Immune Tolerance

The unit aims to develop cell-therapeutic methods and antibody-based therapeutic strategies (immuno-oncology) for the treatment of hematologic-oncologic diseases (e.g. leukemia) and complications resulting from hematopoietic stem cell transplantations (e.g. Graft-versus-Host-Disease, GvHD). The unit also explores innovative therapeutic approaches for the prevention of infections, especially those caused by multiresistant pathogens in the case of transplantations. New immune tolerance concepts are also tested in models developed by the unit, with regard to immunological and therapy-associated complications.

Prevention of GvHD using anti-human CD4 antibodies with preserved GvL effect

Assessing tissue sections under the microscope following transplantation.
© Fraunhofer IZI

Assessing tissue sections under the microscope following transplantation.

Hematopoietic reconstitution in bone marrow following transplantation of grafts treated with antibodies in a clinical trial setting.
© Fraunhofer IZI

Hematopoietic reconstitution in bone marrow following transplantation of grafts treated with antibodies in a clinical trial setting.

The main complication following an allogeneic hematopoietic stem cell transplantation is acute graft-versus-host-disease (aGvHD). The conventional treatment methods can be associated with little long-term success and toxicities. This necessitates the development of less debilitating treatment options. A new approach involves the use of a specific anti-human CD4 antibody. The antibody specifically reduces adverse immune reactions, thus minimizing the chances of GvHD development following stem cell transplantation. The influence of this anti-human CD4 antibody is currently investigated with regard to both, the prevention of GvHD and preservation of the graft-versus-leukemia (GvL) effect in a clinically relevant, humanized leukemia model. For this purpose, models are used which are particularly qualified for the transplantation of human hematopoietic stem cells and human leukemia cells. The findings obtained from these studies are essential in applying the antibody and other new drugs in the clinics. Existing leukemia models will be constantly improved and the anti-human CD4 antibody and other drugs will be evaluated.

By using humanized models, it is possible to gain new insights into immunological processes occuring during GvHD development and the GvL effect. The models and findings are not only extremely valuable for hematopoietic stem cell transplantation and leukemia treatment, but also for stem cell transplantation in other indications (e.g. autoimmune diseases).

Manufacturing and testing of CAR immune cells for the treatment of systemic hematologic-oncologic diseases

Manufacturing chimeric antigen receptor (CAR) cells as therapeutic agents.
© Fraunhofer IZI

Manufacturing chimeric antigen receptor (CAR) cells as therapeutic agents.

Acute myeloid leukemia (AML) is a malignant disease affecting the hematopoietic system whereby the unrestricted proliferation of neoplastic leukemia cells results in the suppression of healthy cells. A new and promising approach are immune cells that are genetically equipped with chimeric antigen receptors (CAR) and thus able to specifically recognize antigens on the surface of tumor cells to eliminate them.

In this project, the unit investigates different CAR cell therapies based on T and NK cells concerning their efficacy against AML cells and associated side effects. The aim is to develop an effective CAR product that demonstrates fewer side effects than conventional CAR cells. Therefore, besides others, established AML models are used which will help to gain clinically relevant insights into the mode of action of the CAR cells.

Development of a GvHD/GvL test system

Development of algorithms to differentiate between GvHD and GvL based on a test system.
© Fraunhofer IZI

Development of algorithms to differentiate between GvHD and GvL based on a test system.

Cellular immuno-oncology therapies resemble an important treatment option for leukemia. This involves the patient receiving not only stem cells but also immunologically functional cells transplanted from a suitable donor. Here, the goal is to achieve healthy hematopoietic regeneration in the patient on one hand and, on the other hand, to destroy residual tumor cells (GvL effect). The GvL effect is highly responsible for the treatment’s success but can be negatively influenced by other necessary therapies, e.g. immunosuppressive agents or certain antibodies. It is important that the GvL response and its progression can be evaluated. Therefore, a specific diagnostic and monitoring system is developed by the unit.

  • Fraunhofer Institute for Microengineering and Microsystems IMM
  • Fraunhofer Institute for Molecular Biology and Applied Ecology IME
  • Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP
  • Fraunhofer Institute for Photonic Microsystems IPMS
  • Fraunhofer Institute for Toxicology and Experimental Medicine ITEM
  • Hannover Medical School (MHH)
  • Klinikum Chemnitz gGmbH, Clinic for Hematology and Internal Oncology / Stem Cell Transplantation
  • Leipzig University, Experimental Centre of the Faculty of Medicine
  • Leipzig University, Institute of Clinical Immunology
  • Leipzig University, Institute of Medical Microbiology and Epidemiology of Infectious Diseases
  • Leipzig University, Institute of Virology
  • Makerere University, Uganda
  • University Hospital Leipzig, Autonomous Department of Hematology, Internal Oncology and Hemostaseology

