@article{DahlhoffManzSteinfattetal.2022,
  author    = {Dahlhoff, Julia and Manz, Hannah and Steinfatt, Tim and Delgado-Tascon, Julia and Seebacher, Elena and Schneider, Theresa and Wilnit, Amy and Mokhtari, Zeinab and Tabares, Paula and B{\"o}ckle, David and Rasche, Leo and Martin Kort{\"u}m, K. and Lutz, Manfred B. and Einsele, Hermann and Brandl, Andreas and Beilhack, Andreas},
  title     = {Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression},
  series = {Leukemia},
  volume    = {36},
  journal   = {Leukemia},
  number    = {3},
  issn      = {1476-5551},
  doi       = {10.1038/s41375-021-01422-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271787},
  pages     = {790-800},
  year      = {2022},
  abstract  = {Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4\(^{+}\)FoxP3\(^{+}\) regulatory T cells (Tregs) are highly abundant amongst CD4\(^{+}\) T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.},
  language  = {en}
}
@article{BaeuerleinQureischiMokhtarietal.2021,
  author    = {B{\"a}uerlein, Carina A. and Qureischi, Musga and Mokhtari, Zeinab and Tabares, Paula and Brede, Christian and Jord{\´a}n Garrote, Ana-Laura and Riedel, Simone S. and Chopra, Martin and Reu, Simone and Mottok, Anja and Arellano-Viera, Estibaliz and Graf, Carolin and Kurzwart, Miriam and Schmiedgen, Katharina and Einsele, Hermann and W{\"o}lfl, Matthias and Schlegel, Paul-Gerhardt and Beilhack, Andreas},
  title     = {A T-Cell Surface Marker Panel Predicts Murine Acute Graft-Versus-Host Disease},
  series = {Frontiers in Immunology},
  volume    = {11},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2020.593321},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224290},
  year      = {2021},
  abstract  = {Acute graft-versus-host disease (aGvHD) is a severe and often life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). AGvHD is mediated by alloreactive donor T-cells targeting predominantly the gastrointestinal tract, liver, and skin. Recent work in mice and patients undergoing allo-HCT showed that alloreactive T-cells can be identified by the expression of α4β7 integrin on T-cells even before manifestation of an aGvHD. Here, we investigated whether the detection of a combination of the expression of T-cell surface markers on peripheral blood (PB) CD8\(^+\) T-cells would improve the ability to predict aGvHD. To this end, we employed two independent preclinical models of minor histocompatibility antigen mismatched allo-HCT following myeloablative conditioning. Expression profiles of integrins, selectins, chemokine receptors, and activation markers of PB donor T-cells were measured with multiparameter flow cytometry at multiple time points before the onset of clinical aGvHD symptoms. In both allo-HCT models, we demonstrated a significant upregulation of α4β7 integrin, CD162E, CD162P, and conversely, a downregulation of CD62L on donor T-cells, which could be correlated with the development of aGvHD. Other surface markers, such as CD25, CD69, and CC-chemokine receptors were not found to be predictive markers. Based on these preclinical data from mouse models, we propose a surface marker panel on peripheral blood T-cells after allo-HCT combining α4β7 integrin with CD62L, CD162E, and CD162P (cutaneous lymphocyte antigens, CLA, in humans) to identify patients at risk for developing aGvHD early after allo-HCT.},
  language  = {en}
}
@article{LangenhorstTabaresGuldeetal.2018,
  author    = {Langenhorst, Daniela and Tabares, Paula and Gulde, Tobias and Becklund, Bryan R. and Berr, Susanne and Surh, Charles D. and Beyersdorf, Niklas and H{\"u}nig, Thomas},
  title     = {Self-recognition sensitizes mouse and human regulatory T cells to low-dose CD28 superagonist stimulation},
  series = {Frontiers in Immunology},
  volume    = {8},
  journal   = {Frontiers in Immunology},
  number    = {1985},
  doi       = {10.3389/fimmu.2017.01985},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159387},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@phdthesis{Tabares2011,
  author    = {Tabares, Paula},
  title     = {Antimicrobial, anti-protease and immunomodulatory activities of secondary metabolites from Caribbean sponges and their associated bacteria},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-67000},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {Marine sponges and their associated bacteria have been proven to be a rich source of novel secondary metabolites with therapeutic usefulness in infection and autoimmunity. This Ph.D. project aimed to isolate bioactive secondary metabolites from the marine sponges Amphimedon compressa, Aiolochroia crassa and Theonella swinhoei as well as from bacteria associated with different Caribbean sponges, specifically actinomycetes and sphingomonads. In this study, amphitoxin was isolated from the crude methanol extract of the sponge A. compressa and it was found to have antibacterial and anti-parasitic activities. Amphitoxin showed protease inhibitory activity when tested against the mammalian protease cathepsin B and the parasitic proteases rhodesain and falcipain-2. Furthermore, miraziridine A was identified in the dichloromethane extract of the sponge T. swinhoei collected offshore Israel in the Red Sea. Miraziridine A, a natural peptide isolated previously from the marine sponge Theonella aff. mirabilis, is a potent cathepsin B inhibitor with an IC50 value of 1.4 g/mL (2.1 M). Secondary metabolites from sponge-derived bacteria were also isolated and identified. A total of 79 strains belonging to 20 genera of the order Actinomycetales and seven strains belonging to two genera of the order Sphingomonadales were cultivated from 18 different Caribbean sponges and identified by 16S rRNA gene sequencing. Seven of these strains are likely to represent novel species. Crude extracts from selected strains were found to exhibit protease inhibition against cathepsins B and L, rhodesain, and falcipain-2 as well as immunomodulatory activities such as induction of cytokine release by human peripheral blood mononuclear cells. The isolates Sphingobium sp. CO105 and Lapillicoccus sp. BA53 were selected for cultivation, extraction and purification of bioactive metabolites based on initial bioactive screening results. The isoalloxazine isolumichrome was isolated from the strain Sphingobium sp. CO105 which inhibited the protease rhodesain with an IC50 of 0.2 M. The strain Lapillicoccus sp. BA53 was found to produce p-aminosalicylic acid methyl ester, which showed activity against the proteases cathepsins B and L, falcipain-2 and rhodesain. These results highlight the significance of marine sponge-associated bacteria to produce bioactive secondary metabolites with therapeutic potential in the treatment of infectious diseases and disorders of the immune system.},
  subject      = {Schw{\"a}mme},
  language  = {en}
}