TRR 127:  Biology of Xenogeneic Cell and Organ Transplantation - From Bench to Bedside

• Subject Area: Biology ; Agriculture, Forestry and Veterinary Medicine ; Medicine ; Social and Behavioural Sciences
• Term: from 2012 to 2024
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213602983

The TRR 127 aims to dissect the biology of xenogeneic cell, tissue and organ transplantation and develops evidence-based concepts that bring xenotransplantation of porcine pancreatic islets, heart valves, and hearts from bench to bedside. Three closely interacting Project Groups A, B and C are supported by the Central Project Group Z that focuses on ethical, legal and societal issues (Z1), microbiological safety (Z2), provision of safe donor pigs with effective and stable genetic modifications (Z3), and non-human primate (NHP) studies (Z4). Project Group A is developing concepts to modulate immune mechanisms at the xenograft-host interface. This includes i) downregulation of swine leukocyte antigens (SLA) and selection of suitable donor-recipient combinations by SLA-HLA (H = human) matching (A1); ii) local immunomodulation by recombinant adeno-associated viral vectors (rAAV), micro-RNAs, or small hairpin (sh) RNAs (A2); and iii) mechanisms of the instant blood-mediated inflammatory reaction after intraportal islet transplantation (A3, A5). In addition, protocols for Treg-mediated tolerance induction will be established (A4).Project Group B is developing and characterising genetically multi-modified donor pigs. Pigs carrying hCD46, hCD55, hCD59, hHO1 and hA20 expression vectors (5tg) will be combined with 4ko pigs that lack SLA class I, GGTA1, CMAH and B4GALNT2 to provide multi-modified pigs for transplantation of xeno-hearts and heart valves (B1&2). Pigs that lack GGTA1 and CCL2 and express LEA29Y, hPD-L1 and hCD47 (2ko, 3tg) are produced as optimised donors of xeno-islets. Single-cell RNA sequencing will be employed to inform and improve methods of maturing neonatal porcine islets (NPIs) (B3).Project Group C will perform preclinical xenotransplantation experiments and develop clinical study protocols. The optimal age and maturation stage of NPIs will be refined and their functionality tested (C1). For intraportal free islet transplantation, NPIs with different combinations of genetic modifications will be used in diabetic NHPs with novel immunosuppressive strategies (C3). A clinical study protocol for macroencapsulated porcine islets has been submitted; this approach will be further optimised employing cutting-edge bio-polymer technologies (C4). Successful efforts to generate haemodynamically effective, immunocompatible xenogeneic pulmonary heart valves from GGTA1/CMAH/B4GALNT2-3ko pigs will be extended using advanced decellularisation and deglycosylation techniques (C7). The world’s first consistent long-term success after orthotopic xenotransplantation of GGTA1-ko, hCD46/hTBM-2tg pig hearts in baboons required perfusion with cold, hyperoncotic, oxygenated preservation solution, appropriate immunosuppression, and medication to prevent overgrowth of the xeno-hearts. In future experiments, hearts from 4ko, 5tg pigs will be tested in the orthotopic transplantation model in baboons with improved immunosuppressive regimens (C8).

