| dc.contributor.advisor | Budde, Holger Dr. | |
| dc.contributor.author | Papert, Susanne | |
| dc.date.accessioned | 2016-05-25T10:41:58Z | |
| dc.date.available | 2016-05-25T10:41:58Z | |
| dc.date.issued | 2016-05-25 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0028-8761-7 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-5663 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | New approaches to improve Extracorporeal Photopheresis for the treatment of Graft-versus-Host Disease | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Reichardt, Holger Prof. Dr. | |
| dc.date.examination | 2016-05-09 | |
| dc.description.abstracteng | Graft-versus-host disease (GvHD) is a severe complication occurring after hematopoietic stem cell transplantation (HSCT). It is caused by alloreactive T cells contained in the graft, and associated with severe morbidity and mortality. Glucocorticoids (GC) are the gold standard for first-line treatment of GvHD but once patients become steroid-refractory, they need to be treated with second-line therapies such as extracorporeal photopheresis (ECP). ECP is an immunomodulatory therapy currently used in the clinic for treating patients suffering acute GvHD (aGvHD) or chronic GvHD (cGvHD). During ECP therapy leukocytes from the patient are collected by apheresis procedure and treated with 8-methoxypsoralen (8-MOP) and ultraviolet light type-A (UV-A) generating apoptotic cells which are then reinfused into the patient. These apoptotic cells are taken up by myeloid dendritic cells (mDCs) and may lead to cross-tolerization of T cells. Whether ECP therapy could be modified by using leukocytes from healthy blood donors instead of the patient’s own cells has not yet been explored although this option would offer the possibility to avoid the exhausting apheresis procedure.
In this study, established mouse models of aGvHD (C57BL/6->BALB/c) and cGvHD (B10D2->BALB/c) were used to evaluate the effects of 8-MOP/UV-A (PUVA)-treated splenocytes derived from healthy genetically different mouse strains. ECP therapy using C3H mice as donors of splenocytes had a significant therapeutic effect on the course and severity of aGvHD whereas this was not the case for splenocytes with BALB/c and C57BL/6 origin. ECP therapy of cGvHD was successful when apoptotic splenocytes from B10D2 were used. Flow cytometric analysis did not reveal any cellular signature of cGvHD. Overall, the obtained results suggest that the therapeutic effect of ECP therapy might be achieved when there are extensive disparities in the human leukocyte antigen (HLA) haplotype between ECP recipient and cell donors.
In addition, efforts were made to identify biomarkers that could predict the risk to develop GvHD and the patient’s response to ECP therapy. Several potential biomarkers were analyzed in peripheral blood by flow cytometry or enzyme-linked immunosorbent assay (ELISA). Reference values were determined for each potential biomarker in healthy blood donors and compared to the values measured in patients suffering from hematological malignancies before HSCT and after engraftment and in cGvHD patients before as well as three and six months after initiation of ECP therapy. Dependent on the time points of blood sampling we found significant differences in the percentages or cell counts of regulatory T (Treg) cells, immature B cells, mDCs, soluble interleukin-2 receptor-α (sIL-2Rα), soluble tumor necrosis-factor receptor 1 (sTNF-R), and hepatocyte growth factor (HGF) between healthy controls, HSCT patients and ECP patients.
Taken together, the combination of GvHD mouse models and the analysis of patient material represent a promising strategy to optimize the clinical application of ECP therapy in the future and should thereby contribute to a safer application of HSCT in patients suffering from hematological malignancies. | de |
| dc.contributor.coReferee | Jarry, Hubertus Prof. Dr. | |
| dc.subject.eng | Extracorporeal Photopheresis, Graft-versus-Host Disease, biomarker | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0028-8761-7-7 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | Medizin (PPN619874732) | de |
| dc.subject.gokfull | Biologie (PPN619875151) | de |
| dc.identifier.ppn | 85981016X | |