Tolerogenic Cell Therapy

Objectives

Long term goals:

  • Establishment of HLA silencing as a robust method for the production of universal cells and tissues to be applied in a randomized manner independently of the patient’s genetic background.
  • Use of HLA-silenced cell products as an alternative therapeutic approach to immunossuppression for the prevention of rejection after allogeneic transplantation, and therefore reducing the costs for the health care system.
  • Use HLA-silenced cells as a strategy towards personalized medicine.
  • Identification of novel mechanisms that might contribute to graft rejection.
  • Comprehensive understanding of the role of Semaphorins in the differentiation of progenitor cells and activation of immune responses.

Milestones for the next 5 years: 

  • Evaluation of the effectiveness of HLA universal platelets (HLA silenced platelets) in a mouse model
  • Evaluation of the effect of HLA silenced endothelial cells in the protection of biomaterials
  • Standardization of HLA silencing in different tissues and organs in their original 3D-structure
  • Evaluation of the beneficial effect of HLA-silencing
  • Characterization of the role of Semaphorins in the regulation of immune responses and cell differentiation

Research Focus

The high variability of the human leukocyte antigen (HLA) remains a major hurdle in transplantation and to the application of in vitro pharmed cell products. Our research group aims at the development of innovative strategies to decrease the immunogenicity of cells, tissues and organs to facilitate their use in allogeneic transplantation. The application of HLA-universal cell-based therapies has the potential to reduce the need for immunosuppression and represent an alternative option for strong alloimmunised patients with lower probabilities to find a compatible tissue or organ. Beside the modification of native tissues and organs, our group focuses in the large-scale production of low immunogenic cell types such as platelets and endothelial cells from HLA-universal induced pluripotent stem cells. Furthermore, we are interested on the characterization of the potential of using members of the Semaphorin family. These might be used as biomarkers for a precise and anticipated detection of deleterious immune responses that may contribute to organ rejection or lead to autoimmunity. We have already demonstrated that Semaphorins play an important role in the regulation of immune responses and in cell differentiation. The generation of HLA-universal cell products represents a new step in the field of regenerative medicine

Collaborations

  • R. Stripecke, REBIRTH Unit Regenerative Immune Therapies: Evaluation of the effect of Semaphorin in the regulation of HLA class II expression in professional and non-professional antigen-presenting cells.
  • A. Schambach, REBIRTH Unit Regenerative Gene Therapy: Construction of a GMP compatible vector for silencing HLA expression.
  • A. Haverich, B. Wiegmann, REBIRTH Unit Biohybrid Lung: Silencing HLA class I expression in endothelial cells for the development of the biohybrid lung.
  • Willem Wolkers, REBIRTH Unit, Biostabilization of tissues and macromolecular assemblies, Long term storage of platelets.
  • Thomas Moritz and Nico Lachmann, REBIRTH Unit Enhanced and synthetic cells for regeneration, Differentiation of iPSCs
  • Ulrich Martin, REBIRTH Unit iPSCs for Disease Modelling, Drug Screening and Cell Therapy, Use iPSCs for blood cell production
  • C. Guzman, K. Schulze, Helmholtz Centre for Infection Biology: Evaluation of the functionality of HLA-silenced platelets. 
  • K. Engelmann, Institute for Anatomy, TU Dresden: HLA silencing in human corneas 
  • M. Valtink, Institute for Anatomy, TU Dresden: HLA silencing in human corneas 
  • T Witte, Clinic for Immunology and Rheumatology, MHH: Evaluation of Sema5A as a biomarker for rheumatoid arthritis 
  • R. Jacobs, Clinic for Immunology and Rheumatology, MHH: Evaluation of Sema5A as a biomarker for rheumatoid arthritis 
  • German Society for tissue Transplantation – HLA silencing in tissues 
  • Alexandra Marques, University of Minho, Portugal: HLA-silenced endothelial cells for protection of biomaterials

Publications

2013 - ongoing

2017

Lau S, Eicke D, Carvalho Oliveira M, Wiegmann B, Schrimpf C, Haverich A, Blasczyk R, Wilhelmi M, Figueiredo C, Boer U. Low immunogenic endothelial cells maintain morphofunctional properties needed for tissue engineering. Tissue Eng Part A. 2017/10/06 ed2017.

