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Rotationsprojekt 10

Project leader:  

Dr. med. Katrin Wetzko
Assistenzärztin / Wissenschaftliche Mitarbeiterin
Medizinische Klinik und Poliklinik I
Universitätsklinikum Carl Gustav Carus
der Technischen Universität Dresden
Fetscherstraße 74
01307 Dresden

Project title:    Reconstitution of myeloid-derived suppressor cells (MDSC) after allogeneic hematopoietic stem cell transplantation
Involved SFB members (co-leaders):    

Prof. Dr. Martin Bornhäuser
Medizinische Klinik und Poliklinik I
Universitätsklinikum Carl Gustav Carus
der Technischen Universität Dresden
SFB-Teilprojekt B2

Prof. Dr. Triantafyllos Chavakis
Medizinische Klinik und Poliklinik III
Universitätsklinikum Carl Gustav Carus
an der Technischen Universität Dresden
SFB-Teilprojekt B10

Funding period:    1. Oktober 2012 - 30. September 2013 
Abstract:    Recently, a novel cell type has been described as an endogenous modulator of immune responses in the context of cancer immunity, infectious diseases and allogeneic HSCT(4). The so called ‘myeloid-derived suppressor cells’ (MDSC) have been shown to be able to mediate immune suppression. They are derived from the myeloid lineage and represent a heterogeneous population of myelomonocytic and granulocytic origin. So far these cells have been studied mainly in murine models and their functional role in the human setting of allogeneic HSCT has not been elucidated.
The major focus of the current rotation project and the task of the applicant is to measure the frequency of the recently described  MDSC subset of granulocytic origin in various graft sources (mobilized blood, bone marrow and cord blood) and in the recipient at defined time-points after allogeneic HSCT. Therefore a multiparameter FACS protocol will be developed to quantify CD11c++/CD62Ldim/CD11b++/CD16++ neutrophil subsets before and after allogeneic HSCT. Their frequency in longitudinal analyses will be correlated with i) the frequency of immune effector cells (CD4+/CD8+ T cells, NK cells, B cells and Tregs) ii) the graft source and iii) clinical parameters after allogeneic HSCT including the occurrence of organ toxicity, infection and GvHD. Finally, neutrophilic MDSC will be isolated by FACS and their DNA will be isolated in order to quantify the percentage of donor cells at given time-points after allogeneic HSCT.  The sorted neutrophilic MDSC subset will tested in-vitro for its suppressive capacity against activated CD4+ and CD8+ T cells. This will include the intracellular staining for Interferon- and IL-4 in CD4+ cells after stimulation. Moreover, we will attempt to identify functional indicators of MDSC activity. In particular, the expression levels and more importantly the activation status of adhesion molecules, such as  LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18) and VLA-4/-5 on this cellular subset will be assessed. This will further include the analysis of the physical interaction of MDSC with T cells. Another specific aim is to analyze whether this subset of MDSC is mobilized by G-CSF in healthy donors and with CXCR-4 antagonists in cancer patients and/or donors.
Relevant publications:  
  1. Appelbaum FR. Hematopoietic-cell transplantation at 50. N Engl J Med 2007;357:1472-1475.
  2. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, Negrin RS. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003;9:1144-1150.



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