TY  - JOUR
A1  - Langenhorst, Daniela
A1  - Tabares, Paula
A1  - Gulde, Tobias
A1  - Becklund, Bryan R.
A1  - Berr, Susanne
A1  - Surh, Charles D.
A1  - Beyersdorf, Niklas
A1  - Hünig, Thomas
T1  - Self-recognition sensitizes mouse and human regulatory T cells to low-dose CD28 superagonist stimulation
JF  - Frontiers in Immunology
N2  - In rodents, low doses of CD28-specific superagonistic monoclonal antibodies (CD28 superagonists, CD28SA) selectively activate regulatory T cells (Treg). This observation has recently been extended to humans, suggesting an option for the treatment of autoimmune and inflammatory diseases. However, a mechanistic explanation for this phenomenon is still lacking. Given that CD28SA amplify T cell receptor (TCR) signals, we tested the hypothesis that the weak tonic TCR signals received by conventional CD4\(^{+}\) T cells (Tconv) in the absence of cognate antigen require more CD28 signaling input for full activation than the stronger TCR signals received by self-reactive Treg. We report that in vitro, the response of mouse Treg and Tconv to CD28SA strongly depends on MHC class II expression by antigen-presenting cells. To separate the effect of tonic TCR signals from self-peptide recognition, we compared the response of wild-type Treg and Tconv to low and high CD28SA doses upon transfer into wild-type or H-2M knockout mice, which lack a self-peptide repertoire. We found that the superior response of Treg to low CD28SA doses was lost in the absence of self-peptide presentation. We also tested if potentially pathogenic autoreactive Tconv would benefit from self-recognition-induced sensitivity to CD28SA stimulation by transferring TCR transgenic OVA-specific Tconv into OVA-expressing mice and found that low-dose CD28SA application inhibited, rather than supported, their expansion, presumably due to the massive concomitant activation of Treg. Finally, we report that also in the in vitro response of human peripheral blood mononuclear cells to CD28SA, HLA II blockade interferes with the expansion of Treg by low-dose CD28SA stimulation. These results provide a rational basis for the further development of low-dose CD28SA therapy for the improvement of Treg activity.
KW  - D665
KW  - regulatory T cells
KW  - self-reactivity
KW  - autoimmunity
KW  - CD28 superagonists
KW  - TGN1412
KW  - TAB08
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159387
VL  - 8
IS  - 1985
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  -