Pub Date : 2024-05-02DOI: 10.1038/s41551-024-01211-9
David W. Wolfson, Nam Kyun Kim, Ki Hong Lee, Jared P. Beyersdorf, Jonathan J. Langberg, Natasha Fernandez, Dahim Choi, Nadine Zureick, Tae Yun Kim, Seongho Bae, Jin-Mo Gu, Jonathan L. Kirschman, Jinqi Fan, Christina Y. Sheng, Danielle Gottlieb Sen, Bret Mettler, Jung Hoon Sung, Young-sup Yoon, Sung-Jin Park, Philip J. Santangelo, Hee Cheol Cho
The adenovirus-mediated somatic transfer of the embryonic T-box transcription factor 18 (TBX18) gene can convert chamber cardiomyocytes into induced pacemaker cells. However, the translation of therapeutic TBX18-induced cardiac pacing faces safety challenges. Here we show that the myocardial expression of synthetic TBX18 mRNA in animals generates de novo pacing and limits innate and inflammatory immune responses. In rats, intramyocardially injected mRNA remained localized, whereas direct myocardial injection of an adenovirus carrying a reporter gene resulted in diffuse expression and in substantial spillover to the liver, spleen and lungs. Transient expression of TBX18 mRNA in rats led to de novo automaticity and pacemaker properties and, compared with the injection of adenovirus, to substantial reductions in the expression of inflammatory genes and in activated macrophage populations. In rodent and clinically relevant porcine models of complete heart block, intramyocardially injected TBX18 mRNA provided rate-adaptive cardiac pacing for one month that strongly correlated with the animal’s sinus rhythm and physical activity. TBX18 mRNA may aid the development of biological pacemakers. Intramyocardial injection of synthetic mRNA coding for the embryonic T-box transcription factor 18 gene generates rate-adaptive cardiac pacing and limits innate and inflammatory immune responses, as shown in rodents and pigs.
{"title":"Transient pacing in pigs with complete heart block via myocardial injection of mRNA coding for the T-box transcription factor 18","authors":"David W. Wolfson, Nam Kyun Kim, Ki Hong Lee, Jared P. Beyersdorf, Jonathan J. Langberg, Natasha Fernandez, Dahim Choi, Nadine Zureick, Tae Yun Kim, Seongho Bae, Jin-Mo Gu, Jonathan L. Kirschman, Jinqi Fan, Christina Y. Sheng, Danielle Gottlieb Sen, Bret Mettler, Jung Hoon Sung, Young-sup Yoon, Sung-Jin Park, Philip J. Santangelo, Hee Cheol Cho","doi":"10.1038/s41551-024-01211-9","DOIUrl":"10.1038/s41551-024-01211-9","url":null,"abstract":"The adenovirus-mediated somatic transfer of the embryonic T-box transcription factor 18 (TBX18) gene can convert chamber cardiomyocytes into induced pacemaker cells. However, the translation of therapeutic TBX18-induced cardiac pacing faces safety challenges. Here we show that the myocardial expression of synthetic TBX18 mRNA in animals generates de novo pacing and limits innate and inflammatory immune responses. In rats, intramyocardially injected mRNA remained localized, whereas direct myocardial injection of an adenovirus carrying a reporter gene resulted in diffuse expression and in substantial spillover to the liver, spleen and lungs. Transient expression of TBX18 mRNA in rats led to de novo automaticity and pacemaker properties and, compared with the injection of adenovirus, to substantial reductions in the expression of inflammatory genes and in activated macrophage populations. In rodent and clinically relevant porcine models of complete heart block, intramyocardially injected TBX18 mRNA provided rate-adaptive cardiac pacing for one month that strongly correlated with the animal’s sinus rhythm and physical activity. TBX18 mRNA may aid the development of biological pacemakers. Intramyocardial injection of synthetic mRNA coding for the embryonic T-box transcription factor 18 gene generates rate-adaptive cardiac pacing and limits innate and inflammatory immune responses, as shown in rodents and pigs.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 9","pages":"1124-1141"},"PeriodicalIF":26.8,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01211-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1038/s41551-024-01202-w
Zhuo Yang, Yingqin Hou, Geramie Grande, Jong Hyun Cho, Chao Wang, Yujie Shi, Jaroslav Zak, Yue Wan, Ke Qin, Dongfang Liu, John R. Teijaro, Richard A. Lerner, Peng Wu
Bispecific T-cell engagers (BiTEs) bring together tumour cells and cytotoxic T cells by binding to specific cell-surface tumour antigens and T-cell receptors, and have been clinically successful for the treatment of B-cell malignancies. Here we show that a BiTE–sialidase fusion protein enhances the susceptibility of solid tumours to BiTE-mediated cytolysis of tumour cells via targeted desialylation—that is, the removal of terminal sialic acid residues on glycans—at the BiTE-induced T-cell–tumour-cell interface. In xenograft and syngeneic mouse models of leukaemia and of melanoma and breast cancer, and compared with the parental BiTE molecules, targeted desialylation via the BiTE–sialidase fusion proteins enhanced the formation of immunological synapses, T-cell activation and T-cell-mediated tumour-cell cytolysis in the presence of the target antigen. The targeted desialylation of tumour cells may enhance the potency of therapies relying on T-cell engagers. The removal of terminal sialic acid residues on glycans at the T-cell–tumour-cell interface via a sialidase fused to a bispecific T-cell engager enhances the susceptibility of solid cancers to T-cell-mediated cytolysis.
