Toleranzinduktion und Exosomen myeloider Suppressorzellen in der Therapie der Alopecia Areata
Immunologie
Zusammenfassung der Projektergebnisse
MDSC are a major hindrance in tumor immunotherapy and chronic infections, whereas MDSC and Treg inefficacy are central features of autoimmune diseases. There is additional evidence that MDSC mainly act via Exo. Exo are delivered by most cells of an organism and distribute throughout the body. Exo components are function competent and deliver their messages into target cells. Exo binding and uptake severely modulating target structures and cells, they are suggested to be most potent intercellular communicators. Facilitated by easy in vitro modulation, Exo are supposed to become powerful therapeutics in the near future. We here focused on open questions in Exo distribution, targeting and target cell modulation. We demonstrate that only a minority of Exo are “freely” available in body fluids and that targeting structures are of prime importance for directed delivery. Based on these results we proceeded characterizing MDSC-Exo. We demonstrate that MDSC-Exo dispose of the central features of MDSC and, most importantly, that MDSC-Exo derived from in vitro cultured BMC are functionally equivalent to inflammatory MDSC-Exo. This finding provided a solid base elaborating the action of MDSC-Exo in autoimmune disease using AA as a model. MDSC-Exo application sufficed to prevent AA progression and supported a partial hair regrowth. Exploring the underlying mechanism unraveled that MDSC-Exo are equipped to preferentially target Treg and activated T cells, the findings being corroborated by comprehensive proteome analyses. An ex vivo deep sequencing RNA analysis of leukocytes from MDSC-Exo-treated AA mice compellingly confirmed a striking impact on Treg expansion and activation as well as on activated T cell suppression, a shift in cytokine delivery and distinct changes in chemokine and chemokine receptor expression, which all fitted to reestablish peripheral tolerance and to dampen autoaggression. The finding that MDSC-Exo from healthy donor BMC efficiently cope with autoimmune disease progression confirms the power of Exo and opens a most promising therapeutic option for more severe autoimmune diseases. We have not yet evaluated the mechanism underlying expansion and activation of Treg and only partly the signaling pathways that mitigate activated T cell proliferation and cytotoxic activity. According to our preliminary results, we expect an initial hub by Exo signaling molecules and the armament of Exo to provoke transcription, translation and RNA processing. The results of those studies can straightforwardly be translated into therapeutic settings due to the ease of Exo tailoring and transfection. Thus, MDSC-Exo generated from healthy donor BMC in vitro can be expected to provide a homogeneous and reliably reproducible therapeutic that may reach beyond autoimmune disease treatment to support transplant acceptance as well as tissue regeneration and repair.
Projektbezogene Publikationen (Auswahl)
- Murine and human pancreatic tumor exosome recovery in mouse serum: diagnostic, prognostic and therapeutic potential. Canc Lett. 403: 1-12, 2017
Erb U, Zhao K, Wang Z, Xiao L, Zöller M
(Siehe online unter https://doi.org/10.1016/j.canlet.2017.06.005) - (2018) Immunoregulatory effects of myeloid-derived suppressor cell exosomes in mouse model of autoimmune alopecia areata. Frontiers in immunology 9 1279
Zöller, Margot; Zhao, Kun; Kutlu, Natalia; Bauer, Nathalie; Provaznik, Jan; Hackert, Thilo; Schnölzer, Martina
(Siehe online unter https://doi.org/10.3389/fimmu.2018.01279) - Distorted leukocyte migration, angiogenesis, wound repair and metastasis in Tspan8 and Tspan8/CD151 double knockout mice indicate complementary activities of Tspan8 and CD51. BBA Mol Cell Res. 1865: 379-391, 2018
Zhao K, Erb U, Hackert T, Zöller M, Yue S
(Siehe online unter https://doi.org/10.1016/j.bbamcr.2017.11.007) - Janus-faced myeloid-derived suppressor cell exosomes for the good and the bad in cancer and autoimmune disease. Frontiers Immunol. 9: 137, 2018
Zöller M
(Siehe online unter https://doi.org/10.3389/fimmu.2018.00137)
