Research Projects

Research Topics:

Mechanisms and Models of renal and peritoneal injury (Group leader: Prof. Dr. med. Stephan Segerer)
Stephan Seger is a nephrologist and senior scientist with a clinical focus on renal replacement therapy. The laboratory is focused on two main interests. The first are mechanisms of renal inflammation particularly the role of cytokines and chemokines as potential therapeutic targets. The second field of interest are mechanisms of peritoneal injury, particularly the pathogenesis of the encapsulating peritoneal sclerosis.

Current projects are:

1. The role of lymphotoxins in renal inflammation. In this project we address the role of lymphotoxin β receptor signaling in renal inflammation. We describe the lymphotoxin system in the mouse and human kidney. Targeting lymphotoxin β receptor signaling is used in vitro and in vivo.

2. The role of lymphatic vessels and podoplanin in encapsulating peritoneal sclerosis (EPS) EPS is a rare but potentially lethal complication of peritoneal dialysis. We have described podoplanin positive myofibroblasts in peritoneal biopsies from patients with this disease. The current project evaluates the role of these cells in the pathogenesis of EPS and as potential biomarker.

Group members:

Discovery of therapeutics and biomarkers to develop individualized treatment for polycystic kidney disease (PKD). (Group leader PD Dr. Andreas L. Serra)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of end-stage renal disease (ESRD), affecting more than 4.5 Mio worldwide and more than 10’000 patients in Switzerland. Mutation in PKD1 and PKD2 (the genes encoding for polycystin-1 (PC1) and polycystin-2 (PC2), respectively are the principal cause of the disease where there is no causal treatment. As a physician-scientist I work at the interface between the research laboratory and patient care. My hope is that such a translational research and medicine change the outcome of this serious disease. My research focus is on the following:

1. Targeting the excessive renal tubular epithelial cell proliferation to slow PKD progression

2. Explore the role of hypoxia by visualization and quantification of hypoxia in animals and human ADPKD to monitor disease progression and treatment

3. Identification and validation of prognostic biomarker in ADPKD in blood and urine

4. Ongoing prospective cohort of young ADPKD patients with annual follow-up (SUISSE ADPKD Cohort)

Group members:

Mechanisms and models of allograft rejection and tolerance induction (Group leader Prof. Thomas Fehr)

Project 1: Pharmacological apoptosis modulation - a novel approach to immunosuppression and tolerance induction

Apoptosis plays a pivotal role for central and peripheral tolerance and is essential for the regulation of immune reactions. New substances targeting pro- and antiapoptotic proteins allow selective apoptosis induction. ABT-737 is a new rationally designed small molecule that selectively inhibits anti-apoptotic Bcl-2 proteins. As lymphocyte activation profoundly changes the expression of important actors of the intrinsic apoptotic pathway, we hypothesize that ABT-737 could selectively induce apoptosis in alloantigen-activated cells after solid organ transplantation. Thus, specific aims of this project are

1. To evaluate in vitro the potency of ABT-737 to inhibit alloantigen-activated T cells of murine and human origin;
2. To study in vivo the effects of ABT-737 alone or in combination with conventional immunosuppressants on murine allograft rejection;
3. To explore in vivo the potential of ABT-737 to induce donor-specific tolerance in the context of a mixed chimerism model (see project 2).

Based on preliminary data, we expect a potent effect of ABT-737 on suppression of alloreactive T cell responses in vitro and on allograft rejection in vivo, which makes this compound with its concomitant antineoplastic effects an attractive candidate for a new class of immunosuppressants in organ transplantation.


Project 2: “Split tolerance” after combined kidney and bone marrow transplantation: a bedside-to-bench approach to development and analysis of a new model

Although solid organ transplantation has had a huge success, major problems such as chronic rejection are still unresolved. Most of these issues could be resolved by achieving donor-specific immunological tolerance. This goal has been reached in rodents, pigs, non-human primates and humans by induction of mixed lymphohematopoietic chimerism via non-myeloablative bone marrow transplantation.

However, before a widespread clinical application of such protocols, several issues have to be resolved:

1. The current conditioning regimens to establish mixed chimerism are still too toxic for a routine clinical application;
2. The translation of first generation mixed chimerism models using intense T cell depletion from the mouse to large animals and humans has led to a state of split tolerance (i.e. rejection of one organ [bone marrow] and tolerance of a second organ [kidney] originating from the same donor), which is immunologically not understood and raises questions about the robustness of tolerance;
3. Second generation mixed chimerism protocols using costimulatory blockade by anti-CD154 mAb have revealed unexpected toxicity, when introduced to large animals and humans.

Aims:

1. establishment of an experimental model to study the phenomenon of “split tolerance” by means of a murine model of combined bone marrow and kidney transplantation.
2. analysis of tolerance mechanisms using an established alloreactive TCR-transgenic model to analyze precise mechanisms of tolerance in fully versus split tolerant mice.
3. generation of a new monoclonal antibody to block the CD40/CD154 pathway on the side of the receptor CD40 in order to avoid the toxicity of thromboembolism induced by CD154 blockade.

This project represents a novel “bedside-to-bench” approach aiming at understanding of the precise immunological mechanism behind split tolerance, by generating a new tool for analyzing donor-specific alloreactive T and B cells and by creating a new costimulatory blocking agent for development of a less toxic and clinically better applicable protocol.

Group members: