KFO 243

Project Description

ELITE "Early Immunological Determinants of Late Transplant Outcome", also known as Klinische Forschergruppe (KFO) 243, is a six-year (2010-2016) Clinical Research Unit project funded by the DFG and supported by the University Hospital Regensburg and the University of Regensburg. It is dedicated to investigating the early immunologic factors that determine the long-term success of transplanted allografts and will use the integrative knowledge obtained from our various interdisciplinary research groups to design novel therapeutic approaches that can be applied clinically to reduce late transplant complication and achieve long-term success. Research from our various workgroups will be directed towards two principal immunologic aspects that are likely to affect transplant outcome, namely recipient innate and adaptive immune responses. The study of both the innate and cellular immune response within our KFO is expected to reveal new insights into which immunological factors are critical in forming favourable, versus poor, allogeneic transplant outcomes. By understanding these complex early events more fully, we hope to develop new therapeutic strategies to control and monitor pathologic posttransplant alloreactivity, thereby improving long-term transplant outcome.

Long-term graft acceptance is the ultimate goal of transplantation medicine. However, the sophisticated immune defences of the transplant recipient serve to confound this objective, making late transplant complications and tissue rejection major obstacles in this area of therapeutic surgery. KFO 243 is centered on the view that long-term immunological destruction in solid organ transplantation, and in prevailing graft-versus-host reactions in stem cell transplantation, is the inescapable consequence of a chain of events initiated in the early post-transplant period. The early immunological determinants of late transplant outcome are many and multiply-redundant; therefore, an integrative understanding of the pathways by which early responses to transplants feed-forward into late rejection and graft-versus-host disease (GvHD) processes is needed.

Through investigation of early phase (peri-transplant) immunological events, we aim to identify the immunological factors that are critical in forming favourable, versus poor, allogeneic transplant outcomes. The research projects in KFO 243 focus on the most important junctures between early post-transplant triggers and the processes of late graft damage by studying selected early innate and cellular interactions that could potentially be monitored or harnessed therapeutically to improve late transplant outcome.

Non-specific innate recognition mechanisms are particularly important in shaping very early reactions to transplants, establishing the chain of consequences that ultimately results in chronic allograft-related pathology. Orchestrating this response is the balance between effector and regulatory subsets of key cell types, including T cells, B cells, NK cells and macrophages. These cells can be triggered by innate immune responses and determine allograft rejection, or tolerance, by their ability to migrate towards immunological hot-spots, where their complex interactions coordinate immune reactions. The workgroups within our KFO cooperatively integrate the study of both innate and adaptive immune responses to allogeneic transplanted tissues, in order to establish a dynamic model of host transplant immunology.

The ELITE team has chosen to study selected early innate and cellular interactions that could potentially be monitored or harnessed therapeutically. Our ultimate goal is to use the knowledge gained from several areas of interdisciplinary research to develop novel therapeutic strategies to control and monitor pathologic post-transplant alloreactivity, thereby translating innovative basic science concepts into the clinical transplant setting and improving long-term transplant outcome.





Strategic Research Interests

The Universitätsklinikum Regensburg has an international reputation of excellence in the field of basic and applied Transplantation Immunology. Transplantation Medicine and Immuno-pathology/therapy are two primary strategic areas of interest in our Medical Faculty. Thus we have assembled an interdisciplinary research group involving both laboratory scientists and clinicians within the University Hospital Regensburg, which is devoted to the aim of translating innovative basic science concepts into the clinical transplant setting.

This research focus led to the development of another Clinical Research Unit (KFO 146: “Cell-mediated suppression of auto- and allo-reactive immune responses”), and very close interactions between KFO146 and this KFO are aimed at fostering the development of cell therapy strategies in the transplant setting. Since 2008, the University of Regensburg has been the coordinating centre of the Bavarian immune therapy network (BayImmuNet) and currently runs several BayImmuNet projects. This infrastructure – in conjunction with the new GMP-facility “José-Carreras Center for Somatic Cell Therapy” – provides an ideal setting for translational immunological research in transplantation.

The ELITE investigators are well-established and recognized within their field as experts, or as promising young new key opinion leaders. Our senior investigators are known internationally for their innovative research and have long publication records in respected transplantation and immunology journals. Several young scientists with outstanding potential have also established integral roles in this KFO group.

