Mission Statement

“Understanding CD4+  T cell responses and their cytokine mediators in immune mediated renal diseases”

— Oliver Michael Steinmetz, MD

Team Members

PhD student

Laura Ehnold

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Clinician Scientist

Frederic Feindt, MD

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Post Doc

Julia Hagenstein, PhD

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MD Student

Sophia Hegselmann

Clinician scientist

Georg Herrnstadt, MD

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Technician

Inken Holtze

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MD Student

Viona Laas

Clinician scientist

Simon Melderis, MD

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MD Student

Christoph Niehus

Clinician scientist

Christina Thompson

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MD Student

Matthias Warkotsch

Clinician scientist

Tingting Xiong, MD

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Research

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 Thelper 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 of note, 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, as predominantly sarcoidosis, Sjögren´s Syndrome or 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.

CV

Current Position

Research Group Leader

University Training
1993 - 2001

Studies of Human Medicine at the Universities of Cologne and Hamburg

Academic qualifications
2018 - 2020

APL Professor (§17 HmbHG)

2012

Habilitation in Internal Medicine, University of Hamburg

2003

MD thesis Centre for Molecular Neurobiology Hamburg, ZMNH, Prof. Dr. O. Pongs 

Previous professional career

Clinical postgraduate education:

2021

Board certification in Immunology

2011

Board certification in Internal Medicine and Nephrology

2001 - 2012

Postdoctoral Research Fellow, University Hospital Hamburg Eppendorf (UKE), III. Medical Clinic, Nephrology (Heads: Prof. Dr. R.A.K. Stahl, since 2017 Prof. Dr. T.B. Huber)

Scientific postgraduate education:

2008 - 2010

Postdoctoral Research Fellow at the Centre for Inflammatory Diseases, Monash University, Clayton, Australia (Head: Prof. Dr. Stephen R. Holdsworth)

Selected awards and honors
2015 - 2020

Dr. Liselotte-Brauns Award for Internal Medicine

2015

Hans-U.-Zollinger Immunology Award of the German Society of Nephrology (DGfN)

Selected publications

1.

The Amphiregulin/EGFR axis protects from lupus nephritis via downregulation of pathogenic CD4+ T helper cell responses.
Melderis S, Warkotsch MT, Dang J, Hagenstein J, Ehnold LI, Herrnstadt GR, Niehus CB, Feindt FC, Kylies D, Puelles VG, Berasain C, Avila MA, Neumann K, Tiegs G, Huber TB, Tharaux PL, Steinmetz OM. J Autoimmun. 129:102829. doi: 10.1016/j.jaut.2022.102829., 2022.

2.

Amphiregulin Aggravates Glomerulonephritis via Recruitment and Activation of Myeloid Cells.
Melderis S, Hagenstein J, Warkotsch MT, Dang J, Herrnstadt GR, Niehus CB, Neumann K, Panzer U, Berasain C, Avila MA, Tharaux PL, Tiegs G, Steinmetz OM. J Am Soc Nephrol. 31: 1996-2012, 2020.11

3.

A Novel Role for IL-6 Receptor Classic Signaling: Induction of RORγt+Foxp3+ Tregs with Enhanced Suppressive Capacity.
Hagenstein J, Melderis S, Nosko A, Warkotsch MT, Richter JV, Ramcke T, Herrnstadt GR, Scheller J, Yan I, Mittrücker HW, Kluger MA, Steinmetz OM. J Am Soc Nephrol. 30: 1439-1453, 2019.

4.

IL-10 receptor signaling empowers regulatory T cells to control Th17 responses and protects from GN.IL-10 receptor signaling empowers regulatory T cells to control Th17 responses and protects from GN.
Diefenhardt Paul, Nosko A, Kluger MA, Richter JV, Wegscheid C, Kobayashi Y, Tiegs G, Huber S, Flavell RA, Stahl RAK, Steinmetz OM. J Am Soc Nephrol, 29: 1825-1837, 2018.

5.

T-Bet Enhances Regulatory T Cell Fitness and Directs Control of Th1 Responses in Crescentic GN.T-Bet Enhances Regulatory T Cell Fitness and Directs Control of Th1 Responses in Crescentic GN.
Nosko A, Kluger MA, Diefenhardt P, Melderis S, Wegscheid C, Tiegs G, Stahl RA, Panzer U, Steinmetz OM. J Am Soc Nephrol, 28: 185-196, 2017.

6.

Treg17 cells are programmed by Stat3 to suppress Th17 responses in systemic lupus.
Kluger MA, Melderis S, Nosko A, Goerke B, Luig M, Meyer MC, Turner JE, Meyer-Schwesinger C, Wegscheid C, Tiegs G, Stahl RA, Panzer U, Steinmetz OM. Kidney Int, 89:158-66, 2016.

7.

RORγt+Foxp3+ Cells are an Independent Bifunctional Regulatory T Cell Lineage and Mediate Crescentic GN.RORγt+Foxp3+ Cells are an Independent Bifunctional Regulatory T Cell Lineage and Mediate Crescentic GN.
Kluger MA, Meyer MC, Nosko A, Goerke B, Luig M, Wegscheid C, Tiegs G, Stahl RA, Panzer U, Steinmetz OM. J Am Soc Nephrol, 27:454-465, 2016.

8.

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN.Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN.
Luig M, Kluger MA, Goerke B, Meyer M, Nosko A, Yan I, Scheller J, Mittrücker HW, Rose-John S, Stahl RAK, Panzer U, Steinmetz OM. J Am Soc Nephrol, 26: 1597-15607, 2015.

9.

Stat3 Programs Th17-Specific Regulatory T Cells to Control GN.Stat3 Programs Th17-Specific Regulatory T Cells to Control GN.
Kluger MA, Luig M, Wegscheid C, Goerke B, Paust HJ, Brix S, Yan I, Mittrücker HW, Hagl B, Renner ED, Tiegs G, Wiech T, Stahl RAK, Panzer U, Steinmetz OM. J Am Soc Nephrol, 25: 1291-1302, 2014.

10.

Funding

Martinistraße 52
Campus Research N27
20246 Hamburg Germany
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University Medical Center Hamburg - Eppendorf