TY  - JOUR
A1  - Hartung, Andreas
A1  - Seufert, Florian
A1  - Berges, Carsten
A1  - Gessner, Viktoria H.
A1  - Holzgrabe, Ulrike
T1  - One-Pot Ugi/Aza-Michael Synthesis of Highly Substituted 2,5-Diketopiperazines with Anti-Proliferative Properties
JF  - Molecules
N2  - The well-known Ugi reaction of aldehydes with amines, carboxylic acids and isocyanides leads to the formation of acyclic alpha-acylaminocarboxamides. Replacement of the carboxylic acid derivatives with beta-acyl substituted acrylic acids gives access to highly substituted 2,5-diketopiperazines in one single reaction-step without additives or complex reaction procedures. The obtained diketopiperazines show anti-proliferative effects on activated T cells and represent therefore potential candidates for targeting unwanted T cell-mediated immune responses.
KW  - multicomponent Ugi-type reaction
KW  - intramolecular Michael addition
KW  - strategy
KW  - derivates
KW  - diketopiperazines
KW  - chemistry
KW  - T cell
KW  - 2,5-diketopiperazines
KW  - anti-proliferative effects
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130423
VL  - 17
IS  - 12
ER  - 
TY  - JOUR
A1  - Bedke, Tanja
A1  - Iannitti, Rossana G.
A1  - De Luca, Antonella
A1  - Giovannini, Gloria
A1  - Fallarino, Francesca
A1  - Berges, Carsten
A1  - Latgé, Jean-Paul
A1  - Einsele, Hermann
A1  - Romani, Luigina
A1  - Topp, Max S.
T1  - Distinct and complementary roles for Aspergillus fumigatus-specific Tr1 and \(Foxp3^+\) regulatory T cells in humans and mice
JF  - Immunology and Cell Biology
N2  - Unlike induced \(Foxp3^+\) regulatory T cells (\(Foxp3^+\) \(iT_{reg}\)) that have been shown to play an essential role in the development of protective immunity to the ubiquitous mold Aspergillus fumigatus, type-(1)-regulatory T cells (Tr1) cells have, thus far, not been implicated in this process. Here, we evaluated the role of Tr1 cells specific for an epitope derived from the cell wall glucanase Crf-1 of A. fumigatus (Crf-1/p41) in antifungal immunity. We identified Crf-1/p41-specific latent-associated \(peptide^+\) Tr1 cells in healthy humans and mice after vaccination with Crf-1/p41+zymosan. These cells produced high amounts of interleukin (IL)-10 and suppressed the expansion of antigen-specific T cells in vitro and in vivo. In mice, in vivo differentiation of Tr1 cells was dependent on the presence of the aryl hydrocarbon receptor, c-Maf and IL-27. Moreover, in comparison to Tr1 cells, \(Foxp3^+\) \(iT_{reg}\) that recognize the same epitope were induced in an interferon gamma-type inflammatory environment and more potently suppressed innate immune cell activities. Overall, our data show that Tr1 cells are involved in the maintenance of antifungal immune homeostasis, and most likely play a distinct, yet complementary, role compared with \(Foxp3^+\) \(iT_{reg}\).
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121449
VL  - 92
IS  - 8
ER  - 
TY  - JOUR
A1  - Berges, Carsten
A1  - Kerkau, Thomas
A1  - Werner, Sandra
A1  - Wolf, Nelli
A1  - Winter, Nadine
A1  - Hünig, Thomas
A1  - Einsele, Hermann
A1  - Topp, Max S.
A1  - Beyersdorf, Niklas
T1  - Hsp90 inhibition ameliorates CD4\(^{+}\) T cell-mediated acute Graft versus Host disease in mice
JF  - Immunity, Inflammation and Disease
N2  - Introduction:
For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co‐transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life‐threatening complication.

Methods:
Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD.

Results:
Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4\(^{+}\) T cell transplantation with the Hsp90 inhibitor 17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia‐bearing mice after transplantation of allogeneic CD4\(^{+}\) and CD8\(^{+}\) T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4\(^{+}\) T cells with a relative resistance of CD4\(^{+}\) regulatory and CD8\(^{+}\) T cells toward Hsp90 inhibition.

Conclusions:
Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect.
KW  - Hsp90
KW  - leukemia
KW  - acute Graft versus Host Disease
KW  - Graft versus Tumor
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168318
VL  - 4
IS  - 4
ER  -