biTregs

Steinmetz

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Background

Glomerulonephritides are immune mediated diseases of the kidney, which often lead to end stage renal disease. Their pathophysiology is poorly understood and current therapeutic options are unsatisfying as they are unspecific and cause severe side effects. The search for new treatment modalities therefore is a priority for nephrologists worldwide.

The infiltration of leukocytes into the kidney is a typical finding in human and experimental glomerulonephritis. Among these, IFNy secreting T helper cells, termed Th1 and IL-17 secreting Th17 cells, are of special interest. We and others have shown that both Th1 and Th17 cell mediated immune responses are of central importance for initiation and progression of renal disease. While the pathogenic potency of Th1 and Th17 cells is well established, their regulation and counter regulation remains to be elucidated. Understanding T helper cell immunology is of special interest as Th1 and Th17 directed therapies have recently been introduced into clinical practice.Our research projects particularly address the following points:

1: Th1 and Th17 lineage specific regulatory T cells in glomerulonephritis

The potent pro-inflammatory Th1 and Th17 cells need to be tightly controlled by our immune system to avoid autoimmune disease. Central players of anti-inflammatory immune surveillance are the so called regulatory T cells. Very recent studies have suggested the concept of specialized regulatory T cells which specifically counter regulate Th1 and Th17 responses respectively. Currently we are characterizing these cells in acute and chronic glomerulonephritis. This is done by use of different knockout mice with gene deficiencies specifically in regulatory T cells. Also adoptive transfer models of sorted cells have been established.

2.: The role of biTregs in Glomerulonephritis

Recently we and others have discovered a new subset of T cells with both regulatory and pro-inflammatory properties. This intriguing novel lymphocyte population was shown to co-express the classical Treg transcription factor Foxp3 and the Th17 prototype transcription factor RORyt. Importantly, our studies could show that these RORyt+Foxp3+ cells constitute an independent and hitherto unrecognized cell population which differs from both classical Tregs and Th17 cells. Given their bi-functional nature (pro- and anti-inflammatory), we named this novel T cell lineage biTregs.
Currently, our group aims to further characterize the general properties of biTregs and investigate their role in glomerulonephritis. This is done by studies in various strains of knockout mice as well as biTreg reporter mouse strains. Furthermore, we investigate the potential role of biTregs in human autoimmune diseases as ANCA vasculitis and Lupus Erythematosus.

3: The dual role of IL-6 for generation of Th17 and Tr1 cells in glomerulonephrits

IL-6 is a pleiotropic cytokine which is central to the development of pro-inflammatory Th17 cells. However, accumulating evidence suggests that IL-6 is also critically involved in generation of anti-inflammatory type 1 regulatory T cells (Tr1). Recently, an IL-6 receptor antibody has been established for the treatment of various human autoimmune diseases. Studies in inflammatory renal disease are still lacking. We therefore analyse the effects of IL-6 blockade or deficiency on acute and chronic forms of experimental glomerulonephritis. This is done by use of general or leukocyte specific IL-6 signalling knockout mice as well as different blocking antibodies

Dr. med. Simon Melderis, MME (Postdoc)
Dr. med. Georg R. Herrnstadt (Postdoc)
Julia Hagenstein, M.sc. (wissenschaftliche Doktorandin)

Inken Holtze (BTA)

Christoph Niehus (medizinscher Doktorand)
Matthias Warkotsch (medizinischer Doktoran)
Frederic Feindt (medizinischer Doktorand)
Johannes Richter (medizinischer Doktorand)
Torben Ramcke (medizinischer Doktorand)