双特异性T细胞吞噬因子（BiTE）通过与特异性细胞表面肿瘤抗原和T细胞受体结合，将肿瘤细胞和细胞毒性T细胞结合在一起，在临床上成功治疗了B细胞恶性肿瘤。在这里，我们展示了 BiTE-硅糖苷酶融合蛋白通过靶向去硅烷基化--即在 BiTE 诱导的 T 细胞-肿瘤细胞界面上去除聚糖上的末端硅酸残基--来提高实体瘤对 BiTE 介导的肿瘤细胞溶解的敏感性。在白血病、黑色素瘤和乳腺癌的异种移植和合成小鼠模型中，与亲代 BiTE 分子相比，通过 BiTE-sialidase 融合蛋白进行的靶向脱ialylation 能在靶抗原存在的情况下增强免疫突触的形成、T 细胞活化和 T 细胞介导的肿瘤细胞细胞溶解。对肿瘤细胞进行有针对性的脱硅烷基化可增强依赖于T细胞吸引剂的疗法的效力。
{"title":"Targeted desialylation and cytolysis of tumour cells by fusing a sialidase to a bispecific T-cell engager","authors":"Zhuo Yang, Yingqin Hou, Geramie Grande, Jong Hyun Cho, Chao Wang, Yujie Shi, Jaroslav Zak, Yue Wan, Ke Qin, Dongfang Liu, John R. Teijaro, Richard A. Lerner, Peng Wu","doi":"10.1038/s41551-024-01202-w","DOIUrl":"10.1038/s41551-024-01202-w","url":null,"abstract":"Bispecific T-cell engagers (BiTEs) bring together tumour cells and cytotoxic T cells by binding to specific cell-surface tumour antigens and T-cell receptors, and have been clinically successful for the treatment of B-cell malignancies. Here we show that a BiTE–sialidase fusion protein enhances the susceptibility of solid tumours to BiTE-mediated cytolysis of tumour cells via targeted desialylation—that is, the removal of terminal sialic acid residues on glycans—at the BiTE-induced T-cell–tumour-cell interface. In xenograft and syngeneic mouse models of leukaemia and of melanoma and breast cancer, and compared with the parental BiTE molecules, targeted desialylation via the BiTE–sialidase fusion proteins enhanced the formation of immunological synapses, T-cell activation and T-cell-mediated tumour-cell cytolysis in the presence of the target antigen. The targeted desialylation of tumour cells may enhance the potency of therapies relying on T-cell engagers. The removal of terminal sialic acid residues on glycans at the T-cell–tumour-cell interface via a sialidase fused to a bispecific T-cell engager enhances the susceptibility of solid cancers to T-cell-mediated cytolysis.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 5","pages":"499-512"},"PeriodicalIF":28.1,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140817620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-23DOI: 10.1038/s41551-024-01213-7
The widening range of strategies to alter the phenotypes and functions of mammalian cells is a boon for their biomedical applications.
改变哺乳动物细胞表型和功能的策略范围不断扩大，为其生物医学应用带来了福音。
{"title":"The myriad ways to engineer cells","authors":"","doi":"10.1038/s41551-024-01213-7","DOIUrl":"10.1038/s41551-024-01213-7","url":null,"abstract":"The widening range of strategies to alter the phenotypes and functions of mammalian cells is a boon for their biomedical applications.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 4","pages":"337-338"},"PeriodicalIF":28.1,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01213-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140636995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-19DOI: 10.1038/s41551-024-01194-7
DaeYong Lee, Kristin Huntoon, Yifan Wang, Minjeong Kang, Yifei Lu, Seong Dong Jeong, Todd M. Link, Thomas D. Gallup, Yaqing Qie, Xuefeng Li, Shiyan Dong, Benjamin R. Schrank, Adam J. Grippin, Abin Antony, JongHoon Ha, Mengyu Chang, Yi An, Liang Wang, Dadi Jiang, Jing Li, Albert C. Koong, John A. Tainer, Wen Jiang, Betty Y. S. Kim
Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS–STING (for cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells. In syngeneic mouse models of locally advanced and metastatic breast cancers, the polypeptides led to potent DNA-sensor-mediated antitumour responses when intravenously given as monotherapy or with immune checkpoint inhibitors. The activation of multiple innate immune pathways via engineered cationic polypeptides may offer therapeutic advantages in the generation of antitumour immune responses. The hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate antitumour innate immune responses via endoplasmic reticulum stress in antigen-presenting cells.