Baigger A, Blasczyk R, Figueiredo C. Towards the Manufacture of Megakaryocytes and Platelets for Clinical Application. Transfus Med Hemother. 2017/06/20 ed2017. p. 165-73.

2016

Borger AK, Eicke D, Wolf C, Gras C, Aufderbeck S, Schulze K, Engels L, Eiz-Vesper B, Schambach A, Guzman CA, Lachmann N, Moritz T, Martin U, Blasczyk R, Figueiredo C. Generation of HLA-universal iPSCs-derived megakaryocytes and platelets for survival under refractoriness conditions. Molecular medicine. 2016;22.

2015

Bunse CE, Fortmeier V, Tischer S, Zilian E, Figueiredo C, Witte T, Blasczyk R, Immenschuh S, Eiz-Vesper B. Modulation of Heme Oxygenase-1 by Metalloporphyrins Increases Anti-Viral T Cell Responses. Clin Exp Immunol. 2015;179(2):265-76.

Ratuszny D, Gras C, Bajor A, Borger AK, Pielen A, Borgel M, Framme C, Blasczyk R, Figueiredo C. Mir-145 Is a Promising Therapeutic Target to Prevent Cornea Scarring. Hum Gene Ther. 2015;26(10):698-707. Epub 2015/07/15.

Gras C, Ratuszny D, Hadamitzky C, Zhang H, Blasczyk R, Figueiredo C. Mir-145 Contributes to Hypertrophic Scarring of the Skin by Inducing Myofibroblast Activity. Mol Med. 2015;21:296-304.

Lachmann N, Ackermann M, Frenzel E, Liebhaber S, Brennig S, Happle C, Hoffmann D, Klimenkova O, Luttge D, Buchegger T, Kuhnel MP, Schambach A, Janciauskiene S, Figueiredo C, Hansen G, Skokowa J, Moritz T. Large-Scale Hematopoietic Differentiation of Human Induced Pluripotent Stem Cells Provides Granulocytes or Macrophages for Cell Replacement Therapies. Stem Cell Reports. 2015;4(2):282-96.

Sundarasetty BS, Kloess S, Oberschmidt O, Naundorf S, Kuehlcke K, Daenthanasanmak A, Gerasch L, Figueiredo C, Blasczyk R, Ruggiero E, Fronza R, Schmidt M, von Kalle C, Rothe M, Ganser A, Koehl U, Stripecke R. Generation of Lentivirus-Induced Dendritic Cells under Gmp-Compliant Conditions for Adaptive Immune Reconstitution against Cytomegalovirus after Stem Cell Transplantation. J Transl Med. 2015;13:240.

Figueiredo C, Blasczyk R. A Future with Less Hla: Potential Clinical Applications of Hla-Universal Cells. Tissue Antigens. 2015;85(6):443-9.

Daenthanasanmak A, Salguero G, Sundarasetty BS, Waskow C, Cosgun KN, Guzman CA, Riese P, Gerasch L, Schneider A, Ingendoh A, Messerle M, Gabaev I, Woelk B, Ruggiero E, Schmidt M, von Kalle C, Figueiredo C, Eiz-Vesper B, von Kaisenberg C, Ganser A, Stripecke R. Engineered Dendritic Cells from Cord Blood and Adult Blood Accelerate Effector T Cell Immune Reconstitution against Hcmv. Mol Ther Methods Clin Dev. 2015;1:14060.

