[Research Articles] Spatiotemporal single-cell profiling reveals that invasive and tissue-resident memory donor CD8+ T cells drive gastrointestinal acute graft-versus-host disease
Organ infiltration by donor T cells is critical to the development of acute graft-versus-host disease (aGVHD) in recipients after allogeneic hematopoietic stem cell transplant (allo-HCT). However, deconvoluting the transcriptional programs of newly recruited donor T cells from those of tissue-resident T cells in aGVHD target organs remains a challenge. Here, we combined the serial intravascular staining technique with single-cell RNA sequencing to dissect the tightly connected processes by which donor T cells initially infiltrate tissues and then establish a pathogenic tissue residency program in a rhesus macaque allo-HCT ...
Source: Science Translational Medicine - January 13, 2021 Category: Biomedical Science Authors: Tkachev, V., Kaminski, J., Potter, E. L., Furlan, S. N., Yu, A., Hunt, D. J., McGuckin, C., Zheng, H., Colonna, L., Gerdemann, U., Carlson, J., Hoffman, M., Olvera, J., English, C., Baldessari, A., Panoskaltsis-Mortari, A., Watkins, B., Qayed, M., Suessmu Tags: Research Articles Source Type: research
[Research Articles] Neuronal delivery of antibodies has therapeutic effects in animal models of botulism
Botulism is caused by a potent neurotoxin that blocks neuromuscular transmission, resulting in death by asphyxiation. Currently, the therapeutic options are limited and there is no antidote. Here, we harness the structural and trafficking properties of an atoxic derivative of botulinum neurotoxin (BoNT) to transport a function-blocking single-domain antibody into the neuronal cytosol where it can inhibit BoNT serotype A (BoNT/A1) molecular toxicity. Post-symptomatic treatment relieved toxic signs of botulism and rescued mice, guinea pigs, and nonhuman primates after lethal BoNT/A1 challenge. These data demonstrate that ato...
Source: Science Translational Medicine - January 6, 2021 Category: Biomedical Science Authors: McNutt, P. M., Vazquez-Cintron, E. J., Tenezaca, L., Ondeck, C. A., Kelly, K. E., Mangkhalakhili, M., Machamer, J. B., Angeles, C. A., Glotfelty, E. J., Cika, J., Benjumea, C. H., Whitfield, J. T., Band, P. A., Shoemaker, C. B., Ichtchenko, K. Tags: Research Articles Source Type: research
[Research Articles] Necrotizing enterocolitis induces T lymphocyte-mediated injury in the developing mammalian brain
Necrotizing enterocolitis (NEC) causes acute intestinal necrosis in premature infants and is associated with severe neurological impairment. In NEC, Toll-like receptor 4 is activated in the intestinal epithelium, and NEC-associated brain injury is characterized by microglial activation and white matter loss through mechanisms that remain unclear. We now show that the brains of mice and humans with NEC contained CD4+ T lymphocytes that were required for the development of brain injury. Inhibition of T lymphocyte influx into the brains of neonatal mice with NEC reduced inflammation and prevented myelin loss. Adoptive intrace...
Source: Science Translational Medicine - January 6, 2021 Category: Biomedical Science Authors: Zhou, Q., Nino, D. F., Yamaguchi, Y., Wang, S., Fulton, W. B., Jia, H., Lu, P., Prindle, T., Pamies, D., Morris, M., Chen, L. L., Sodhi, C. P., Hackam, D. J. Tags: Research Articles Source Type: research
[Research Articles] Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide
Cell-based therapies are emerging as effective agents against cancer and other diseases. As autonomous "living drugs," these therapies lack precise control. Chimeric antigen receptor (CAR) T cells effectively target hematologic malignancies but can proliferate rapidly and cause toxicity. We developed ON and OFF switches for CAR T cells using the clinically approved drug lenalidomide, which mediates the proteasomal degradation of several target proteins by inducing interactions between the CRL4CRBN E3 ubiquitin ligase and a C2H2 zinc finger degron motif. We performed a systematic screen to identify "super-degron" tags with ...
Source: Science Translational Medicine - January 6, 2021 Category: Biomedical Science Authors: Jan, M., Scarfo, I., Larson, R. C., Walker, A., Schmidts, A., Guirguis, A. A., Gasser, J. A., Słabicki, M., Bouffard, A. A., Castano, A. P., Kann, M. C., Cabral, M. L., Tepper, A., Grinshpun, D. E., Sperling, A. S., Kyung, T., Sievers, Q. L., Birnb Tags: Research Articles Source Type: research
[Research Articles] Mitochondrial metabolic reprogramming controls the induction of immunogenic cell death and efficacy of chemotherapy in bladder cancer
Although chemotherapeutic agents have been used for decades, the mechanisms of action, mechanisms of resistance, and the best treatment schedule remain elusive. Mitomycin C (MMC) is the gold standard treatment for non–muscle-invasive bladder cancer (NMIBC). However, it is effective only in a subset of patients, suggesting that, aside from cytotoxicity, other mechanisms could be involved in mediating the success of the treatment. Here, we showed that MMC promotes immunogenic cell death (ICD) and in vivo tumor protection. MMC-induced ICD relied on metabolic reprogramming of tumor cells toward increased oxidative phosph...