  • Hilger N, Müller C, Stahl L, Müller AM, Zoennchen B, Dluczek S, Halbich C, Wickenhauser C, Gerloff D, Wurm AA, Behre G, Kretschmer A, Fricke S. Incubation of Immune Cell Grafts with MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival after Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia. Front. Immunol, 2018 Sep 28, DOI: dx.doi.org/10.3389/fimmu.2018.02408.
  • Walcher L, Müller C, Hilger N, Kretschmer A, Stahl L, Wigge S, Rengelshausen J, Müller AM, Fricke S. Effect of combined sublethal X-ray irradiation and cyclosporine A treatment in NOD scid gamma (NSG) mice. Exp Anim. 2018 Aug 3. DOI: dx.doi.org/10.1538/expanim.18-0056.
  • Namasu CY, Katzerke C, Bräuer-Hartmann D, Wurm AA, Gerloff D, Hartmann JU, Schwind S, Müller-Tidow C, Hilger N, Fricke S, Christopeit M, Niederwieser D, Behre G. ABR, a novel inducer of transcription factor C/EBPα, contributes to myeloid differentiation and is a favorable prognostic factor in acute myeloid leukemia. Oncotarget. 2017 Oct 26;8(61):103626-103639. DOI: dx.doi.org/10.18632/oncotarget.22093.
  • Wurm AA, Zjablovskaja P, Kardosova M, Gerloff D, Bräuer-Hartmann D, Katzerke C, Hartmann JU, Benoukraf T, Fricke S, Hilger N, Müller AM, Bill M, Schwind S, Tenen DG, Niederwieser D, Alberich-Jorda M, Behre G. Disruption of the C/EBPα-miR-182 balance impairs granulocytic differentiation. Nat Commun. 2017 Jun 29;8(1):46. DOI: dx.doi.org/10.1038/s41467-017-00032-6.
  • Diehl R, Ferrara F, Müller C, Dreyer AY, McLeod DD, Fricke S, Boltze J. Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches. Cell Mol Immunol. 2017 Feb;14(2):146-179. DOI: dx.doi.org/10.1038/cmi.2016.39.
  • Hilger N, Glaser J, Müller C, Halbich C, Müller A, Schwertassek U, Lehmann J, Ruschpler P, Lange F, Boldt A, Stahl L, Sack U, Oelkrug C, Emmrich F, Fricke S. Attenuation of graft-versus-host-disease in NOD scid IL-2Rγ(-/-) (NSG) mice by ex vivo modulation of human CD4(+) T cells. Cytometry A. 2016 Sep;89(9):803-15. DOI: dx.doi.org/10.1002/cyto.a.22930.
  • Sack U, Boldt A, Mallouk N, Gruber R, Krenn V, Berger-Depincé AE, Conrad K, Tarnok A, Lambert C, Reinhold D, Fricke S. Cellular analyses in the monitoring of autoimmune diseases. Autoimmun Rev. 2016 Sep;15(9):883-9. DOI: dx.doi.org/10.1016/j.autrev.2016.07.010.
  • Schmidt F, Hilger N, Oelkrug C, Svanidze E, Ruschpler P, Eichler W, Boldt A, Emmrich F, Fricke S. Flow cytometric analysis of the graft-versus-Leukemia-effect after hematopoietic stem cell transplantation in mice. Cytometry A. 2015 Apr;87(4):334-45. DOI: dx.doi.org/10.1002/cyto.a.22619.
  • Boldt A, Kahlenberg F, Fricke S, Rasche FM, Sack U. Flow cytometric phenotyping of lymphocytes in patients with systemic lupus erythematosus. Cytometry A. 2014 Jul;85(7):567-9.DOI: dx.doi.org/10.1002/cyto.a.22477.
  • Boldt A, Kentouche K, Fricke S, Borte S, Kahlenberg F, Sack U. Differences in FOXP3 and CD127 expression in Treg-like cells in patients with IPEX syndrome. Clinical Immunoloy. 2014 Jul;153(1):109-11. DOI: dx.doi.org/10.1016/j.clim.2014.04.001.
  • Fricke S, Hilger N, Fricke C, Schönfelder U, Behre G, Ruschpler P, Boldt A, Oelkrug C, Sack U, Emmrich F. Prevention of graft-versus-host-disease with preserved graft-versus-leukemia-effect by ex vivo and in vivo modulation of CD4(+) T-cells. Cellular and Molecular Life Science. 2014 Jun;71(11):2135-48.DOI: dx.doi.org/10.1007/s00018-013-1476-0.
  • Boldt A, Borte S, Fricke S, Kentouche K, Emmrich F, Borte M, Kahlenberg F, Sack U. Eight-color immunophenotyping of T-, B-, and NK-cell subpopulations for characterization of chronic immunodeficiencies. Cytometry B Clinical Cytometry. 2014 May;86(3):191-206.DOI: dx.doi.org/10.1002/cyto.b.21162.