The role of tubulointerstitial inflammation.
BACKGROUND
Exploration of the role of tubulointerstitial inflammation in experimental chronic renal disease (CRD) is an essential step to understanding and finding new treatments for human CRD. Adriamycin nephrosis (AN) is an experimental analogue of human focal glomerular sclerosis and tubulointerstitial inflammation.


METHODS
Using murine and rat AN, we have systematically investigated the pathogenic roles of chemokines, costimulatory molecules, and inflammatory cells, such as macrophages and effector and regulatory T lymphocytes. The profile of humoral and cellular mediators was studied in vitro and in vivo. The pathogenic significance of various factors was investigated by DNA vaccination, leukocyte reconstitution and depletion, retroviral transduction, and blockade with monoclonal antibodies.


RESULTS
Renal cortical and tubular cell CC-chemokines, including MCP-1, RANTES, and MIP-1alpha, were up-regulated via mediation of NFkappaB, and contributed to disease by attracting inflammatory cells into the interstitium. The role of these chemokines was confirmed by DNA vaccination. CD40-CD40L costimulation signals were involved in expansion and activation of the inflammatory infiltrate, whereas PD-1 signals were inhibitory, and CD28-B7 appeared to have a neutral effect. Macrophage and CD8+ T cells were shown to be effectors of injury, whereas CD4+CD25+ and gammadelta T cells acted as regulatory cells. FoxP3 transduction was able to convert naive T cells to CD4+CD25+ regulatory T cells.


CONCLUSIONS
There is a broad range of humoral and cellular factors involved in the pathogenesis of experimental CRD, some of which are potential targets for treatment of human CRD.
Zheng
Guoping
G
Centre for Transplantation and Renal Research, the University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
Wang
Yiping
Y
Mahajan
Deepika
D
Qin
Xiaohong
X
Wang
Ying
Y
Wang
Yuanmin
Y
Alexander
Stephen I
SI
Harris
David C H
DC
D000818:Animals; D018925:Chemokines / Q000276:immunology*; D009395:Nephritis, Interstitial / Q000276:immunology* / Q000503:physiopathology*; D013601:T-Lymphocytes / Q000276:immunology*
D018925:Chemokines