Dorresteijn MJ, Paine A, Zilian E, Fenten MG, Frenzel E, Janciauskiene S, Figueiredo C, Eiz-Vesper B, Blasczyk R, Dekker D, Pennings B, Scharstuhl A, Smits P, Larmann J, Theilmeier G, van der Hoeven JG, Wagener FA, Pickkers P, Immenschuh S. Cell-Type-Specific Downregulation of Heme Oxygenase-1 by Lipopolysaccharide Via Bach1 in Primary Human Mononuclear Cells. Free Radic Biol Med. 2015;78:224-32.

2014

Muller T, Schlahsa L, Zhang HJ, Skaik Y, Eiz-Vesper B, Immenschuh S, Blasczyk R, Figueiredo C. Allogeneic and Xenogeneic Anti-Tumor Effect of Callithrix Jacchus Natural Killer Cells Is Dependent on Nkp30 and B7-H6 Interaction. J Biol Regul Homeost Agents. 2014;28(2):183-93.

Zhang H, Goudeva L, Immenschuh S, Schambach A, Skokowa J, Eiz-Vesper B, Blasczyk R, Figueiredo C. Mir-155 Is Associated with the Leukemogenic Potential of the Class Iv Granulocyte Colony-Stimulating Factor Receptor in Cd34(+) Progenitor Cells. Mol Med. 2014;20:736-46.

Gras C, Eiz-Vesper B, Jaimes Y, Immenschuh S, Jacobs R, Witte T, Blasczyk R, Figueiredo C. Secreted Semaphorin 5a Activates Immune Effector Cells and Is a Biomarker for Rheumatoid Arthritis. Arthritis Rheumatol. 2014;66(6):1461-71.

Saragih H, Zilian E, Jaimes Y, Paine A, Figueiredo C, Eiz-Vesper B, Blasczyk R, Larmann J, Theilmeier G, Burg-Roderfeld M, Andrei-Selmer LC, Becker JU, Santoso S, Immenschuh S. Pecam-1-Dependent Heme Oxygenase-1 Regulation Via an Nrf2-Mediated Pathway in Endothelial Cells. Thromb Haemost. 2014;111(6):1077-88.

Salguero G, Daenthanasanmak A, Munz C, Raykova A, Guzman CA, Riese P, Figueiredo C, Langer F, Schneider A, Macke L, Sundarasetty BS, Witte T, Ganser A, Stripecke R. Dendritic Cell-Mediated Immune Humanization of Mice: Implications for Allogeneic and Xenogeneic Stem Cell Transplantation. J Immunol. 2014;192(10):4636-47.

Tischer S, Dieks D, Sukdolak C, Bunse C, Figueiredo C, Immenschuh S, Borchers S, Stripecke R, Maecker-Kolhoff B, Blasczyk R, Eiz-Vesper B. Evaluation of Suitable Target Antigens and Immunoassays for High-Accuracy Immune Monitoring of Cytomegalovirus and Epstein-Barr Virus-Specific T Cells as Targets of Interest in Immunotherapeutic Approaches. J Immunol Methods. 2014;408:101-13.

Figueiredo C, Blaszczyk R. Genetically Engineered Blood Pharming: Generation of Hla-Universal Platelets Derived from Cd34+ Progenitor Cells. J Stem Cells. 2014;9(3):149-61.

Schlahsa L, Zhang H, Battermann A, Verboom M, Immenschuh S, Eiz-Vesper B, Stripecke R, Engelmann K, Blasczyk R, Figueiredo C. Semaphorin 3a Alters Endothelial Cell Immunogenicity by Regulating Class Ii Transactivator Activity Circuits. Transfusion. 2014;54(8):1961-70.

Wiegmann B, Figueiredo C, Gras C, Pflaum M, Schmeckebier S, Korossis S, Haverich A, Blasczyk R. Prevention of Rejection of Allogeneic Endothelial Cells in a Biohybrid Lung by Silencing Hla-Class I Expression. Biomaterials. 2014;35(28):8123-33.

