SFB 738: Optimisation of Conventional and Innovative Transplants
Final Report Abstract
The focus of CRC 738 "Optimization of conventional and innovative transplants" was the development of improved (therapeutic) interventions for solid organ and stem cell transplantation. With the ongoing short-age of organs in Germany, one of the goals of transplantation medicine is to bring every available donor organ into the patient with optimal efficiency and best prognoses. After organ transplantation patients have to be treated for a lifetime with medication that drastically suppresses their immune system. This intervention is inevitably and without alternative because this is the only way an allogeneic organ can survive in the recipient without being rejected by its immune system. However, this treatment leads to drastic side effects, such as higher infection rates, higher probability of carcinogenesis, kidney dysfunction or development of diabetes. One of the outstanding findings of this research network was to identify the influence of the immunological elements of the recipient immune system in relation to the protection of transplanted organ. With the help of these regulatory immune cells, the researchers at CRC738 were able to demonstrate in preclinical models that the transplanted organs (e.g. skin, lungs, pulmonary arteries) were tolerated by the recipient immune system. The molecular understanding of the function and improvement of these cells, which has been researched by various projects of the CRC738, has also contributed to the fact that this option of therapy will be used and implemented in patients in a first worldwide clinical trial in 2020. The medical standard for the treatment of hematopoietic diseases (e.g. leukemia) is stem cell transplantation of a tissue-compatible donor. For the treatment the patient's immune system has to be completely eradicated beforehand. But even with tissue compatibility, life-threatening secondary diseases after transplantation can occur, which lead to the development of a “graft-versus-host” disease (GvHD) often resulting in systemic organ failure and finally in death. Furthermore, a stem cell transplantation completed is no guarantee for the successful treatment of leukemia. The likelihood of recurrent leukemia is too great. The scientists of CRC738 were able to develop therapies that could not only significantly reduce the probability of GvHD, but also generated strategies to prevent relapse. These forms of therapy developed in CRC738 are already part of everyday medical practice at Hannover Medical School (MHH). The third pillar of the CRC738 focused on the optimization of the grafts by its optimal preservation in the period between removal and transplantation. Techniques and methods have been developed that influence the short or long-term outcome of graft survival. With the identification of the responsible cells and the mechanisms that lead to organ damage after the so-called ischemia reperfusion injury, protocols and methods were developed that prevented this transplant damage and thus minimized damage to the organ and the associated malfunction or rejection after transplantation. In retrospect, the CRC738 has achieved remarkable and trend-setting success during its twelve-year tenure. Results from the individual CRC738 projects led to the fact that many of the findings summarized here already belong to the standard repertoire in the clinical treatment of patients at Hannover Medical School.
Publications
- 2011. Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV- specific CD8+ T cells. PLoS pathogens 7:e1002045
Schlaphoff V, Lunemann S, Suneetha PV, Jaroszewicz J, Grabowski J, Dietz J, Helfritz F, Bektas H, Sarrazin C, Manns MP, Cornberg M, Wedemeyer H
(See online at https://doi.org/10.1371/journal.ppat.1002045) - Augmentation of Transient Donor Cell Chimerism and Alloantigen-Specific Regulation of Lung Transplants in Miniature Swine Am. J. Transplant.
