Systemic lupus erythematosus is a multisystem disorder, predominantly affecting females in the reproductive age group. Renal involvement in the form of glomerulonephritis (GN) is a frequent manifestation associated with high morbidity and morality. This research proposal addresses mechanisms underlying the pathogenesis and prevention of lupus GN. During the past several years, a murine model of spontaneous SLE, NZM2328 strain has been investigated. It has been established that autoantibody production, acute and chronic GN are distinct phenotypes, under unique genetic controls. Published and preliminary data demonstrate that autoantibody responses to dsDNA, DNA-histone or immune complex deposition in the kidney are not sufficient to cause GN. Chronic GN and renal failure are associated with increasing T cell infiltration in the kidney and activation of T and B cells in the regional lymph nodes. These data support the hypothesis that an immune response to kidney antigens is required for chronic GN and will be addressed in Specific Aim 1. The proposed experiments will make use of two congenic strains NZM2328. C57Lc4 and NZM2328. C57Lc1 that have unique phenotypes. An adoptive cell transfer model will be established to demonstrate the direct role of kidney reactive T cells in mediating chronic GN. Antibodies from nephritic mice will be used to identify potential target antigens for lupus nephritis. In addition, a model of accelerated SLE induced by thymectomy on day 3 of life (d3tx) has been established in NZM2328. The d3tx NZM2328 model shows that enhanced autoantibody responses are associated with increased glomerular immune complexes and acute GN in male and female mice. However, only female mice progress to chronic GN while males do not. This suggests gender dependent factors regulating the susceptibility to end organ damage and will be investigated in Specific Aim 2. The role of chemokines, cytokines and apoptosis in the kidneys will be studied. The proposed experiments will demonstrate that chronic GN and renal failure requires a T cell response to kidney antigens and the susceptibility to end organ damage is determined by gender. These studies will provide insights into pathogenesis of lupus nephritis and identify checkpoints for intervention in patients. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK069769-01A2
Application #
7105176
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Flessner, Michael Francis
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
1
Fiscal Year
2006
Total Cost
$311,087
Indirect Cost
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Nandula, Seshagiri-Rao; Dey, Paromita; Corbin, Kathryn L et al. (2013) Salivary gland hypofunction induced by activation of innate immunity is dependent on type I interferon signaling. J Oral Pathol Med 42:66-72
Scindia, Yogesh; Nackiewicz, Dominika; Dey, Paromita et al. (2012) Activated CD4+ T cells target mesangial antigens and initiate glomerulonephritis. Nephron Exp Nephrol 121:e1-9
Bagavant, Harini; Kalantarinia, Kambiz; Scindia, Yogesh et al. (2011) Novel therapeutic approaches to lupus glomerulonephritis: translating animal models to clinical practice. Am J Kidney Dis 57:498-507
Bagavant, Harini; Scindia, Yogesh; Nackiewicz, Dominika et al. (2011) Deficiency of a transcriptional regulator, inhibitor of differentiation 3, induces glomerulonephritis in apolipoprotein E-deficient mice: a model linking hyperlipidemia and renal disease. Am J Pathol 179:651-60
Nandula, S-R; Scindia, Y M; Dey, P et al. (2011) Activation of innate immunity accelerates sialoadenitis in a mouse model for Sjögren's syndrome-like disease. Oral Dis 17:801-7
Scindia, Yogesh M; Deshmukh, Umesh S; Bagavant, Harini (2010) Mesangial pathology in glomerular disease: targets for therapeutic intervention. Adv Drug Deliv Rev 62:1337-43
Bagavant, Harini; Fu, Shu Man (2009) Pathogenesis of kidney disease in systemic lupus erythematosus. Curr Opin Rheumatol 21:489-94
Deshmukh, Umesh S; Nandula, Seshagiri Rao; Thimmalapura, Pushpa-Rekha et al. (2009) Activation of innate immune responses through Toll-like receptor 3 causes a rapid loss of salivary gland function. J Oral Pathol Med 38:42-7
Sim, Davis L; Bagavant, Harini; Scindia, Yogesh M et al. (2009) Genetic complementation results in augmented autoantibody responses to lupus-associated antigens. J Immunol 183:3505-11
Scindia, Yogesh; Deshmukh, Umesh; Thimmalapura, Pushpa-Rekha et al. (2008) Anti-alpha8 integrin immunoliposomes in glomeruli of lupus-susceptible mice: a novel system for delivery of therapeutic agents to the renal glomerulus in systemic lupus erythematosus. Arthritis Rheum 58:3884-91

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