Regenerative Immunology and Aging
Our work area is focusing on alterations of the immune system caused by the natural aging process, infections or diseases. We are interested in the cellular and molecular changes that cause the immune system to age. During aging, natural changes take place in the immune system making it vulnerable to infections or cancer and reducing vaccination efficiency. The mechanisms responsible for this reduced immunocompetence have not yet been identified - this is where our multidisciplinary research comes in. Our current and future projects focus primarily on clinical immunology, immune monitoring, immune-cell therapies and diagnostics.
Age-related Changes in the Immune System
Despite intensive research, it is still unclear why immunocompetence is reduced in older people. It can most likely be ascribed to systemic causes which can vary from patient to patient. Together with systems biologists, we evaluate large volumes of data and examine the correlations. Taking this as a basis, we study the fundamental mechanisms of altered immunity in older people. Our goal is to allow people to age with dignity and in good health.
Organ transplant patients rely on long-term immunosuppression (i.e. permanent suppression of the immune response) to prevent organ rejection. These immunosuppressants inhibit efficient T-cell-mediated immunity against pathogens, such as viruses. In such cases, adoptive cell therapy with virus-specific T-cells from seropositive donors can be an effective treatment option in the clinical setting. Our aim is to selectively isolate antigen-specific T-cells according to activation-marker signatures with the help of recently developed methods. Magnetic-activated cell sorting (MACS) is a common technique for separating cells according to their surface markers. We were able to demonstrate that two surface markers (CD154 and CD137) are required for efficient targeted isolation of antigen-specific naïve T-cells.
Regenerative Therapies/ Adoptive T-Cell Therapies
Regulatory T-cells (Tregs) can inhibit the activity of the immune system and are therefore the focus of adoptive T-cell therapies aimed to suppress unwanted immune responses, e.g. in autoimmune diseases. Hence, the isolation and enrichment of antigen-specific regulatory T-cells makes a valuable contribution to adoptive T-cell therapies. Our group's latest findings have shown that antigen-specific Tregs and conventional T-cells can be analyzed simultaneously, thus raising the possibility of new cellular therapies with antigen-specific Tregs.
CD8 Helper T-Cells
Furthermore, we work on a newly defined cell subtype: CD8 helper T-cells. Here, we are concentrating on CD8 T-cells that express CD40L, a main molecule for T-cell help. CD40L+ CD8+ T cells provide potent helper functions, such as APC activation and expression patterns which are similar to CD4 T-cells. This new CD8 T-cell subtype is a promising candidate for cellular immunotherapies, especially for treating tumors.
We use classical flow cytometry – one of the key technologies used in conventional clinical diagnostics – in all our projects. The Core Unit "Flow Cytometry", led by Dr. Désirée Kunkel, has been integrated into our group since the BCRT was established.
Quantitative and qualitative immune analyses and the diagnostic techniques derived from these are at the heart of all our research interests. Our aim is to conduct basic research that can be easily translated to human diseases and applied in diagnostic and prognostic studies.
Dr. Julian Braun
Phone: +49 (0)30 450 539 505
Dr. Lucie Loyal
Phone: +49 (0)30 450 539 528
Dr. Lil Meyer-Arndt
Phone: +49 (0)30 450 539 457
Phone: +49 (0)30 450 539 457
Alberto Sada Japp
Dr. Jun Dong
Phone: +49 (0)30 450 539 458
Dr. Nadine Matzmohr
Phone: +49 (0)30 450 539 498
Julia Nora Mälzer
Telefon: +49 (0)30 450 539 528
Dr. Mikalai Nienen
Dr. Regina Stark
Dr. Anne Schönbrunn
- Flow cytometry
- Cell culture assays
- In vivo models/assays
- Isolation and enrichment of antigen-specific T cells
- Molecular biology methods (PCR)
- Epigenetic methods (analysis of DNA methylation and histone modification by means of bisulfite sequencing and/or chromatin immunoprecipitation)
Braun J, Kurtz A, Barutcu N, Bodo J, Thiel A, Dong J. Concerted regulation of CD34 and CD105 accompanies mesenchymal stromal cell derivation from human adventitial stromal cell. Stem Cells Dev. 2013 Mar 1;22(5):815-27. doi: 10.1089/scd.2012.0263.
