TY  - JOUR
A1  - Drechsler, Johannes
A1  - Groetzinger, Joachim
A1  - Hermanns, Heike M.
T1  - Characterization of the Rat Oncostatin M Receptor Complex Which Resembles the Human, but Differs from the Murine Cytokine Receptor
JF  - PLoS One
N2  - Evaluation of a pathophysiological role of the interleukin-6-type cytokine oncostatin M (OSM) for human diseases has been complicated by the fact that mouse models of diseases targeting either OSM or the OSM receptor (OSMR) complex cannot fully reflect the human situation. This is due to earlier findings that human OSM utilizes two receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) (type I) and gp130/OSMR (type II), both with wide expression profiles. Murine OSM on the other hand only binds to the gp130/OSMR (type II) receptor complex with high affinity. Here, we characterize the receptor usage for rat OSM. Using different experimental approaches (knock-down of the OSMR expression by RNA interference, blocking of the LIFR by LIF-05, an antagonistic LIF variant and stably transfected Ba/F3 cells) we can clearly show that rat OSM surprisingly utilizes both, the type I and type II receptor complex, therefore mimicking the human situation. Furthermore, it displays cross-species activities and stimulates cells of human as well as murine origin. Its signaling capacities closely mimic those of human OSM in cell types of different origin in the way that strong activation of the Jak/STAT, the MAP kinase as well as the PI3K/Akt pathways can be observed. Therefore, rat disease models would allow evaluation of the relevance of OSM for human biology.
KW  - in vitro
KW  - leukemia-inhibitory factor
KW  - ciliary neurotrophic factor
KW  - T cell development
KW  - swiss model
KW  - fetal liver
KW  - interleukin-6-type cytokines
KW  - rheumatoid arthritis
KW  - signal transduction
KW  - growth regulator
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133879
VL  - 7
IS  - 8
ER  - 
TY  - JOUR
A1  - Zadeh-Khorasani, Maryam
A1  - Nolte, Thomas
A1  - Mueller, Thomas D.
A1  - Pechlivanis, Markos
A1  - Rueff, Franziska
A1  - Wollenberg, Andreas
A1  - Fricker, Gert
A1  - Wolf, Eckhard
A1  - Siebeck, Matthias
A1  - Gropp, Roswitha
T1  - NOD-scid IL2R \(\gamma^{null}\) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways
JF  - Journal of Translational Medicine
N2  - Background: Animal models of human inflammatory diseases have limited predictive quality for human clinical trials for various reasons including species specific activation mechanisms and the immunological background of the animals which markedly differs from the genetically heterogeneous and often aged patient population. 
Objective: Development of an animal model allowing for testing therapeutics targeting pathways involved in the development of Atopic Dermatitis (AD) with better translatability to the patient. 
Methods: NOD-scid IL2R \(\gamma^{null}\) mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from AD and healthy volunteers were treated with IL-4 and the antagonistic IL-4 variant R121/Y124D (Pitrakinra). Levels of human (h) IgE, amount of B-, T- and plasma-cells and ratio of CD4 : CD8 positive cells served as read out for induction and inhibition of cell proliferation and hIgE secretion. Results were compared to in vitro analysis. 
Results: hIgE secretion was induced by IL-4 and inhibited by the IL-4 antagonist Pitrakinra in vivo when formulated with methylcellulose. B-cells proliferated in response to IL-4 in vivo; the effect was abrogated by Pitrakinra. IL-4 shifted CD4 : CD8 ratios in vitro and in vivo when hPBMC derived from healthy volunteers were used. Pitrakinra reversed the effect. Human PBMC derived from patients with AD remained inert and engrafted mice reflected the individual responses observed in vitro. 
Conclusion: NOD-scid IL2R \(\gamma^{null}\) mice engrafted with human PBMC reflect the immunological history of the donors and provide a complementary tool to in vitro studies. Thus, studies in this model might provide data with better translatability from bench to bedside.
KW  - atopic dermatitis
KW  - T-cells
KW  - rheumatoid arthritis
KW  - human interleukin-4
KW  - TGN1412
KW  - oxazolone colitis
KW  - cytokine release
KW  - expression
KW  - antagonists
KW  - responses
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122960
SN  - 1479-5876
VL  - 11
IS  - 4
ER  -