Biomarkers for cGVHD
Wolff D, Greinx H, Lee SJ, et al. Biomarkers in Chronic Graft-Versus-Host Disease: Quo Vadis?. Bone Marrow Transplantation 2018; 53 (7): 837
According to a study published in Bone Marrow Transplantation, the slower development of biomarkers for diagnosing and treating chronic graft-versus-host disease (cGVHD), compared with acute GVHD, can be attributed to a wider variety of manifestations, overlap with acute GVHD, more variation in time to onset and maximum severity, and a dearth of sufficient patient samples within prospective trials. In March 2017, a North-American and European consortium hosted an international workshop in France to discuss strategies for future biomarker development to guide cGVHD therapy. The meeting led to prioritizing both development of prognostic biomarkers for subsequent onset of moderate/severe cGVHD, and development of qualified clinical-grade assays for biomarker measurement. Prognostic serum biomarkers with the most promise include CXCL9, ST2, matrix metalloproteinase-3, osteopontin, CXCL10, CXCL11, and CD163. Urine-proteomics and cellular subsets represent additional possible prognostic cGVHD biomarkers. Collaboration is needed to confirm the outcomes of exploratory trials before any of the potential candidates is ready for validation and clinical application.
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Bim Regulates CD8+ Tregs
Agle K, Vincent BG, Piper C, et al. Bim Regulates the Survival and Suppressive Capability of CD8+ FOXP3+ Regulatory T Cells During Murine GVHD. Blood 2018; 132 (4): 435- 447
According to a study published in Blood, Bim regulates the survival and suppressive capability of CD8+ Foxp3+ T cells (Tregs), which may have implications for their use in regulatory T-cell therapy. Using an experimental model of graft-versus-host disease (GVHD), researchers observed that CD8+ Tregs were significantly less potent than CD4+ Tregs for the suppression of GVHD. Transcriptional profiling indicated that CD8+ Tregs had a canonical Treg transcriptional signature that was similar to that observed in CD4+ Tregs but distinct from conventional CD8+ T cells. However, pathway analysis showed that CD8+ Tregs had differential gene expression in pathways involved in cell death and survival, which was further confirmed by detailed mRNA sequence analysis and protein expression studies. Transplantation with CD8+ Foxp3+ Bim-/- Tregs led to extended Treg survival and lower GVHD mortality compared with wild-type CD8+ Tregs, providing functional confirmation that greater expression of Bim was responsible for decreased in vivo efficacy.
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Study Shows Successful In Vivo HSPC Genome Editing by CRISPR/Cas9
Li C, Psatha N, Sova P, et al. Reactivation of γ-Globin in Adult ß-YAC Mice After Ex Vivo and In Vivo Hematopoietic Stem Cell Genome Editing. Blood 2018; 131 (26): 2028
A study published in Blood is the first to show successful in vivo hematopoietic stem/progenitor cell (HSPC) genome editing by CRISPR/Cas9 (HDAd-HBG-CRISPR). Researchers used a helper-dependent human CD46-targeting adenovirus vector expressing CRISPR/Cas9 to disrupt a repressor binding region within the γ-globin promoter. They transduced HSPCs from ß-YAC/human CD46–transgenic mice ex vivo and then transplanted them into irradiated recipients, and used an in vivo HSPC transduction approach that involves HSPC mobilization and the intravenous injection of HDAd-HBG-CRISPR into ß-YAC/CD46–transgenic mice. In both models, they demonstrated efficient target site disruption, leading to a marked switch from human ß- to γ-globin expression in red blood cells of adult mice that was maintained after secondary transplantation of HSPCs. Long-term follow-up studies revealed no hematological abnormalities, which suggests that HBG promoter editing does not have a negative impact on hematopoiesis.
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