• DFG Programme: CRC/Transregios

Current projects

• A01 - Targeting stimulatory and inhibitory receptor/ligand interactions to diminish human anti-pig immune responses (Project Heads Figueiredo, Constanca ;  Hundrieser, Joachim ;  Schwinzer, Reinhard )
• A02 - Local immunomodulation by viral vectors and genetic modifications (Project Heads Bähr, Andrea ;  Hinkel, Rabea ;  Kupatt, Christian ;  Michel, Sebastian ;  Murray, Peter J. )
• A03 - Analysis of inflammatory circuits during the Instant Blood-Mediated Inflammatory Reaction (Project Heads Chavakis, Triantafyllos ;  Ludwig, Barbara ;  Waskow, Claudia )
• A04 - Regulatory T cells (Tregs) in xenotransplantation (Project Heads Jaeckel, Elmar ;  Noyan, Fatih ;  Pohla, Heike )
• A05 - Immunogenicity of islets of different clinically relevant sources in a preclinical humanized mouse model (Project Heads Klymiuk, Nikolai ;  Linkermann, Andreas ;  Ludwig, Barbara ;  Waskow, Claudia )
• B01 - Modifying the porcine genome for xeno-organ transplantation (Project Heads Fischer, Konrad ;  Kues, Wilfried A. ;  Lucas-Hahn, Andrea ;  Niemann, Heiner ;  Petersen, Björn ;  Schnieke, Angelika )
• B03 - Genetically engineered donor pigs with improved pancreatic islets (Project Heads Böttcher, Anika ;  Kemter, Elisabeth Gabriele ;  Klymiuk, Nikolai ;  Wolf, Eckhard ;  Wünsch, Annegret )
• C01 - Optimization of porcine neonatal islet like cell clusters for clinical transplantation therapy (Project Heads Bonifacio, Ph.D., Ezio ;  Cohrs, Christian ;  Gavalas, Ph.D., Anthony ;  Kemter, Elisabeth Gabriele ;  Solimena, Michele ;  Speier, Stephan )
• C03 - Treatment of type 1 diabetes with porcine islet cells: transplantation of multi-transgenic islets expressing immunomodulatory molecules (Project Heads Seissler, Jochen ;  Wolf-van Bürck, Lelia )
• C04 - Optimizing porcine islet macroencapsulation for the treatment of patients with insulin-dependent diabetes mellitus (Project Heads Bornstein, Ph.D., Stefan R. ;  Brendel, Mathias ;  Ludwig, Barbara ;  Peakman, Ph.D., Mark ;  Sancho Zapatero, Rocio ;  Welzel, Petra B. )
• C07 - Preclinical assessment of decellularised (antigen-reduced), gene-modified porcine heart valves (Project Heads Büttner, Falk ;  Cebotari, Serghei ;  Haverich, Axel ;  Hilfiker, Andres ;  Martin, Ulrich ;  Niemann, Heiner )
• C08 - Steps to clinical xenogeneic cardiac replacement (Project Heads Abicht, Jan-Michael ;  Brenner, Paolo ;  Buchholz, Stefan ;  Guethoff, Sonja ;  Längin, Matthias ;  Reichart, Bruno )
• V - Administration (Project Head Wolf, Eckhard )
• Z01 - Ethical, legal, psychosocial, and societal issues (ELSI) of xenotransplantation (XT) (Project Heads Hoppe, Nils ;  Marckmann, Georg ;  Reichart, Bruno ;  Sautermeister, Jochen )
• Z02 - Microbiological safety including virological safety (Project Heads Denner, Joachim ;  Godehardt, Antonia Wiga ;  Kaufer, Ph.D., Benedikt Bertold ;  Tönjes, Ralf R. )
• Z03 - Core facility for genetically engineered pig lines (Project Heads Kaup, Franz-Josef ;  Keßler, Barbara ;  Kues, Wilfried A. ;  Lucas-Hahn, Andrea ;  Niemann, Heiner ;  Petersen, Björn ;  Schnieke, Angelika ;  Wolf, Eckhard )
• Z04 - Core facility for non-human primates (NHP) (Project Heads Hinkel, Rabea ;  Kaup, Franz-Josef ;  Lampe, Karen ;  Schönmann, Uwe )

Completed projects

• B02 - Genetically modified pigs to modulate vascular and cellular rejection (Project Heads Flisikowska, Ph.D., Tatiana ;  Knolle, Percy Alexander ;  Schnieke, Angelika )
• C06 - Xenogeneic activation of complement and coagulation (Project Heads Johanning, Kai ;  Ramackers, Wolf ;  Tiede, Andreas ;  Winkler, Michael )

• Applicant Institution: Ludwig-Maximilians-Universität München
• Co-Applicant Institution: Medizinische Hochschule Hannover; Technische Universität Dresden
• Participating University: Freie Universität Berlin; Technische Universität München (TUM)
• Participating Institution: Deutsches Primatenzentrum GmbH (DPZ); Leibniz-Institut für Primatenforschung; Leibniz-Institut für Polymerforschung Dresden e.V.; Institut Biofunktionelle Polymermaterialien; im Max Bergmann Center of Biomaterials Dresden; Helmholtz Zentrum München, GmbH; Deutsches Forschungszentrum für Gesundheit und Umwelt; Institut für Diabetesforschung; Friedrich-Loeffler-Institut ; Bundesforschungsinstitut für Tiergesundheit ; Institut für Nutztiergenetik; Max-Planck-Institut für Biochemie (MPIB); Paul-Ehrlich-Institut; Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel; DZD-Paul-Langerhans-Institut Dresden (PLID); am Universitätsklinikum Carl Gustav Carus der TU Dresden
• Spokespersons: Professor Dr. Bruno Reichart, until 6/2016; Professor Dr. Eckhard Wolf, since 7/2017