Avsar M, Jansson K, Sommer W, Kruse B, Thissen S, Dreckmann K, Knoefel AK, Salman J, Gottlieb J, Hafer C, Hecker J, Buechler G, Karstens JH, Jonigk D, Länger F, Kaever V, Falk CS, Hewicker-Trautwein M, Ungefroren H, Haverich A, Strüber M, Warnecke G
(See online at https://doi.org/10.1111/ajt.13629) - (2016). MicroRNA-125b-5p mimic inhibits acute liver failure. Nat Commun. 7:11916
Yang D, Yuan Q, Balakrishnan A, Bantel H, Klusmann JH, Manns MP, Ott M, Cantz T, Sharma AD
(See online at https://doi.org/10.1038/ncomms11916) - Alpharetroviral selfinactivating vectors produced by a superinfection-resistant stable packaging cell line allow genetic modification of primary human T lymphocytes. Biomaterials. 2016;97:97-109
Labenski V, Suerth JD, Barczak E, Heckl D, Levy C, Bernadin O, Charpentier E, Williams DA, Fehse B, Verhoeyen E, Schambach A
(See online at https://doi.org/10.1016/j.biomaterials.2016.04.019) - Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments. J Am Soc Nephrol. 2016; 27: 1609
Baisantry A, Bhayana S, Rong S, Ermeling E, Wrede C, Hegermann J, Pennekamp P, Sörensen-Zender I, Haller H, Melk A, Schmitt R
(See online at https://doi.org/10.1681/asn.2014111059) - Chemokines and Chemokine Receptors in Lymphoid Tissue Dynamics. Annu Rev Immunol 34: 203-244 (2016)
Schulz O, Hammerschmidt SI, Moschovakis GL, Forster R
(See online at https://doi.org/10.1146/annurev-immunol-041015-055649) - Direct Reprogramming of Hepatic Myofibroblasts into Hepatocytes In Vivo Attenuates Liver Fibrosis. Cell Stem Cell. 2016 2;18(6):797-808
Song G, Pacher M, Balakrishnan A, Yuan Q, Tsay HC, Yang D, Reetz J, Brandes S, Dai Z, Pützer BM, Araúzo-Bravo MJ, Steinemann D, Luedde T, Schwabe RF, Manns MP, Schöler HR, Schambach A, Cantz T, Ott M, Sharma AD
(See online at https://doi.org/10.1016/j.stem.2016.01.010) - Gene Insertion Into Genomic Safe Harbors for Human Gene Therapy. Mol Ther. 2016 Apr;24(4):678-84
Papapetrou EP, Schambach A
(See online at https://doi.org/10.1038/mt.2016.38) - Generation of genetically engineered precursor T cells from human umbilical cord blood using an optimized alpharetroviral vector platform. Mol Ther. 2016 Aug;24(7):1216-26
Hübner J, Hoseini SS, Suerth JD, Hoffmann D, Maluski M, Herbst J, Maul H, Ghosh A, Eiz-Vesper B, Yuan Q, Ott M, Heuser M, Schambach A, Sauer MG
(See online at https://doi.org/10.1038/mt.2016.89) - Hepatic Infiltrates in Operational Tolerant Patients After Liver Transplantation Show Enrichment of Regulatory T Cells Before Proinflammatory Genes Are Downregulated. Am J Transplant. 2016 Apr;16(4):1285-93
Taubert R, Danger R, Londoño MC, Christakoudi S, Martinez-Picola M, Rimola A, Manns MP, Sánchez-Fueyo A, Jaeckel E
(See online at https://doi.org/10.1111/ajt.13617) - Host cell mTORC1 is required for HCV RNA replication. Gut. 2016 Dec; 65(12):2017-2028
Stöhr S, Costa R, Sandmann L, Westhaus S, Pfaender S, Anggakusuma, Dazert E, Meuleman P, Vondran FW, Manns MP, Steinmann E, von Hahn T, Ciesek S
(See online at https://doi.org/10.1136/gutjnl-2014-308971) - In Vivo Development of Transplant Arteriosclerosis in Humanized Mice Reflects Alloantigen Recognition and Peripheral Treg Phenotype of Lung Transplant Recipients. Am J Transplant. 2016 Nov;16(11):3150-3162
