There is compelling evidence that cellular immunity plays a role in the pathogenesis of glomerulonephritis (GN). Our recent data indicate that both alpha/beta and the less common gamma/delta T cells, are required for the development of experimental GN in mice. Mice deficient in either of these two T cell subsets developed minimal glomerular injury and interstitial macrophage accumulation in an anti-glomerular basement membrane (GBM) model of GN. This demonstrates that both T cell subsets are required for the progression of disease and is the foundation of our hypothesis that regulatory interactions between alpha/beta and gamma/delta T cells culminates in the production of cytokines, that regulate macrophages, the immune effector cells in GN. The effector phase of specific immunity requires the recruitment of T cells to sites of antigen exposure. Members of the selectin family of leukocyte adhesion receptors are important in alpha/beta and gamma/delta T cell interactions with endothelial cells, in vitro. In vivo, our studies during the current funding period revealed a hitherto unexpected complexity for the role of selectins in GN. Mice deficient in P-selectin, had increased indices of glomerular injury and leukocyte accumulation following experimental GN. This was associated with an absence of endothelial derived soluble P-selectin, which is anti- inflammatory in vitro. On the other hand, L- or E-selectin deficient mice had a significant reduction in disease and in renal alpha/beta T cell and macrophage accumulation suggesting a role for selectins in alpha/beta T cell recruitment/function. We will critically test the hypothesis that L-selectin and the selectin ligands on alpha/beta T cells play a dominant role in T cell recruitment and that soluble P-selectin is a potent stop signal for continued leukocyte influx in GN. Like alpha/beta T cells, gamma/delta T cells may also be recruited into the kidney in GN, although this is not known and will be directly examined in this application.
The specific aims are to I) Examine the determinants of alpha/beta and gamma/delta T cell recruitment, and functional cooperation in GN, II) Determine the role of alpha/beta and gamma/delta T cell derived effector cytokines in GN, and III) Examine the contribution of selectins in alpha/beta T cell mediated glomerular injury. The unique advantages of knock-out mice, transgenic mice with green fluorescent protein (GFP) labelled alpha/beta and gamma/delta T cells and adoptive transfer experiments will be emphasized in these studies. The information gained from these studies will help delineate the T cell subpopulations, and mechanisms that downregulate injurious T cell mediated responses in GN and may thus define new targets for therapeutic intervention in the treatment of human glomerulonephritides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051643-08
Application #
6818101
Study Section
Pathology A Study Section (PTHA)
Program Officer
Flessner, Michael Francis
Project Start
1996-08-20
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
8
Fiscal Year
2005
Total Cost
$243,413
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Venkatesh, Deepak; Ernandez, Thomas; Rosetti, Florencia et al. (2013) Endothelial TNF receptor 2 induces IRF1 transcription factor-dependent interferon-? autocrine signaling to promote monocyte recruitment. Immunity 38:1025-37
Sehrawat, Seema; Ernandez, Thomas; Cullere, Xavier et al. (2011) AKAP9 regulation of microtubule dynamics promotes Epac1-induced endothelial barrier properties. Blood 117:708-18
Vielhauer, Volker; Mayadas, Tanya N (2007) Functions of TNF and its receptors in renal disease: distinct roles in inflammatory tissue injury and immune regulation. Semin Nephrol 27:286-308
Hirahashi, Junichi; Mekala, Divya; Van Ziffle, Jessica et al. (2006) Mac-1 signaling via Src-family and Syk kinases results in elastase-dependent thrombohemorrhagic vasculopathy. Immunity 25:271-83
Liu, Zhi; Zhao, Minglang; Li, Ning et al. (2006) Differential roles for beta2 integrins in experimental autoimmune bullous pemphigoid. Blood 107:1063-9
Vielhauer, Volker; Stavrakis, George; Mayadas, Tanya N (2005) Renal cell-expressed TNF receptor 2, not receptor 1, is essential for the development of glomerulonephritis. J Clin Invest 115:1199-209
Stokol, Tracy; O'Donnell, Peter; Xiao, Ling et al. (2004) C1q governs deposition of circulating immune complexes and leukocyte Fcgamma receptors mediate subsequent neutrophil recruitment. J Exp Med 200:835-46
Hochegger, Kathrin; Knight, Sara; Hugo, Christian et al. (2004) Role of thrombospondin-1 in the autologous phase of an accelerated model of anti-glomerular basement membrane glomerulonephritis. Nephron Exp Nephrol 96:e31-8
Coxon, A; Cullere, X; Knight, S et al. (2001) Fc gamma RIII mediates neutrophil recruitment to immune complexes. a mechanism for neutrophil accumulation in immune-mediated inflammation. Immunity 14:693-704
Barkalow, F J; Barkalow, K L; Mayadas, T N (2000) Dimerization of P-selectin in platelets and endothelial cells. Blood 96:3070-7

Showing the most recent 10 out of 17 publications