The Medical Faculty and ELITE are devoted to the education of young researchers. The motivation for scientific work by medical students is fostered by systematic presentations of scientific topics within the Faculty (“Doktorandenbörse”). All scientists and “Doktoranden” of the ELITE project participate in an “immunological seminar” series, held at two-week intervals together with KFO 146 to optimize exchange between the two KFO units. We expect to establish lasting, highly competitive structures that bridge the gap between basic researchers and clinical scientists.

Collaborations between basic scientists and surgeons in the transplant clinic, within and between the workgroups in KFO 243, enable a dynamic union of scientific expertise. Each individual group cooperates with at least three other projects in the consortium, and the C1 and C2 central projects offer essential laboratory resources and administrative support to all ELITE researchers. The interactions between members of this KFO are absolutely essential to meeting our ultimate aim of integrating and translating basic science knowledge into novel clinical approaches aimed at improving long-term allograft survival.



Principal Investigators and Project Titles

First 3-year funding period starting 01.08.2010
Second 3-year funding period starting 28.08.2013

Nr.

Project Title

Principal Investigators

Dept/Clinic
Institute/Division

P1

The role of beta-defensins in allogeneic transplantation

Thomas Hehlgans
Ernst Holler

Immunology
Haem/Oncology

P2

Interplay between receptors of innate immunity and vitamin D3 for the induction of alloreactions through antigen-presenting cells

Ernst Holler
Marina Kreutz
Sigrid Karrer

Haem/Oncology

Dermatology

P3

Role of IL-13 and TGF-β in the development of chronic rejection in solid organ transplantation

Stefan Fichtner-Feigl

Surgery

P4

Basophils as potential modulators of humoral and cellular allo-immune responses

Matthias Mack

Nephrology

P5

Role of natural killer cells in transplantation tolerance and rejection

Alexander Krömer
Elke Eggenhofer
Edward K. Geissler

Surgery
Experimental Surgery

P6

Humoral immune reconstitution after allogeneic stem cell transplantation

Matthias Edinger

Haem/Oncology

P8

First Funding Period  (01.08.2010 – 28.08.2013)

Comparing the early immunological responses of liver transplant recipients treated under a bottom-up immunosuppressive regimen utilising either CsA or Everolimus

James Hutchinson
Andreas Schnitzbauer
Hans J. Schlitt

Experimental Surgery
Surgery

C1

First Funding Period  (01.08.2010 – 28.08.2013)
Project still ongoing

Central provision of organ transplant models and flow cytometry facilities

James A. Hutchinson
Gudrun Koehl
Bernhard Banas

Experimental Surgery

Nephrology

C2

Coordination and Administration

Edward K. Geissler, Coordinator
Hans J. Schlitt, Speaker

Experimental Surgery
Surgery






Project Summaries & Leaders

P1: The role of beta-defensins in allogeneic transplantation
Prof. Dr. rer. nat. Thomas Hehlgans  -  Immunology
Prof. Dr. Ernst Holler  -  Haematology/Oncology

Beta-defensins are small antimicrobial peptides that play an important role in innate immunity. Members of the beta-defensin family also have the ability to act as chemokines and activators of other immune cell types, thereby promoting both local innate inflammatory and systemic adaptive immune responses. The expression of several beta-defensins is induced by a group of intracellular pattern recognition receptors (NODs), and single nucleotide polymorphisms (SNPs) in NOD genes are associated with severe complications following transplantation. Thomas Hehlgans and Ernst Holler aim to identify and functionally characterize the role of beta-defensins and beta-defensin receptors in allogeneic transplantation, using mice transgenic for beta-defensin expression. As a translational approach, this project also analyzes human beta-defensin expression in bone marrow transplant and liver transplant recipients.
Prof. Dr. Thomas Hehlgans

Contact:
Prof. Dr. Thomas Hehlgans
Institute of Immunology
University of Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: + 49 941 944 5463
Telefax: + 49 941 944 5462
E-Mail: thomas.hehlgans@ukr.de

Prof. Dr. Ernst Holler

Contact:
Prof. Dr. Ernst Holler
Head of Allogenic Transplantation
Dept. of Hematology and Oncology
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telefon: +49 941 944 5542 (Secretariat)
Telefax: +49 941 944 5543
E-Mail: ernst.holler@ukr.de