Siemeni T, Knöfel AK, Madrahimov N, Sommer W, Avsar M, Salman J, Ius F, Frank N, Büchler G, Jonigk D, Jansson K, Maus U, Tudorache I, Falk CS, Haverich A, Warnecke G
(See online at https://doi.org/10.1111/ajt.13905) - miR-21 promotes fibrosis in an acute cardiac allograft transplantation model. Cardiovasc Res 110: 215-26 (2016)
Gupta SK, Itagaki R, Zheng X, Batkai S, Thum S, Ahmad F, Van Aelst LN, Sharma A, Piccoli MT, Weinberger F, Fiedler J, Heuser M, Heymans S, Falk CS, Forster R, Schrepfer S, Thum T
(See online at https://doi.org/10.1093/cvr/cvw030) - Production of Mature Healthy Hematopoietic Cells from Induced Pluripotent Stem Cells Derived from an AML Diagnostic Sample Containing the t(8;21) Translocation. Stem Cells. 2016;34(3):797-9
Hoffmann D, Göhring G, Heuser M, Ganser A, Schambach A, Morgan MA
(See online at https://doi.org/10.1002/stem.2207) - The yin and yang of autophagy in acute kidney injury. Autophagy. 2016; 12: 596
Melk A, Baisantry A, Schmitt R
(See online at https://doi.org/10.1080/15548627.2015.1135284) - Tumoral immune cell exploitation in colorectal cancer liver metastases can be targeted effectively by anti- CCR5 therapy in cancer patients. Cancer Cell. 2016 29(4):587-601
Halama N, Zoernig I, Spille A, Kahlert C, Klupp F, Suetterlin T, Brand K, Krauss J, Lasitschka F, Lerchl T, Luckner-Minden C, Ulrich A, Koch M, Weitz J, Schneider M, Buechler MW, Zitvogel L, Herrmann T, Benner A, Kunz C, Luecke S, Springfeld C, Grabe N, Falk CS, Jaeger D
(See online at https://doi.org/10.1016/j.ccell.2016.03.005) - Association of Higher CD4+ CD25high CD127low , FoxP3+ , and IL-2+ T Cell Frequencies Early After Lung Transplantation With Less Chronic Lung Allograft Dysfunction at Two Years. Am J Transplant. 2017 Jun;17(6):1637-1648
Salman J, Ius F, Knoefel AK, Sommer W, Siemeni T, Kuehn C, Tudorache I, Avsar M, Nakagiri T, Preissler G, Hatz R, Greer M, Welte T, Haverich A, Warnecke G
(See online at https://doi.org/10.1111/ajt.14148) - Dendritic cell migration in health and disease. Nat Rev Immunol 17: 30-48 (2017)
Worbs T, Hammerschmidt SI, Forster R
(See online at https://doi.org/10.1038/nri.2016.116) - IL-1β limits the extent of human 6-sulfo LacNAc dendritic cell (slanDC)-mediated NK cell activation and regulates CD95-induced apoptosis. Cell Mol Immunol. 2017 Dec;14(12):976-985
Tufa DM, Ahmad F, Chatterjee D, Ahrenstorf G, Schmidt RE, Jacobs R
(See online at https://doi.org/10.1038/cmi.2016.17) - Plexiform vasculopathy in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2017; 196(8)
Ackermann M, Gaumann A, Mentzer SJ, Hinrichs JB, Warnecke G, Hoeper MM, Braubach P, Kuehnel M, Mägel L, Jonigk D
(See online at https://doi.org/10.1164/rccm.201703-0591im) - Prevention of allograft rejection by use of regulatory T cells with an MHC- specific chimeric antigen receptor. Am J Transplant. 2017;17(4):917-930
Noyan F, Zimmermann K, Hardtke-Wolenski M, Knoefel A, Schulde E, Geffers R, Hust M, Huehn J, Galla M, Morgan M, Jokuszies A, Manns MP, Jaeckel E
(See online at https://doi.org/10.1111/ajt.14175) - Repulsive behavior in germinal centers. Science 356: 703-704 (2017)
