Effector Treg subtypes in glomerulonephritis (GN) and interstitial nephritis (IN)
A key role for CD4+ T cells as mediators of inflammatory diseases, including GN, has been firmly established. In particular, effector T cells of the T-helper 1 (Th1) and T-helper 17 (Th17) lineages were shown to be highly nephritogenic. On the other hand, regulatory T cells (Treg) have been identified as potent counter regulators of overshooting immune responses and protect from renal tissue injury. Pioneering studies have thus begun to evaluate Treg based therapies for immune mediated diseases. Interestingly, however, it has become clear in the recent past that Tregs are by no means a uniform population. Rather, highly specialized subtypes of effector Tregs exist which are tailor-made for the control of a particular type of immune response. Treg1 cells can potently target Th1 and Treg17 cells down-regulate Th17 immunity. In addition, a unique Treg subset has been discovered by us and others, which surprisingly expresses the Th17 master transcription factor RORγt and can produce the cytokine IL-17A. These RORγt+ Tregs have been shown to be effector Tregs with enhanced immunosuppressive capacity and potently protect from renal tissue injury. In line with their IL- 17A secretion, however, this unusual Treg population seems to have additional proinflammatory potential. How and under which conditions RORγt+ Tregs exert their pro- and anti-inflammatory functions remains largely unknown to date. We thus aim to improve our understanding of effector Treg subtypes and identify their mechanisms of action. In the long term, we aim to develop Treg based treatment strategies for renal inflammatory diseases.
The cell type specific roles of Amphiregulin (AREG) in renal inflammation
The multi-functional cytokine AREG has recently been identified by us and others as an important mediator of inflammatory diseases, including GN. AREG belongs to the epidermal growth factor (EGF) family and mediates its effects via binding to the promiscuous EGF-receptor (EGFR). A better understanding of AREG's immune functions is highly warranted, since EGFR blockers are already in use for tumor therapy and various AREG directed compounds are currently being developed, so that they could also be applied to treat immune mediated diseases. It is remarkable, however, that both, pro- as well as anti-inflammatory AREG effects, have been reported. In this respect, data by us and others suggest that the cellular source of AREG might be important for the resulting function. While resident tissue cell derived AREG seems to have pro-inflammatory and pro-fibrotic effects, leukocyte derived AREG was shown to be predominantly anti-inflammatory and reparative. We therefore aim to clarify the cell type specific differential roles of AREG in GN and IN to lay the groundwork for AREG directed therapies. Furthermore, our work aims to unravel the currently ill-defined immune-regulatory mechanisms initiated by AREG signaling and identify the cellular players involved herein.
Characterization of the cellular immune responses in interstitial nephritis (IN)
IN is a common cause of acute and chronic renal failure worldwide. In roughly 15-27% of all renal biopsies, which are performed due to renal injury, IN is identified as the causative pathology. While 60-80% are considered hypersensitivity reactions to medications, roughly 15-20% of IN cases are due to systemic diseases, predominantly sarcoidosis, Sjögren's Syndrome and IgG4 related renal disease. So far there are no prospective, randomized studies to guide our therapies. Furthermore, there are no specific biomarkers to monitor IN activity apart from the serum creatinine. In order to close these clinically important knowledge gaps, a better understanding of the pathophysiology of IN is essential.
Our group has therefore established an outpatient clinic for patients with IN which are monitored longitudinally. In order to better understand which immune cells are involved in renal inflammation of the different subtypes of IN, we routinely analyze the patients' urinary cytokine levels as well as their urinary leukocytes by flow cytometry. Furthermore, we try to get a better picture of the renal cellular infiltrate by performing single cell mRNAseq as well as Cite-seq analyses of renal biopsies from IN patients. In the long run, we aim to identify better biomarkers which help to guide our therapies, as well as develop novel therapeutic strategies for the treatment of IN.
