Benutzerspezifische Werkzeuge

Transplantation Immunology Lab (AG TxI)

Introduction

As part of the Excellence Cluster and in collaboration with the German Bone Marrow Donor Centre (DKMS), our lab focuses on the biology and function of immune effector cells after transplantation in patients with leukemia. In particular, T cells and natural killer (NK) cells are studied in various functional and molecular aspects.

Projects

About T cell research

Acute myeloid leukemia is a heterogenous malignant disease of the hematopoietic system. Therapeutic options for treating AML are still limited, with allogeneic hematopoietic cell transplantation (alloHCT) being the only curative approach for most patients. Treatment with leukemia-specific T-cells might help to avoid the risk of an alloHCT or further improve it’s efficacy.

T cells play an important role in the immune response against leukemia. T cells are able to kill cancer cells after recognition of neo-epitopes presented by major histocompatibility complexes class I molecules (MHC I) on the cell surface. The key molecule on the surface of T cells which defines specificity is the T-cell receptor (TCR).

However, remaining challenges have limited the discovery of leukemia-specific T cells. First, T cells specific for a given leukemia antigen are very rare in the peripheral blood. Second, only a small number of immunogenic leukemia specific epitopes is known. Third, both TCRs and MHCs are polyspecific, allowing binding of several peptides with sequence similarity. Fourth, the affinities of TCRs to peptide MHC complexes might be very low.

A promising approach to detect leukemia-specific T cells is the antigen-directed detection method, which consider exclusively leukemia-specific antigens and the use of the sensitive multimer technology for detection. Our research group works on this approach (see Figure 1)

to (I) identify and isolate novel leukemia-specific T cell clones by multimer technology and flowcytometry,

to (II) to characterize the leukemia specific T cells by multi-color flowcytometry and flowcytometry based degranulation assays and

to (III) sequence the TCR of functional leukemia-specific T cells for the use in T cell-based immunotherapy for leukemia patients after transplantation.

Figure 1. Workflow for the Detection of Neoantigen-specific T cells.

NK-cell research

Natural killer (NK) cells play a pivotal role in the immune response against malignant cells. After HCT for leukemia, donor derived NK cells have the potential to attack residual leukemic cells - thereby contributing to the prevention of relapse. Anti-leukemic activity of NK cells might depend on the gene content of the donor, who is equipped with a donor specific set of NK cell receptor genes. Killer-cell Immunoglobulin-like Receptor (KIR) genes are of special interest for our group.

We would like to investigate whether information on the constitution of donor KIR genes in combination with the patients KIR ligands might be exploited for optimizing HCT-donor selection in order to improve success of the therapy. Therefore we analyze phenotype and function of peripheral blood NK cells or of generated NK-cell clones and correlate results to genetic information on KIR and KIR ligands. The immunophenotype of NK cells is characterized by us using multi-color flowcytometry and CyTOF. Degranulation and cytotoxic potential is evaluated by flowcytometry-based functional assays with primary AML blasts, and genetically and phenotypically characterized cell lines as target cells.

Figure 2. NK cells mediated killing of leukemic cells triggered by missing inhibitory ligands on target cell.

Members

Prof. Dr. med. Johannes Schetelig
+49- 0351 458-15604

Dr. rer. nat. Falk Heidenreich
+49- 0351 458-2924

Dr. rer. nat. Elke Rücker-Braun
+49- 0351 458-2924

Dr. rer. nat. Dana Vu Van
+49- 0351 458-2924

Heike Uhlemann

Nicole Heymann