Source: Science Translational Medicine - January 6, 2021 Category: Biomedical Science Authors: Oresta, B., Pozzi, C., Braga, D., Hurle, R., Lazzeri, M., Colombo, P., Frego, N., Erreni, M., Faccani, C., Elefante, G., Barcella, M., Guazzoni, G., Rescigno, M. Tags: Research Articles Source Type: research
[Research Articles] Delivery of single-domain antibodies into neurons using a chimeric toxin-based platform is therapeutic in mouse models of botulism
Efficient penetration of cell membranes and specific targeting of a cell type represent major challenges for developing therapeutics toward intracellular targets. One example facing these hurdles is to develop post-exposure treatment for botulinum neurotoxins (BoNTs), a group of bacterial toxins (BoNT/A to BoNT/G) that are major potential bioterrorism agents. BoNTs enter motor neurons, block neurotransmitter release, and cause a paralytic disease botulism. Members of BoNTs such as BoNT/A exhibit extremely long half-life within neurons, resulting in persistent paralysis for months, yet there are no therapeutics that can inh...
Source: Science Translational Medicine - January 6, 2021 Category: Biomedical Science Authors: Miyashita, S.-I., Zhang, J., Zhang, S., Shoemaker, C. B., Dong, M. Tags: Research Articles Source Type: research
[Research Articles] Bacteria-specific phototoxic reactions triggered by blue light and phytochemical carvacrol
Development of alternatives to antibiotics is one of the top priorities in the battle against multidrug-resistant (MDR) bacterial infections. Here, we report that two naturally occurring nonantibiotic modalities, blue light and phytochemical carvacrol, synergistically kill an array of bacteria including their planktonic forms, mature biofilms, and persisters, irrespective of their antibiotic susceptibility. Combination but not single treatment completely or substantially cured acute and established biofilm-associated Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus infections of full thickness murine...
Source: Science Translational Medicine - January 6, 2021 Category: Biomedical Science Authors: Lu, M., Wang, S., Wang, T., Hu, S., Bhayana, B., Ishii, M., Kong, Y., Cai, Y., Dai, T., Cui, W., Wu, M. X. Tags: Research Articles Source Type: research
[Research Articles] A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence
Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9–based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid...
Source: Science Translational Medicine - January 6, 2021 Category: Biomedical Science Authors: Wang, W., Zheng, Y., Sun, S., Li, W., Song, M., Ji, Q., Wu, Z., Liu, Z., Fan, Y., Liu, F., Li, J., Esteban, C. R., Wang, S., Zhou, Q., Belmonte, J. C. I., Zhang, W., Qu, J., Tang, F., Liu, G.-H. Tags: Research Articles Source Type: research
[Editors' Choice] A protein sandwich enables real-time in vivo biomarker measurement
Biosensors allow rapid, accurate, continuous measurement of glucose and insulin in live rats. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 6, 2021 Category: Biomedical Science Authors: Roche, E. T. Tags: Editors ' Choice Source Type: research
[Editors' Choice] Unraveling the mysteries of microsatellite instability
DNA polymerase proofreading and mismatch repair deficiency have different microsatellites signatures. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 6, 2021 Category: Biomedical Science Authors: Ileana-Dumbrava, E. Tags: Editors ' Choice Source Type: research
[Editors' Choice] CRISPR cuts disease course short in blood disorders
Gene editing for sickle cell disease and β-thalassemia results in potential curative response. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 6, 2021 Category: Biomedical Science Authors: György, B. Tags: Editors ' Choice Source Type: research
[Research Articles] Receptor-gated IL-2 delivery by an anti-human IL-2 antibody activates regulatory T cells in three different species
Stimulation of regulatory T (Treg) cells holds great promise for the treatment of autoimmune, chronic inflammatory, and certain metabolic diseases. Recent clinical trials with low-dose interleukin-2 (IL-2) to expand Treg cells led to beneficial results in autoimmunity, but IL-2 immunotherapy can activate both Treg cells and pathogenic T cells. Use of IL-2 receptor α (IL-2Rα, CD25)–biased IL-2/anti–IL-2 antibody complexes improves IL-2 selectivity for Treg cells; however, the mechanism of action of such IL-2 complexes is incompletely understood, thus hampering their translation into clinical trials. ...
Source: Science Translational Medicine - December 16, 2020 Category: Biomedical Science Authors: Karakus, U., Sahin, D., Mittl, P. R. E., Mooij, P., Koopman, G., Boyman, O. Tags: Research Articles Source Type: research
[Editors' Choice] Brain rejuvenation by inhibiting stress response
Age-related cognitive decline can be reversed with small molecule inhibition of the stress response pathway. (Source: Science Translational Medicine)
Source: Science Translational Medicine - December 16, 2020 Category: Biomedical Science Authors: Xinyi, S. Tags: Editors ' Choice Source Type: research
[Editors' Choice] Metabolic vulnerabilities of intratumoral T cells and tumor cells
Tumor-infiltrating CD8+ T cells exhibit more metabolic vulnerabilities than tumor cells. (Source: Science Translational Medicine)
Source: Science Translational Medicine - December 16, 2020 Category: Biomedical Science Authors: Shi, L. Z. Tags: Editors ' Choice Source Type: research
[Editors' Choice] Reprogramming to help the old see like the young
Transcription factors associated with pluripotency restore molecular and functional characteristics resembling youth in aged mouse retinal ganglion cells. (Source: Science Translational Medicine)
Source: Science Translational Medicine - December 16, 2020 Category: Biomedical Science Authors: Aguilar, C. A. Tags: Editors ' Choice Source Type: research