P2: Interplay between receptors of innate immunity and vitamin D3 for the induction of alloreactions through antigen-presenting cells
Prof. Dr. Ernst Holler - Haematology/Oncology
Prof. Dr. rer. nat. Marina Kreutz - Haematology/Oncology
Prof. Dr. Sigrid Karrer - Dermatology

Tissue injury as a consequence of transplantation often results in loss of epithelial barrier function leading to microbial exposure and antigen-presenting cell (APC) activation. In this context, interactions between pattern recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs) trigger the early (innate) immune response. Polymorphisms within certain PRRs have been associated with more severe graft-versus host disease (GvHD) and a worse outcome in allogeneic stem cell transplantation (SCT). Ernst Holler and his co-investigators aim to analyze the influence of variations in PRR expression on the phenotype and function of APCs, to characterize the development of either excessive or tolerogenic immune states. This project directly links the innate and adaptive immune systems, and may prove helpful in predicting which transplant recipients might be most susceptible or resistant to disturbances in their early immune response.
Prof. Dr. Ernst Holler

Contact:
Prof. Dr. Ernst Holler
Head of Allogenic Transplantation
Dept. of Hematology and Oncology
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telefon: +49 941 944 5542 (Secretariat)
Telefax: +49 941 944 5543
E-Mail: ernst.holler@ukr.de

Prof. Dr. Marina Kreutz

Contact:
Prof. Dr. Marina Kreutz
Department of Hematology and Oncology
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 5577
Telefax: +49 941 944 5593
E-Mail: marina.kreutz@ukr.de

Prof. Dr. Sigrid Karrer

Contact:
Prof. Dr. Sigrid Karrer
Department of Dermatology
University Hospital Regensburg
Franz-Josef-Strauss Allee 11
93053 Regensburg, Germany
Telephone: + 49 941 944 9656 or 9603
Telefax: + 49 941 944 9657
E-mail: sigrid.karrer@ukr.de




P3: Role of IL-13 and TGF-β in the development of chronic rejection in solid organ transplantation
Prof. Dr. Stefan Fichtner-Feigl - Surgery

Although great progress has been made to reduce the problem of acute rejection in transplant recipients, chronic rejection and fibrosis still remain significant obstacles for long-term transplant survival. Approximately 30% of renal transplant recipients ultimately lose their graft due to this process. To make fresh progress towards reducing this problem, it is essential to understand the early ongoing sources of immunologic activity that promote the fibrotic process. Key players of the fibrotic program are the cytokines IL-13 and TGF-β1, connected through a recently identified IL-13 receptor. Stefan Fichtner-Feigl hypothesises that the IL-13 – TGF-β1 interaction is responsible for the induction of allograft fibrosis. By studying the fibrotic program following heart transplantation in mice, he aims to show that early-mid-stage manipulation of this interaction could open new therapeutic approaches to preventing allograft fibrosis and chronic organ failure.
PD Dr. Stefan Fichtner-Feigl

Contact:
Prof. Dr. Stefan Fichtner-Feigl 
Department of Surgery
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 6868
Telefax:  +49 941 944 6802
E-Mail: stefan.fichtner@ukr.de




P4: Basophils as potential modulators of humoral and cellular allo-immune responses
Prof. Dr. Matthias Mack - Nephrology

Until recently, basophils were considered mainly as effector cells of an innate immune response linked to allergy and parasite infection. However, basophils have now become recognized as important regulators of adaptive immunity. A memory type immune response predominates in transplantation, especially following acute rejections or in the setting of chronic transplant rejection. Matthias Mack studies the role of basophils as modulators of humoral and cellular immune responses during acute and chronic transplant rejection, with the hypothesis that activation of basophils is a good indicator for ongoing memory immune responses. Preliminary data suggest that alloantigens from allografts activate basophils and that CD4 cell secretion of IL-3 promotes this process, thus increasing both acute and chronic rejection. By understanding this process in a transplantation setting, he anticipates to design strategies to inhibit this basophil-mediated promotion of tissue rejection.
Prof. Dr. Matthias Mack