Dong J, Chang HD, Ivascu C, Qian Y, Rezai S, Okhrimenko A, Cosmi L, Maggi L, Eckhardt F, Wu P, Sieper J, Alexander T, Annunziato F, Gossen M, Li J, Radbruch A, Thiel A. Loss of methylation at the IFNG promoter and CNS-1 is associated with the development of functional IFN-γ memory in human CD4(+) T lymphocytes. Eur J Immunol. 2013 Mar;43(3):793-804. doi: 10.1002/eji.201242858.
Alexander T, Schneider S, Hoyer B, Cheng Q, Thiel A, Ziemer S, Burmester GR, Arnold R, Radbruch A, Hiepe F. Development and resolution of secondary autoimmunity after autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: competition of plasma cells for survival niches? Ann Rheum Dis. 2013 Jan 29. [Epub ahead of print] No abstract available.
Na IK, Wittenbecher F, Dziubianau M, Herholz A, Mensen A, Kunkel D, Blau O, Blau I, Thiel E, Uharek L, Scheibenbogen C, Rieger K, Thiel A. Rabbit antithymocyte globulin (Thymoglobulin(R)) impairs the thymic output of both conventional and regulatory CD4+ T cells after allogeneic hematopoietic stem cell transplantation in adult patients. Haematologica. 2013 Jan;98(1):23-30. doi: 10.3324/haematol.2012.067611.
Alexander T, Sattler A, Templin L, Kohler S, Groß C, Meisel A, Sawitzki B, Burmester GR, Arnold R, Radbruch A, Thiel A, Hiepe F. Foxp3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus. Ann Rheum Dis. 2012 Dec 21. [Epub ahead of print]
Schoenbrunn A, Frentsch M, Kohler S, Keye J, Dooms H, Moewes B, Dong J, Loddenkemper C, Sieper J, Wu P, Romagnani C, Matzmohr N, Thiel A. A converse 4-1BB and CD40 ligand expression pattern delineates activated regulatory T cells (Treg) and conventional T cells enabling direct isolation of alloantigen-reactive natural Foxp3+ Treg. J Immunol. 2012 Dec 15;189(12):5985-94. doi: 10.4049/jimmunol.1201090.
Kohler S, Bethke N, Böthe M, Sommerick S, Frentsch M, Romagnani C, Niedrig M, Thiel A. The early cellular signatures of protective immunity induced by live viral vaccination. Eur J Immunol. 2012 Sep;42(9):2363-73. doi: 10.1002/eji.201142306.
Trydzenskaya H, Sattler A, Müller K, Schachtner T, Dang-Heine C, Friedrich P, Nickel P, Hoerstrup J, Schindler R, Thiel A, Melzig MF, Reinke P, Babel N. Novel approach for improved assessment of phenotypic and functional characteristics of BKV-specific T-cell immunity. Transplantation. 2011 Dec 15;92(11):1269-77.
Appel H, Wu P, Scheer R, Kedor C, Sawitzki B, Thiel A, Radbruch A, Sieper J, Syrbe U. Synovial and peripheral blood CD4+FoxP3+ T cells in spondyloarthritis. J Rheumatol. 2011 Nov;38(11):2445-51. doi: 10.3899/jrheum.110377.
Ergin A, Syrbe U, Scheer R, Thiel A, Adam T, Büssow K, Duchmann R, Zeitz M, Sieper J. Impaired peripheral Th1 CD4+ T cell response to Escherichia coli proteins in patients with Crohn's disease and ankylosing spondylitis. J Clin Immunol. 2011 Dec;31(6):998-1009. doi: 10.1007/s10875-011-9575-x.
Appel H, Maier R, Wu P, Scheer R, Hempfing A, Kayser R, Thiel A, Radbruch A, Loddenkemper C, Sieper J. Analysis of IL-17(+) cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res Ther. 2011 Jun 20;13(3):R95. doi: 10.1186/ar3370.
Mueller K, Schachtner T, Sattler A, Meier S, Friedrich P, Trydzenskaya H, Hinrichs C, Trappe R, Thiel A, Reinke P, Babel N. BK-VP3 as a new target of cellular immunity in BK virus infection. Transplantation. 2011 Jan 15;91(1):100-7.
Stittrich AB, Haftmann C, Sgouroudis E, Kühl AA, Hegazy AN, Panse I, Riedel R, Flossdorf M, Dong J, Fuhrmann F, Heinz GA, Fang Z, Li N, Bissels U, Hatam F, Jahn A, Hammoud B, Matz M, Schulze FM, Baumgrass R, Bosio A, Mollenkopf HJ, Grün J, Thiel A, Chen W, Höfer T, Loddenkemper C, Löhning M, Chang HD, Rajewsky N, Radbruch A, Mashreghi MF. The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol. 2010 Nov;11(11):1057-62. doi: 10.1038/ni.1945.