Moschovakis GL, Forster R
(See online at https://doi.org/10.1126/science.aan5222) - The human cytomegalovirus glycoprotein pUL11 acts via CD45 to induce T cell IL-10 secretion.. PLoS Pathog. 2017 Jun 19;13(6)
Zischke J, Mamareli P, Pokoyski C, Gabaev I, Buyny S, Jacobs R, Falk CS, Lochner M, Sparwasser T, Schulz TF, Kay-Fedorov PC
(See online at https://doi.org/10.1371/journal.ppat.1006454) - The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development J Autoimmun. 2017 Mar;78:39-45
Hardtke-Wolenski M, Dywicki J, Fischer K, Hapke M, Sievers M, Schlue J, Anderson MS, Taubert R, Noyan F, Manns MP, Jaeckel E
(See online at https://doi.org/10.1016/j.jaut.2016.12.001) - WO2017/211617 A1: Medicament for the treatment of acute liver failure
Sharma AD, Ott T, Cantz T, Yang D
- 2018. Systemic inflammation and immune cell phenotypes are associated with neuro-psychiatric symptoms in patients with chronic inflammatory liver diseases.Liver Int. 38:2317-2328
Aregay A, Dirks M, Schlaphoff V, Owusu Sekyere S, Haag K, Falk CS, Hengst J, Bremer B, Schuppner R, Manns MP, Pflugrad H, Cornberg M, Wedemeyer H, Weissenborn K
(See online at https://doi.org/10.1111/liv.13869) - Bioreactor-based mass production of human iPSC-derived macrophages enables immunotherapies against bacterial airway infections. Nat Commun. 2018;9(1):5088
Ackermann M, Kempf H, Hetzel M, Hesse C, Hashtchin AR, Brinkert K, Schott JW, Haake K, Kühnel MP, Glage S, Figueiredo C, Jonigk D, Sewald K, Schambach A, Wronski S, Moritz T, Martin U, Zweigerdt R, Munder A, Lachmann N
(See online at https://doi.org/10.1038/s41467-018-07570-7) - Human Teratoma-Derived Hematopoiesis Is a Highly Polyclonal Process Supported by Human Umbilical Vein Endothelial Cells. Stem Cell Reports. 2018;11(5):1051-1060
Philipp F, Selich A, Rothe M, Hoffmann D, Rittinghausen S, Morgan MA, Klatt D, Glage S, Lienenklaus S, Neuhaus V, Sewald K, Braun A, Schambach A
(See online at https://doi.org/10.1016/j.stemcr.2018.09.010) - Manifold Roles of CCR7 and Its Ligands in the Induction and Maintenance of bronchus-Associated Lymphoid Tissue. Cell Rep 23: 783-795 (2018)
Fleige H, Bosnjak B, Permanyer M, Ristenpart J, Bubke A, Willenzon S, Sutter G, Luther SA, Forster R
(See online at https://doi.org/10.1016/j.celrep.2018.03.072) - (2019). Hepatocyte-specific suppression of microRNA-221-3p mitigates liver fibrosis. J Hepatol. 70(4):722-34
Tsay HC, Yuan Q, Balakrishnan A, Kaiser M, Möbus S, Kozdrowska E, Farid M, Tegtmeyer PK, Borst K, Vondran FWR, Kalinke U, Kispert A, Manns MP, Ott M, Sharma AD
(See online at https://doi.org/10.1016/j.jhep.2018.12.016) - 2019. Elimination of hepatitis C virus has limited impact on the functional and mitochondrial impairment of HCV- specific CD8+ T cell responses. J Hepatol. 2019 Jul 8
Aregay A, Owusu Sekyere S, Deterding K, Port K, Dietz J, Berkowski C, Sarrazin C, Manns MP, Cornberg M, Wedemeyer H
(See online at https://doi.org/10.1016/j.jhep.2019.06.025) - Back signaling of HLA class I molecules and T/NK cell receptor ligands in epithelial cells reflects the rejectionspecific microenvironment in renal allograft biopsies. Am J Transplant.