Contact:
Prof. Dr. Matthias Mack
Department of Nephrology
University Hospital Regensburg
Franz-Josef-Strauss Allee 11
93053 Regensburg, Germany
Telefon: +49 941 944 7315
Telefax: +49 941 944 7302
E-Mail: matthias.mack@ukr.de




P5: Role of natural killer cells in transplantation tolerance and rejection
Dr. Alexander Krömer - Surgery
PD Dr. rer. nat. Elke Eggenhofer - Experimental Surgery
Prof. Edward K. Geissler, PhD - Experimental Surgery

Natural killer (NK) cells are crucial albeit dichotomous players in solid organ transplantation, as they have recently been shown to be critical contributors to both allograft rejection and tolerance induction. This dichotomous role can be explained by differences in NK cells’ cytokine-dependent activation status. Recent data demonstrate that NK cells are functionally heterogeneous and that distinct NK cell subsets respond differently to cytokine-mediated activation. Based on this, Alexander Krömer speculates that NK cells can be classified into pro-tolerant and pro-inflammatory subsets according to “high” and “low” responsiveness to cytokine-dependent activation. His research suggests that early cytokine activation of distinct NK cell subsets may be critical in determining the development of either a long-term tolerance, or inflammatory, state following transplantation. Since the role of NK cells as effector cells in transplantation has not been adequately addressed, Dr. Krömer’s work may have an important impact on the development of new clinical tolerance induction protocols.
Dr. Alexander Krömer

Contact:
Dr. Alexander Krömer
Department of Surgery
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 6944
Telefax:  +49 941 944 6802
E-Mail: alexander.kroemer@ukr.de

PD Dr. Elke Eggenhofer

Contact:
PD Dr. rer. nat. Elke Eggenhofer
Experimental Surgery
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 6914 or 6983
Telefax:  +49 941 944 4877
E-Mail: elke.eggenhofer@ukr.de

Prof. Edward Geissler

Contact:
Prof. Edward K. Geissler, PhD
Head of Experimental Surgery
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 6964 or 6961
Telefax:  +49 941 944 6886
E-Mail: edward.geissler@ukr.de




P6: Humoral immune reconstitution after allogeneic stem cell transplantation
Prof. Dr. Matthias Edinger - Haematology/Oncology

Graft-versus-host disease (GvHD) is a major complication after allogeneic stem cell transplantation (SCT). Patients with GvHD suffer from prolonged immunodeficiency, which is usually attributed to the required immunosuppressive therapy. Using appropriate mouse models, Matthias Edinger aims to examine whether GvHD itself contributes to the delayed immune reconstitution. By analyzing the reconstitution of humoral immunity, Prof. Edinger hopes to evaluate the entire adoptive immune system in drug-free transplantation models. The final goal of this project is the identification of crucial cellular and molecular mechanisms causing immunodeficiency in GvHD and the development of new strategies fostering tolerance and immunity after transplantation. This idea is based on the hypothesis that if early GvHD can be inhibited with T regulatory cell therapy, the immune system will re-establish itself more quickly after SCT, thus improving patient recovery and late outcome.
Prof. Dr. Matthias Edinger

Contact:
Prof. Dr. Matthias Edinger
Dept. of Hematology and Oncology
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 5580 or 5582 (Sec.)
Telefax: +49 941 944 5581
E-Mail: matthias.edinger@ukr.de



First Funding Period  (01.08.2010 – 28.08.2013)

P8: Comparing the early immunological responses of liver transplant recipients 124 treated under a bottom-up immunosuppressive regimen utilising either CsA or everolimus
Dr. Dr. James A. Hutchinson - Experimental Surgery
PD Dr. Andreas Schnitzbauer - Surgery
Prof. Dr. med. Hans J. Schlitt - Surgery