Juelke K, Killig M, Luetke-Eversloh M, Parente E, Gruen J, Morandi B, Ferlazzo G, Thiel A, Schmitt-Knosalla I, Romagnani C. CD62L expression identifies a unique subset of polyfunctional CD56dim NK cells. Blood. 2010 Aug 26;116(8):1299-307. doi: 10.1182/blood-2009-11-253286.
Juelke K, Killig M, Thiel A, Dong J, Romagnani C. Education of hyporesponsive NK cells by cytokines. Eur J Immunol. 2009 Sep;39(9):2548-55. doi: 10.1002/eji.200939307.
Sattler A, Wagner U, Rossol M, Sieper J, Wu P, Krause A, Schmidt WA, Radmer S, Kohler S, Romagnani C, Thiel A. Cytokine-induced human IFN-gamma-secreting effector-memory Th cells in chronic autoimmune inflammation. Blood. 2009 Feb 26;113(9):1948-56. doi: 10.1182/blood-2008-02-139147.
Alexander T, Thiel A, Rosen O, Massenkeil G, Sattler A, Kohler S, Mei H, Radtke H, Gromnica-Ihle E, Burmester GR, Arnold R, Radbruch A, Hiepe F. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood. 2009 Jan 1;113(1):214-23. doi: 10.1182/blood-2008-07-168286.
Babel N, Brestrich G, Gondek LP, Sattler A, Wlodarski MW, Poliak N, Bethke N, Thiel A, Hammer MH, Reinke P, Maciejewski JP. Clonotype analysis of cytomegalovirus-specific cytotoxic T lymphocytes. J Am Soc Nephrol. 2009 Feb;20(2):344-52. doi: 10.1681/ASN.2007111225.
Kohler S, Thiel A. Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets. Blood. 2009 Jan 22;113(4):769-74. doi: 10.1182/blood-2008-02-139154.
Meier S, Stark R, Frentsch M, Thiel A. The influence of different stimulation conditions on the assessment of antigen-induced CD154 expression on CD4+ T cells. Cytometry A. 2008 Nov;73(11):1035-42. doi: 10.1002/cyto.a.20640.
Thiel A, Alexander T, Schmidt CA, Przybylski GK, Kimmig S, Kohler S, Radtke H, Gromnica-Ihle E, Massenkeil G, Radbruch A, Arnold R, Hiepe F. Direct assessment of thymic reactivation after autologous stem cell transplantation. Acta Haematol. 2008;119(1):22-7. doi: 10.1159/000117824.
Kirchhoff D, Frentsch M, Leclerk P, Bumann D, Rausch S, Hartmann S, Thiel A, Scheffold A. Identification and isolation of murine antigen-reactive T cells according to CD154 expression. Eur J Immunol. 2007 Sep;37(9):2370-7.
Dong J, Ivascu C, Chang HD, Wu P, Angeli R, Maggi L, Eckhardt F, Tykocinski L, Haefliger C, Möwes B, Sieper J, Radbruch A, Annunziato F, Thiel A. IL-10 is excluded from the functional cytokine memory of human CD4+ memory T lymphocytes. J Immunol. 2007 Aug 15;179(4):2389-96.
Thiel A, Wu P, Lanowska M, Dong J, Radbruch A, Sieper J. Identification of immunodominant CD4+ T cell epitopes in patients with Yersinia-induced reactive arthritis by cytometric cytokine secretion assay. Arthritis Rheum. 2006 Nov;54(11):3583-90.
Frentsch M, Arbach O, Kirchhoff D, Moewes B, Worm M, Rothe M, Scheffold A, Thiel A. Direct access to CD4+ T cells specific for defined antigens according to CD154 expression. Nat Med. 2005 Oct;11(10):1118-24.
Romagnani C, Della Chiesa M, Kohler S, Moewes B, Radbruch A, Moretta L, Moretta A, Thiel A. Activation of human NK cells by plasmacytoid dendritic cells and its modulation by CD4+ T helper cells and CD4+ CD25hi T regulatory cells. Eur J Immunol. 2005 Aug;35(8):2452-8.
Kohler S, Wagner U, Pierer M, Kimmig S, Oppmann B, Möwes B, Jülke K, Romagnani C, Thiel A. Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults. Eur J Immunol. 2005 Jun;35(6):1987-94.