Skaik Y, Vahlsing S, Goudeva L, Eiz-Vesper B, Battermann A, Blasczyk R, Figueiredo C. Secreted Β(3)-Integrin Enhances Natural Killer Cell Activity against Acute Myeloid Leukemia Cells. PLoS ONE. 2014;9(6):e98936.

2013

Gras C, Eiz-Vesper B, Seltsam A, Immenschuh S, Blasczyk R, Figueiredo C. Semaphorin 7a Protein Variants Differentially Regulate T-Cell Activity. Transfusion. 2013;53(2):270-83.

Sukdolak C, Tischer S, Dieks D, Figueiredo C, Goudeva L, Heuft HG, Verboom M, Immenschuh S, Heim A, Borchers S, Mischak-Weissinger E, Blasczyk R, Maecker-Kolhoff B, Eiz-Vesper B. Cmv-, Ebv- and Adv-Specific T Cell Immunity: Screening and Monitoring of Potential Third-Party Donors to Improve Post-Transplantation Outcome. Biol Blood Marrow Transplant. 2013;19(10):1480-92.

Skaik Y, Battermann A, Hiller O, Meyer O, Figueiredo C, Salama A, Blasczyk R. Development of a Single-Antigen Magnetic Bead Assay (Samba) for the Sensitive Detection of Hpa-1a Alloantibodies Using Tag-Engineered Recombinant Soluble Beta3 Integrin. J Immunol Methods. 2013;391(1-2):72-80.

Gras C, Schulze K, Goudeva L, Guzman CA, Blasczyk R, Figueiredo C. Hla-Universal Platelet Transfusions Prevent Platelet Refractoriness in a Mouse Model. Hum Gene Ther. 2013;24(12):1018-28.

Bunse CE, Borchers S, Varanasi PR, Tischer S, Figueiredo C, Immenschuh S, Kalinke U, Kohl U, Goudeva L, Maecker-Kolhoff B, Ganser A, Blasczyk R, Weissinger EM, Eiz-Vesper B. Impaired Functionality of Antiviral T Cells in G-Csf Mobilized Stem Cell Donors: Implications for the Selection of Ctl Donor. PLoS One. 2013;8(12):e77925.

Sundarasetty BS, Singh VK, Salguero G, Geffers R, Rickmann M, Macke L, Borchers S, Figueiredo C, Schambach A, Gullberg U, Provasi E, Bonini C, Ganser A, Woelfel T, Stripecke R. Lentivirus-Induced Dendritic Cells for Immunization against High-Risk Wt1(+) Acute Myeloid Leukemia. Hum Gene Ther. 2013;24(2):220-37.

Figueiredo C, Wedekind D, Muller T, Vahlsing S, Horn PA, Seltsam A, Blasczyk R. Mhc Universal Cells Survive in an Allogeneic Environment after Incompatible Transplantation. Biomed Res Int. 2013;2013:796046.

Rickmann M, Macke L, Sundarasetty BS, Stamer K, Figueiredo C, Blasczyk R, Heuser M, Krauter J, Ganser A, Stripecke R. Monitoring Dendritic Cell and Cytokine Biomarkers During Remission Prior to Relapse in Patients with Flt3-Itd Acute Myeloid Leukemia. Ann Hematol. 2013;92(8):1079-90.

Tischer S, Bunse C, Figueiredo C, Immenschuh S, Blasczyk R, Eiz-Vesper B. The New Hla-B*58:21 Allele Is Predicted to Be Functionally Similar to the B*58:01p Group of Alleles. Tissue Antigens. 2013;81(3):178-9.

Zilian E, Figueiredo C, Eiz-Vesper B, Blasczyk R, Immenschuh S. The New Hla-C Variant Hla-C*05:26 Is Likely to Be Structurally Identical to the C*05:01p Alleles. Tissue Antigens. 2013;81(3):179-80.