Egelkamp J, Chichelnitskiy E, Kühne JF, Wandrer F, Daemen K, Keil J, Bräsen JH, Schmitz J, Bellmàs-Sanz R, Iordanidis S, Katsirntaki K, Hake K, Akhdar A, Neudörfl C, Haller H, Blume C, Falk CS
(See online at https://doi.org/10.1111/ajt.15417) - Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation. Cell Reports. 2019; 26:1854
Garg G, Muschaweckh A, Moreno H, Vasanthakumar A, Floess S, Lepennetier G, Engleitner T, Oellinger R, Zhan Y, Regen T, Hiltensperger M, Peter C, Aly L, Knier B, Palam L, Kapur R, Kaplan M, Waisman A, Rad R, Schotta G, Huehn J, Kallies A, Korn T
(See online at https://doi.org/10.1016/j.celrep.2019.01.070) - Chemokines and other mediators in the development and functional organization of lymph nodes. Immunol Rev 289: 62-83 (2019)
Eckert N, Permanyer M, Yu K, Werth K, Forster R
(See online at https://doi.org/10.1111/imr.12746) - Chimeric antigen receptor-induced BCL11B suppression propagates NK-like cell development. J Clin Invest. 2019
Maluski M, Ghosh A, Herbst J, Scholl V, Baumann R, Huehn J, Geffers R, Meyer J, Maul H, Eiz-Vesper B, Krueger A, Schambach A, van den Brink MR, Sauer MG
(See online at https://doi.org/10.1172/jci126350) - Focusing of the regulatory T cell repertoire after allogeneic stem cell transplantation indicates protection from graft-versus-host disease. Haematologica. 2019 Apr 24. pii: haematol.2019.218206
Odak I, Raha S, Schultze-Florey C, Tavil S, Ravens S, Ganser A, Förster R, Prinz I, Koenecke C
(See online at https://doi.org/10.3324/haematol.2019.218206) - miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity. PLoS Biol. 2019; 17:e2006716
Ziętara N, Łyszkiewicz M, Witzlau K, Föhse L, Brownlie R, Puchalka J, Winter S, Imelmann E, Blume J, Raha S, Sekiya T, Yoshimura A, Huehn J, Weiss S, Gutierrez MG, Prinz I, Zamoyska R, Krueger A
(See online at https://doi.org/10.1371/journal.pbio.2006716) - Optimized induction of mitochondrial apoptosis for chemotherapyfree treatment of BCR-ABL+acute lymphoblastic leukemia. Leukemia. 2019 Jun;33(6):1313-1323
Scherr M, Kirchhoff H, Battmer K, Wohlan K, Lee CW, Ricke-Hoch M, Erschow S, Law E, Kloos A, Heuser M, Ganser A, Hilfiker-Kleiner D, Heidenreich O, Eder M
(See online at https://doi.org/10.1038/s41375-018-0315-6) - Targeted Repair of p47-CGD in iPSCs by CRISPR/Cas9: Functional Correction without Cleavage in the Highly Homologous Pseudogenes. Stem Cell Reports. 2019
Klatt D, Cheng E, Philipp F, Selich A, Dahlke J, Schmidt RE, Schott JW, Büning H, Hoffmann D, Thrasher AJ, Schambach A
(See online at https://doi.org/10.1016/j.stemcr.2019.08.008) - The transcription factor MAZR/PATZ1 regulates the development and function of FOXP3+ regulatory T cells. Cell Reports. 2019 Dec 24;29(13):4447-4459.e6
Andersen L, Gülich AF, Alteneder M, Preglej T, Orola MJ, Dhele N, Stolz V, Schebesta A, Hamminger P, Hladic A, Floess S, Krausgruber T, Faux T, Andrabi S, Huehn J, Knapp S, Sparwasser T, Bock C, Elo L, Laiho A, Rasool O, Lahesmaa R, Sakaguchi S, Ellmeier W
(See online at https://doi.org/10.1016/j.celrep.2019.11.089) - “Induced Dendritic Cells and Uses Thereof” (PCT/EP2013/052485). Priority date 07 February 2013; Published August 14 2014. US patent No: US10,272,111 B2. Date of patent Apr. 30, 2019
R. Stripecke, G. Salguero, A. Daenthasanmak, A. Ganser
