@article{ChopraBiehlSteinfattetal.2016,
  author    = {Chopra, Martin and Biehl, Marlene and Steinfatt, Tim and Brandl, Andreas and Kums, Juliane and Amich, Jorge and Vaeth, Martin and Kuen, Janina and Holtappels, Rafaela and Podlech, J{\"u}rgen and Mottok, Anja and Kraus, Sabrina and Jord{\´a}n-Garotte, Ana-Laura and B{\"a}uerlein, Carina A. and Brede, Christian and Ribechini, Eliana and Fick, Andrea and Seher, Axel and Polz, Johannes and Ottmueller, Katja J. and Baker, Jeannette and Nishikii, Hidekazu and Ritz, Miriam and Mattenheimer, Katharina and Schwinn, Stefanie and Winter, Thorsten and Sch{\"a}fer, Viktoria and Krappmann, Sven and Einsele, Hermann and M{\"u}ller, Thomas D. and Reddehase, Matthias J. and Lutz, Manfred B. and M{\"a}nnel, Daniela N. and Berberich-Siebelt, Friederike and Wajant, Harald and Beilhack, Andreas},
  title     = {Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion},
  series = {Journal of Experimental Medicine},
  volume    = {213},
  journal   = {Journal of Experimental Medicine},
  number    = {9},
  doi       = {10.1084/jem.20151563},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187640},
  pages     = {1881-1900},
  year      = {2016},
  abstract  = {Donor CD4\(^+\)Foxp3\(^+\) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.},
  language  = {en}
}
@article{LauruschkatMuchsinReinetal.2023,
  author    = {Lauruschkat, Chris David and Muchsin, Ihsan and Rein, Alice and Erhard, Florian and Grathwohl, Denise and D{\"o}lken, Lars and K{\"o}chel, Carolin and Falk, Christine Susanne and Einsele, Hermann and Wurster, Sebastian and Grigoleit, G{\"o}tz Ulrich and Kraus, Sabrina},
  title     = {CD4+ T cells are the major predictor of HCMV control in allogeneic stem cell transplant recipients on letermovir prophylaxis},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1148841},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-316982},
  year      = {2023},
  abstract  = {Introduction Human cytomegalovirus (HCMV) causes significant morbidity and mortality in allogeneic stem cell transplant (alloSCT) recipients. Recently, antiviral letermovir prophylaxis during the first 100 days after alloSCT replaced PCR-guided preemptive therapy as the primary standard of care for HCMV reactivations. Here, we compared NK-cell and T-cell reconstitution in alloSCT recipients receiving preemptive therapy or letermovir prophylaxis in order to identify potential biomarkers predicting prolonged and symptomatic HCMV reactivation. Methods To that end, the NK-cell and T-cell repertoire of alloSCT recipients managed with preemptive therapy (n=32) or letermovir prophylaxis (n=24) was characterized by flow cytometry on days +30, +60, +90 and +120 after alloSCT. Additionally, background-corrected HCMV-specific T-helper (CD4+IFNγ+) and cytotoxic (CD8+IFNγ+CD107a+) T cells were quantified after pp65 stimulation. Results Compared to preemptive therapy, letermovir prophylaxis prevented HCMV reactivation and decreased HCMV peak viral loads until days +120 and +365. Letermovir prophylaxis resulted in decreased T-cell numbers but increased NK-cell numbers. Interestingly, despite the inhibition of HCMV, we found high numbers of "memory-like" (CD56dimFcεRIγ- and/or CD159c+) NK cells and an expansion of HCMV-specific CD4+ and CD8+ T cells in letermovir recipients. We further compared immunological readouts in patients on letermovir prophylaxis with non/short-term HCMV reactivation (NSTR) and prolonged/symptomatic HCMV reactivation (long-term HCMV reactivation, LTR). Median HCMV-specific CD4+ T-cell frequencies were significantly higher in NSTR patients (day +60, 0.35 \% vs. 0.00 \% CD4+IFNγ+/CD4+ cells, p=0.018) than in patients with LTR, whereas patients with LTR had significantly higher median regulatory T-cell (Treg) frequencies (day +90, 2.2 \% vs. 6.2 \% CD4+CD25+CD127dim/CD4+ cells, p=0.019). ROC analysis confirmed low HCMV specific CD4+ (AUC on day +60: 0.813, p=0.019) and high Treg frequencies (AUC on day +90: 0.847, p=0.021) as significant predictors of prolonged and symptomatic HCMV reactivation. Discussion Taken together, letermovir prophylaxis delays HCMV reactivation and alters NK- and T-cell reconstitution. High numbers of HCMV-specific CD4+ T cells and low numbers of Tregs seem to be pivotal to suppress post-alloSCT HCMV reactivation during letermovir prophylaxis. Administration of more advanced immunoassays that include Treg signature cytokines might contribute to the identification of patients at high-risk for long-term and symptomatic HCMV reactivation who might benefit from prolonged administration of letermovir.},
  language  = {en}
}