Figueiredo C, Blasczyk R. RNA Interference-Mediated Cell Camouflage: A Novel Approach to Prevent Rejection in Allogeneic Transplantation. Advances in Genetics Research. Volume 10. 2013 ISBN: 978-1-62417-929-7

2006 - 2012

2012

Gras C, Immenschuh S, Eiz-Vesper B, Blasczyk R, Figueiredo C. The Novel Allele Hla-B*35:167 Differs from Hla-B*35:03:01 by the Amino Acid Exchange Val152glu. Tissue Antigens. 2012;79(2):135-7.

Daenthanasanmak A, Salguero G, Borchers S, Figueiredo C, Jacobs R, Sundarasetty BS, Schneider A, Schambach A, Eiz-Vesper B, Blasczyk R, Weissinger EM, Ganser A, Stripecke R. Integrase-Defective Lentiviral Vectors Encoding Cytokines Induce Differentiation of Human Dendritic Cells and Stimulate Multivalent Immune Responses in Vitro and in Vivo. Vaccine. 2012;30(34):5118-31.

Pincha M, Sundarasetty BS, Salguero G, Gutzmer R, Garritsen H, Macke L, Schneider A, Lenz D, Figueiredo C, Blasczyk R, Ruggiero E, Schmidt M, von Kalle C, Puff C, Modlich U, von der Leyen H, Wicke DC, Ganser A, Stripecke R. Identity, Potency, in Vivo Viability, and Scaling up Production of Lentiviral Vector-Induced Dendritic Cells for Melanoma Immunotherapy. Hum Gene Ther Methods. 2012;23(1):38-55.

Wachstein J, Tischer S, Figueiredo C, Limbourg A, Falk C, Immenschuh S, Blasczyk R, Eiz-Vesper B. Hsp70 Enhances Immunosuppressive Function of Cd4(+)Cd25(+)Foxp3(+) T Regulatory Cells and Cytotoxicity in Cd4(+)Cd25(-) T Cells. PLoS One. 2012;7(12):e51747.

Schlahsa L, Immenschuh S, Eiz-Vesper B, Blasczyk R, Figueiredo C. Hla-B*08:01:08- Joining the Fold of Silent Alpha-1 Proline Mutations in Hla-B. Tissue Antigens. 2012;79(3):208-9.

Jaimes Y, Gras C, Goudeva L, Buchholz S, Eiz-Vesper B, Seltsam A, Immenschuh S, Blasczyk R, Figueiredo C. Semaphorin 7a Inhibits Platelet Production from Cd34+ Progenitor Cells. J Thromb Haemost. 2012;10(6):1100-8.

Martens J, Verboom M, Figueiredo C, Eiz-Vesper B, Blasczyk R, Immenschuh S. The New Hla Allele, Hla-a*03:57, Differs from Hla-a*03:01 by Two Amino Acids at Positions 76 and 77 in the Alpha2 Domain Affecting the Pocket F of the Peptide-Binding Groove. Tissue Antigens. 2012;79(2):131-2.

Tischer S, Kaireit T, Figueiredo C, Hiller O, Maecker-Kolhoff B, Geyeregger R, Immenschuh S, Blasczyk R, Eiz-Vesper B. Establishment of the Reversible Peptide-Major Histocompatibility Complex (Pmhc) Class I Histamer Technology: Tool for Visualization and Selection of Functionally Active Antigen-Specific Cd8(+) T Lymphocytes. Int Immunol. 2012;24(9):561-72.

Foll D, Hinrichs J, Tischer S, Battermann A, Schambach A, Figueiredo C, Immenschuh S, Blasczyk R, Eiz-Vesper B. Closing the Gap: Discrimination of the Expression Profile of Hla Questionable Alleles by a Cytokine-Induced Secretion Approach Using Hla-a*32:11q. Tissue Antigens. 2012;79(5):340-50.

