Fachbereich Veterinärmedizin



    Regulatorische T-Zellen als adjuvante Therapie der akuten Graft versus Host Erkrankung im xenogenen Maus-Modell (2017)

    Zobel, Anne (WE 20)
    Berlin: Mensch und Buch Verlag, 2017 — IX, 160 Seiten
    ISBN: 978-3-86387-904-4
    URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/22455
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    Abstract / Zusammenfassung

    Transplantation of allogeneic stem cells is a curative therapy for malignant and nonmalignant disease of the hematopoetic system. The number of transplantations increased continuously over the last years. Despite intensive research and developments in that field acute and chronic rejection remain major limitations for successful stem cell transplantation. Classical immunosuppression is often insufficient to protect patients from disease. Furthermore, the therapy itself is accompanied with several undesired side effects. Regulatory t-cells are natural immunomodulators. Experimental studies, as well as patient data show a connection between regulatory t-cells and the outcome of stem cell and solid organ transplantation. For possible clinical application, establishing of GMP-grade isolation and expansion protocols as well as the analysis of the interplay of Treg with conventional immunosuppressants is inevitable. In the present study, xenogeneic acute GvHD was induced by application of 3*106 humane PBMCs into NOD/SCID Il-2Rgamma -/- mice on day 0. Further therapy included application of cyclosporine a, mycophenolate-mofetil or methylprednisolone, alone or in combination with 0.5*106 polyconal expanded nTreg, from day +1 on. Additionally, nTreg were injected in different dosages (1,5*106, 3*106 und 6*106) on day 0 together with the PBMCs as monotherapy without further immunosuppression. Post mortem, tissues were analyzed for infiltration of humane cells and the amount of FoxP3+ Treg. The organs were analyzed for infiltration and inflammation histologically. Therapy with nTreg alone resulted in prolonged survival and increased clinical appearance only with effector cells / nTreg ratio 1:1 and 1:2, but not 2:1. Surprisingly, especially the treatment with CsA plus nTreg resulted in an increased clinical extending and prolonged overall survival. Especially the liver showed an increased number of FoxP3+ Treg with decreased overall cell numbers of humane cells at the same time. Interestingly, the treatment with methylprednisolone plus nTreg resulted in fast deterioration in some animals, marked by fast weight loss and a reduced number of FoxP3+ Treg within the tissue. This picture differed a lot from what could be observed in mice under therapy with methylprednisolone only. In conclusion, treatment with regulatory t-cells in a ratio 1:1 and 1:2, but not 2:1 compared to diseased animals. Different from what was mostly shown, the treatment with CsA, especially in the combination with nTreg did not inhibit the regulatory cells. Instead it resulted in an increased amount of FoxP3+ Treg within the tissue, especially in the liver. These results show much more a synergistic, proliferation promoting effect of cyclosporine a on Treg. On the other hand the treatment with MMF, as well as the combination of methylprednisolone and nTreg could not sufficiently protect from an acute GvHD.