Conventional immunosuppressive agents are effective in preventing rejection responses, but they can also suppress the development of regulatory responses. It has been suggested that early immunological activation is essential to induce later immunoregulatory processes, and with this in mind, Hans Schlitt, Andreas Schnitzbauer and James Hutchinson have designed a clinical trial that uses a “bottom-up” immunosuppression principle. Liver transplant recipients will be treated based on the delayed introduction of either CsA or Everolimus. This trial protocol therefore affords the unique opportunity to study minimally-hindered early immunological events that may determine a “good” or “poor” transplant outcome. Immunologic monitoring of patients in the trial will serve to systematically categorise or describe the early and late immune status of the stable versus rejecting patients, to test the hypothesis that bottom-up, as opposed to top-down, immunosuppression promotes the early expansion of regulatory cell types. This project hopes to establish an optimised tolerance-promoting immunosuppressive protocol for liver transplant patients that could be used as a suitable platform for testing novel, cell-based immunosuppressive therapies.
Dr. James Hutchinson

Contact:
Dr. James Hutchinson
Department of Surgery
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 6831 or 6987
Telefax:  +49 941 944 6772
E-Mail: james.hutchinson@ukr.de

PD Dr. Andreas Schnitzbauer

Contact:
PD Dr. Andreas Schnitzbauer
Current affiliation:
University Hospital Frankfurt
Department of Surgery
Theodor-Stern-Kai 7
60590 Frankfurt am Main, Germany
Telephone: +49 69 / 6301-5253, 5080 (Sek.)
Telefax:  +49 69 / 6301-6211
E-Mail: andreas.schnitzbauer@kgu.de

Prof. Dr. Hans-Jürgen Schlitt

Contact:
Prof. Dr. Hans-Jürgen Schlitt
Director of Surgery Dept.
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 6801
Telefax: +49 941 944 6802
E-Mail: hans.schlitt@ukr.de



First Funding Period  (01.08.2010 – 28.08.2013)
Project still ongoing

C1: Central provision of organ transplant models and flow cytometry facilities
Dr. Dr. James A. Hutchinson - Experimental Surgery
Dr. rer. nat. Gudrun Koehl - Experimental Surgery
Prof. Dr. med. Bernhard Banas - Nephrology

The central project provides the ELITE research groups with two essential methodologies. Firstly, the C1 project provides access to well-established heart and skin transplant models in mice, centralising collective expertise in these technically challenging microsurgical methods. Selected medical technicians in the Department of Surgery are highly trained in the performance of these intricate surgical techniques and provide for our needs of murine organ transplantation on a regular basis. Secondly, as all projects require access to a polychromatic flow cytometer, the central project also supports KFO 243 with the provision of a central flow cytometry facility. A new FACSCanto-II (BD) cytometer within the Department of Surgery supports the research of all KFO 243 workgroups in the ELITE team.
Dr. James Hutchinson

Contact:
Dr. James Hutchinson
Department of Surgery
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 6831 or 6987
Telefax:  +49 941 944 6772
E-Mail: james.hutchinson@ukr.de

Dr. Gurdun Köhl

Contact:
Dr. Gudrun Köhl
Department of Surgery
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 4875 or 6980
Telefax:  +49 941 944 4877
E-Mail: gudrun.koehl@ukr.de

Prof. Dr. Bernhard Banas

Contact:
Prof. Dr. Bernhard Banas
Department of Nephrology
University Hospital Regensburg
Franz-Josef-Strauss Allee 11
93053 Regensburg, Germany
Telefon: +49 941 944 7301
Telefax: +49 941 944 7302
E-Mail: bernhard.banas@ukr.de




C2: Coordination and Administration
Prof. Edward K. Geissler, PhD - Head of Experimental Surgery
Prof. Dr. Hans J. Schlitt - Director of Surgery

The C2 project serves to centrally administer the KFO 243 group. Within this framework, the coordinating investigators organize seminars and symposia, administer the allotted funds for Gerok positions, flexible research fellowships, travel and publication costs, and also care for public relations and the homepage of the EL.
Prof. Edward Geissler

Contact: KFO243 Coordinator
Prof. Edward K. Geissler, PhD
Head of Experimental Surgery
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 6964 or 6961
Telefax: +49 941 944 6886
E-Mail: edward.geissler@ukr.de

Prof. Dr. Hans-Jürgen Schlitt

Contact: KFO243 Speaker
Prof. Dr. Hans-Jürgen Schlitt
Director of Surgery Dept.
University Hospital Regensburg
Franz-Josef-Strauss-Allee 11
93053 Regensburg, Germany
Telephone: +49 941 944 6801
Telefax: +49 941 944 6802
E-Mail: hans.schlitt@ukr.de