2011

Salguero G, Sundarasetty BS, Borchers S, Wedekind D, Eiz-Vesper B, Velaga S, Jirmo AC, Behrens G, Warnecke G, Knofel AK, Blasczyk R, Mischak-Weissinger E, Ganser A, Stripecke R. Preconditioning Therapy with Lentiviral Vector-Programmed Dendritic Cells Accelerates the Homeostatic Expansion of Antigen-Reactive Human T Cells in Nod.Rag1-/-.Il-2rgammac-/- Mice. Hum Gene Ther. 2011;22(10):1209-24.

Bajor A, Tischer S, Figueiredo C, Wittmann M, Immenschuh S, Blasczyk R, Eiz-Vesper B. Modulatory Role of Calreticulin as Chaperokine for Dendritic Cell-Based Immunotherapy. Clin Exp Immunol. 2011;165(2):220-34.

Jaimes Y, Seltsam A, Eiz-Vesper B, Blasczyk R, Figueiredo C. Regulation of Hla Class Ii Expression Prevents Allogeneic T-Cell Responses. Tissue Antigens. 2011;77(1):36-44.

Schlahsa L, Jaimes Y, Blasczyk R, Figueiredo C. Granulocyte-Colony-Stimulatory Factor: A Strong Inhibitor of Natural Killer Cell Function. Transfusion. 2011;51(2):293-305.

2010

Jaimes Y, Figueiredo C, Blasczyk R. Silencing the Expression of Platelet Endothelial Cell Adhesion Molecule-1 Prevents Allogeneic T-Cell Cytotoxicity. Transfusion. 2010;50(9):1988-2000.

Guech-Ongey M, Verboom M, Pfeiffer RM, Schulz TF, Ndugwa CM, Owor AM, Bakaki PM, Bhatia K, Figueiredo C, Eiz-Vesper B, Blasczyk R, Mbulaiteye SM. Hla Polymorphisms and Detection of Kaposi Sarcoma-Associated Herpesvirus DNA in Saliva and Peripheral Blood among Children and Their Mothers in the Uganda Sickle Cell Anemia Kshv Study. Infect Agent Cancer. 2010;5:21.

Figueiredo C, Goudeva L, Horn PA, Eiz-Vesper B, Blasczyk R, Seltsam A. Generation of Hla-Deficient Platelets from Hematopoietic Progenitor Cells. Transfusion. 2010;50(8):1690-701.

2009

Figueiredo C, Mbulaiteye S, Ndugwa CM, Schulz T, Eiz-Vesper B. Assessment of the Amino Acid Substitution in Hla-B*5719 for Allorecognition. Tissue Antigens. 2009;73(4):376-8.

Figueiredo C, Jaimes Y, Horn PA, Blasczyk R, Eiz-Vesper B. The New Hla-Cw*0524 Allele Increase the Variability of Position 49 in Hla-C. Tissue Antigens. 2009;74(3):258-9.

Figueiredo C, Seltsam A, Blasczyk R. Permanent Silencing of Nkg2a Expression for Cell-Based Therapeutics. J Mol Med (Berl). 2009;87(2):199-210.

Hinrichs J, Figueiredo C, Hirv K, Mytilineos J, Blasczyk R, Horn PA, Eiz-Vesper B. Discrimination of Hla Null and Low Expression Alleles by Cytokine-Induced Secretion of Recombinant Soluble Hla. Mol Immunol. 2009;46(7):1451-7.

Figueiredo C, Wittmann M, Wang D, Dressel R, Seltsam A, Blasczyk R, Eiz-Vesper B. Heat Shock Protein 70 (Hsp70) Induces Cytotoxicity of T-Helper Cells. Blood. 2009;113(13):3008-16.

2007

Figueiredo C, Horn PA, Blasczyk R, Seltsam A. Regulating Mhc Expression for Cellular Therapeutics. Transfusion. 2007;47(1):18-27.

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