Regulatory T cells in kidney disease

CD4 + CD25 + regulatory T cells (Treg) are known to regulate immune responses in various autoimmune diseases. Recently, our group provided compelling evidence that Treg can also limit the immune reaction in anti-glomerular basement (GBM) glomerulonephritis (GN), a model that is close to Goodpasture`s disease. We now plan to extend our findings on the role of Treg in anti-GBM GN and further plan to provide evidence that Treg play also a role in other kidney disease models. In detail, we will transfer Treg as recently described for anti-GBM GN into db/db mice with diabetic nephropathy, lupus-prone NZBxNZW F1 (B/W) mice and mice before induction of renal ischemia reperfusion injury (IRI). For the lupus nephritis and the renal IRI model it is well known that T cells play a major role in the pathogenesis. Only little is known about T cells in diabetic nephropathy, but preliminary data show also a possible role for T cells and Treg in the diabetic nephropathy in db/db mice. Next, we will evaluate the role of endogenous Treg in anti-GBM GN and in the other kidney disease models by depleting Treg. Additionally, the immunosuppressive agent rapamycin has been shown to induce proliferation of Treg in vitro. Recently, we found rapamycin to have beneficial, but also detrimental effects in anti-GBM GN depending on the start of treatment. We now plan to extend these findings and first plan to treat mice subjected to anti-GBM GN with rapamycin and IL-10, since this combinational therapy has been shown to extend the Treg population in vivo. Furthermore, it is intriguing to induce proliferation of Treg in vitro with the help of rapamycin and to test these cells in our anti-GBM GN model. These planned approaches evaluating the function of rapamycin on Treg will also be performed in the above described kidney disease models. And finally, we will evaluate the number of kidney infiltrating Treg in human kidney biopsies and correlate the Treg content with the respective kidney disease and the outcome of the patient. Taken together, adoptive transfer of Treg as shown by our group suggests an alternative way of tipping the balance in favor of resolution of GN. Treg can be driven to enter cell cycle and proliferate given the right stimulus, and so they may be expanded in vitro. Exploring the mechanisms of Treg in renal diseases may prove to be useful for new therapeutic approaches in a number of autoimmune GNs, especially those that occur with a relapsing remitting course, such as systemic lupus erythematosus or systemic vasculitis (which currently require prolonged immunosuppression) or those diseases, such as crescentic IgA nephritis, for which limited established therapeutic options exist.

The project was designed to evaluate the role of regulatory T cells (Tregs) in kidney diseases such as immune-complex glomerulonephritis, diabetic nephropathy and renal calcification. Tregs are a T cell subpopulation, which exerts anti-inflammatory capacities and thereby limits inflammation. We have previously shown that Treg transfer limits glomerulonephritis by inhibiting the T cell activation in the draining lymph node. We found Tregs to interact with mast cells via IL-9 within the draining lymph node thereby limiting disease activity. Next we evaluated the role of Tregs in a murine model of diabetes mellitus type 2, which is accompanied by an early stage of diabetic nephropathy, as well as in a newly established model of renal and cardiac calcification. Tregs were found to improve both models by limiting T cell activation. Whereas Tregs improved both insulin sensitivity and diabetic nephropathy, they only improved the renal phenotype but not the cardiac in the calcification model. Additionally, we found significantly decreased signals for natural Tregs in visceral adipose tissue of adipose patients with diabetes mellitus type 2 suggesting that Tregs are important not only in mice but also men with obesity and diabetes mellitus. Together, we provided evidence that Tregs play important roles not only in a classic inflammatory kidney disease model such as glomerulonephritis, but also in diabetic nephropathy and renal calcification. Our data hopefully clears the way for therapeutic options of Tregs in kidney diseases.