17:522-33

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