The role of regulatory T cells in glomerulonephritis

Many forms of glomerulonephritis (GN) are believed to be autoimmune in origin, with both humoral and cellular immune responses directed against resident or planted antigens. In a proportion of cases the antigens are known (a3 chain of type IV collagen constituent of the glomerular basement membrane (GBM)). In some diseases, antigens from outside the kidney may localize within the glomerulus and subsequently become target of the immune response, while in others preformed immune complexes consisting of antigen and antibody may deposit directly. Clearly, because GN remains relatively uncommon, most individuals are able to prevent this immunological insult from occurring. This is a result of multiple factors, including genetic makeup of the individual, and state of their "natural" immune protective mechanisms. One particular mechanism, which seems to be especially potent and ubiquitous, is the suppression of autoreactive effector lymphocytes by suppressive CD4 + CD25 + regulatory T cells (Treg). They are known to regulate immune responses on one hand by production of suppressive cytokines (such as TGF-ß and IL-10) and on the other hand by a cell-cell contact mechanism. Recently, we reported that Treg prevent crescentic GN in a model of nephrotoxic nephritis, produced by planting an antigen to the GBM and targeting the immune response toward it. Nevertheless, there remain a number of questions to be answered. First of all, we plan to characterize our model of anti-GBM GN in detail and evaluate the distribution of inflammatory cells, such as T effector cells, Treg, dendritic cells and macrophages, at different time points of anti-GBM GN. Next, we will evaluate the role of endogenous Treg, as well as the timing of application of Treg (after onset of disease), and a possible life-long protection against recurrence of disease after one time Treg application in anti-GBM GN. Furthermore, it is intriguing to sort out possibilities for more suppressive subsets of Treg. Additionally, we plan to evaluate the influence of new immunosuppressive agents, such as rapamycin and FTY720, on Treg. And finally, to test whether the findings from experimental GN can be transposed to other T cell-mediated diseases in the kidney, a possible role of Treg will be evaluated in renal ischemia-reperfusion injury. 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, such as crescentic IgA, disease for which limited established therapeutic options exist. Cellular therapy is already well established in the hematologic world, with T cell infusions after bone marrow transplantation. Autologous transfusion of antigen-specific natural regulators for autoimmunity appears to be an attractive form of therapy, especially when compared to adverse effects of our current immunosuppressive arsenal. Therefore, making them a reality in the treatment of autoimmune disease is not far-fetched.