Type 1 Diabetes Immunological Tolerance

Type 1 Diabetes (T1D) is characterized by a breakdown of immunological self-tolerance to the insulin producing islet beta cells, and consequently their destruction by autoreactive T cells. Recently, the specific roles of different T cell subsets during the presymptomatic stage of T1D have begun to reveal how they contribute to immune activation and autoimmunity.

Foxp3+ regulatory (Treg) cells function as key players for the maintenance of peripheral immune tolerance. We have used murine and humanized models to show that the efficient induction of Foxp3+ Tregs from naive CD4+ T cells can be achieved by the application of a strong-agonistic T cell receptor (TCR) ligand under subimmunogenic conditions.

Impairments in Treg induction and function are important contributors to autoimmune disorders such as T1D. However, the cellular and molecular underpinnings promoting such impairments in Treg induction as well as the specific requirements for an efficient induction of Foxp3+Tregs in the setting of ongoing islet autoimmunity remain poorly understood especially in human T1D.

To fill this knowledge gap we aim to dissect mechanisms of aberrant immune activation that can interfere with tolerance induction during islet autoimmunity and that promote progression from islet autoimmunity to clinical T1D.

My lab therefore uses an integrative translational research approach combining cellular and molecular immunology with immunepharmacology. To this end, we integrate murine T1D models with studies in humanized mice and focus on immune cells from non-diabetic children with ongoing islet autoimmunity or with new onset T1D which offer an important resource for studying such signaling pathways involved in aberrant immune activation vs. immune tolerance.

In addition, we are using murine and humanized models to study combinatorial strategies of antigen-specific tolerance induction together with novel pharmacological approaches that can limit T cell activation which have the goal to broaden the window of application closer to the precipitation of autoimmune progression and clinical disease.

Moreover, given our strong interest in dissecting mechanisms of tissue-specific immune tolerance relevant to prevent autoimmune progression in T1D we focus on the role of tissue-Tregs in inhibiting immune activation and inflammation in diabetes.

We strive to integrate these findings into understanding mechanisms of immune tolerance in diabetes with the future goal of developing innovative precision medicines aimed at the safe and specific manipulation of Foxp3+Tregs in children at risk of developing T1D. 

 

