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
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 (5tg) will be combined with 4ko 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 (2ko, 3tg) 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/B4GALNT2-3ko 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-2tg 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 4ko, 5tg pigs will be tested in the orthotopic transplantation model in baboons with improved immunosuppressive regimens (C8).
DFG Programme
CRC/Transregios
Completed 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
)
-
B02 - Genetically modified pigs to modulate vascular and cellular rejection
(Project Heads
Flisikowska, Ph.D., Tatiana
;
Knolle, Percy Alexander
;
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, Stefan R.
;
Brendel, Mathias
;
Ludwig, Barbara
;
Peakman, Ph.D., Mark
;
Sancho Zapatero, Rocio
;
Welzel, Petra B.
)
-
C06 - Xenogeneic activation of complement and coagulation
(Project Heads
Johanning, Kai
;
Ramackers, Wolf
;
Tiede, Andreas
;
Winkler, Michael
)
-
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
)