Contact person: Dr. phil. nat. Carolin Daniel
Tel. +49 89 3187-21 88

Team

Dr. phil. nat. Carolin Daniel
Head

Dr. rer. nat. Isabelle Serr
Post-Doc

Martin Scherm
PhD Student

Verena Ott
PhD Student

Sini Susan Joseph
PhD Student

Maike Becker
PhD Student

Victoria Flynn
PhD Student

Daria Opaleva
PhD Student

Hannah Hipp
PhD Student

Kristina Wutz
MD Student

Publikationen

2018
Serr, I. ; Daniel, C.
Front. Immunol. 9:1729 (2018)
Serr, I. ; Daniel, C.
Diabetologe 14, 257-261 (2018)
Serr, I. ; Scherm, M.G. ; Zahm, A.M. ; Schug, J. ; Flynn, V.K. ; Hippich, M. ; Kälin, S. ; Becker, M. ; Achenbach, P. ; Nikolaev, A. ; Gerlach, K. ; Liebsch, N. ; Loretz, B. ; Lehr, C.M. ; Kirchner, B. ; Spornraft, M. ; Haase, B. ; Segars, J. ; Küper, C. ; Palmisano, R. ; Waisman, A. ; Willis, R.A. ; Kim, W.U. ; Weigmann, B. ; Kaestner, K.H. ; Ziegler, A.G. ; Daniel, C.
Sci. Transl. Med. 10:eaag1782 (2018)
2017
Becker, M. ; Levings, M.K. ; Daniel, C.
Eur. J. Immunol. 47, 1867-1874 (2017)
Kälin, S. ; Becker, M. ; Ott, V. ; Serr, I. ; Hosp, F. ; Mollah, M.M.H. ; Keipert, S. ; Lamp, D. ; Rohner-Jeanrenaud, F. ; Flynn, V.K. ; Scherm, M.G. ; Nascimento, L.F.R. ; Gerlach, K. ; Popp, V. ; Dietzen, S. ; Bopp, T. ; Krishnamurthy, P. ; Kaplan, M.H. ; Serrano, M. ; Woods, S.C. ; Tripal, P. ; Palmisano, R. ; Jastroch, M. ; Blüher, M. ; Wolfrum, C. ; Weigmann, B. ; Ziegler, A.-G. ; Mann, M. ; Tschöp, M.H. ; Daniel, C.
Cell Metab. 26, 475-492.e7 (2017)
Daniel, C. ; Weigmann, B. ; von Boehmer, H.
J. Exp. Med. 214, 2157-2159 (2017)
2016
Serr, I. ; Fürst, R.W. ; Ott, V.B. ; Scherm, M.G. ; Nikolaev, A. ; Gökmen, F. ; Kälin, S. ; Zillmer, S. ; Bunk, M. ; Weigmann, B. ; Kunschke, N. ; Loretz, B. ; Lehr, C.M. ; Kirchner, B. ; Haase, B. ; Pfaffl, M.W. ; Waisman, A. ; Willis, R.A. ; Ziegler, A.G. ; Daniel, C.
Proc. Natl. Acad. Sci. U.S.A. 113, E6659-E6668 (2016)
Scherm, M.G. ; Ott, V. ; Daniel, C.
Curr. Diab. Rep. 16:75 (2016)
Serr, I. ; Fürst, R. ; Achenbach, P. ; Scherm, M.G. ; Gökmen, F. ; Haupt, F. ; Sedlmeier, E.-M. ; Knopff, A. ; Shultz, L. ; Willis, R.A. ; Ziegler, A.-G. ; Daniel, C.
Nat. Commun. 7:10991 (2016)
2015
Steiner, S. ; Daniel, C. ; Fischer, A. ; Atreya, I. ; Hirschmann, S. ; Waldner, M. ; Neumann, H. ; Neurath, M.F. ; Atreya, R. ; Weigmann, B.
Arch. Immunol. Ther. Exp. 63, 53-63 (2015)
2014
Serr, I. ; Weigmann, B. ; Franke, R.K. ; Daniel, C.
Biodrugs 28, 7-16 (2014)
Daniel, C. ; Gerlach, K. ; Väth, M. ; Neurath, M.F. ; Weigmann, B.
Int. J. Cancer 134, 1767-1775 (2014)
2013
von Boehmer, H. ; Daniel, C.
Nat. Rev. Drug Discov. 12, 51-63 (2013)
2012
Weigmann, B. ; Franke, R.K. ; Daniel, C.
Rev. Diabet. Stud. 9, 68-81 (2012)
Gerlach, K. ; Daniel, C. ; Lehr, H.A. ; Nikolaev, A. ; Gerlach, T. ; Atreya, R. ; Rose-John, S. ; Neurath, M.F. ; Weigmann, B.
Cancer Res. 72, 4340-4350 (2012)
Weigmann, B. ; Daniel, C.
Curr. Diab. Rep. 12, 463-470 (2012)
2011
Daniel, C. ; von Boehmer, H.
Semin. Immunol. 23, 410-417 (2011)
Daniel, C. ; Weigmann, B. ; Bronson, R. ; von Boehmer, H.
J. Exp. Med. 208, 1501-1510 (2011)
Daniel, C. ; Ploegh, H. ; von Boehmer, H.
Methods Mol. Biol. 707, 173-185 (2011)
2010
Daniel, C. ; Wennhold, K. ; Kim, H.J. ; von Boehmer, H.
Proc. Natl. Acad. Sci. U.S.A. 107, 16246-16251 (2010)
2009
Nolting, J. ; Daniel, C. ; Reuter, S. ; Stuelten, C. ; Li, P. ; Sucov, H. ; Kim, B.G. ; Letterio, J.J. ; Kretschmer, K. ; Kim, H.J. ; von Boehmer, H.
J. Exp. Med. 206, 2131-2139 (2009)
Daniel, C. ; Nolting, J. ; von Boehmer, H.
Immunotherapy 1, 631-644 (2009)
2008
Daniel, C. ; Sartory, N.A. ; Zahn, N. ; Radeke, H.H. ; Stein, J.M.
J. Pharmacol. Exp. Ther. 324, 23-33 (2008)
2007
Daniel, C. ; Sartory, N.A. ; Zahn, N. ; Schmidt, R. ; Geisslinger, G. ; Radeke, H.H. ; Stein, J.M.
Mol. Immunol. 44, 3305-3316 (2007)
Daniel, C. ; Sartory, N. ; Zahn, N. ; Geisslinger, G. ; Radeke, H.H. ; Stein, J.M.
J. Immunol. 178, 2458-2468 (2007)
Schneider, D. ; Liaw, L. ; Daniel, C. ; Athanasopoulos, A.N. ; Herrmann, M. ; Preissner, K.T. ; Nawroth, P.P. ; Chavakis, T.
Biochem. Biophys. Res. Commun. 357, 282-288 (2007)
Daniel, C. ; Schröder, O. ; Zahn, N. ; Gaschott, T. ; Steinhilber, D. ; Stein, J.M.
J. Cell. Biochem. 102, 1420-1431 (2007)

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