细胞内 DNA 传感器可调节先天性免疫，并为适应性免疫原性提供桥梁。然而，双链 DNA 或环状核苷酸等天然激动剂对抗原递呈细胞（APC）中传感器的激活作用因细胞内传递、血清稳定性、酶降解和快速全身清除等因素而受到阻碍。在这里，我们展示了螺旋多肽的疏水性、静电荷和次级构象可以优化，从而通过内质网应激刺激 APC 的先天性免疫通路。我们设计的三种多肽中的一种通过促进线粒体 DNA 的释放，优先激活了 APCs 中的两条主要细胞内 DNA 传感途径（cGAS-STING（环磷酸鸟苷-单磷酸腺苷合成酶-干扰素基因刺激器）和 Toll 样受体 9），从而高效地启动了效应 T 细胞。在局部晚期和转移性乳腺癌的合成小鼠模型中，多肽作为单一疗法或与免疫检查点抑制剂一起静脉注射，可产生有效的 DNA 传感器介导的抗肿瘤反应。通过工程阳离子多肽激活多种先天性免疫途径可能会为产生抗肿瘤免疫反应提供治疗优势。
{"title":"Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells","authors":"DaeYong Lee, Kristin Huntoon, Yifan Wang, Minjeong Kang, Yifei Lu, Seong Dong Jeong, Todd M. Link, Thomas D. Gallup, Yaqing Qie, Xuefeng Li, Shiyan Dong, Benjamin R. Schrank, Adam J. Grippin, Abin Antony, JongHoon Ha, Mengyu Chang, Yi An, Liang Wang, Dadi Jiang, Jing Li, Albert C. Koong, John A. Tainer, Wen Jiang, Betty Y. S. Kim","doi":"10.1038/s41551-024-01194-7","DOIUrl":"10.1038/s41551-024-01194-7","url":null,"abstract":"Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS–STING (for cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells. In syngeneic mouse models of locally advanced and metastatic breast cancers, the polypeptides led to potent DNA-sensor-mediated antitumour responses when intravenously given as monotherapy or with immune checkpoint inhibitors. The activation of multiple innate immune pathways via engineered cationic polypeptides may offer therapeutic advantages in the generation of antitumour immune responses. The hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate antitumour innate immune responses via endoplasmic reticulum stress in antigen-presenting cells.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 5","pages":"593-610"},"PeriodicalIF":28.1,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140620417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-08DOI: 10.1038/s41551-024-01197-4
Jan-Niklas May, Jennifer I. Moss, Florian Mueller, Susanne K. Golombek, Ilaria Biancacci, Larissa Rizzo, Asmaa Said Elshafei, Felix Gremse, Robert Pola, Michal Pechar, Tomáš Etrych, Svea Becker, Christian Trautwein, Roman D. Bülow, Peter Boor, Ruth Knuechel, Saskia von Stillfried, Gert Storm, Sanyogitta Puri, Simon T. Barry, Volkmar Schulz, Fabian Kiessling, Marianne B. Ashford, Twan Lammers
The clinical prospects of cancer nanomedicines depend on effective patient stratification. Here we report the identification of predictive biomarkers of the accumulation of nanomedicines in tumour tissue. By using supervised machine learning on data of the accumulation of nanomedicines in tumour models in mice, we identified the densities of blood vessels and of tumour-associated macrophages as key predictive features. On the basis of these two features, we derived a biomarker score correlating with the concentration of liposomal doxorubicin in tumours and validated it in three syngeneic tumour models in immunocompetent mice and in four cell-line-derived and six patient-derived tumour xenografts in mice. The score effectively discriminated tumours according to the accumulation of nanomedicines (high versus low), with an area under the receiver operating characteristic curve of 0.91. Histopathological assessment of 30 tumour specimens from patients and of 28 corresponding primary tumour biopsies confirmed the score’s effectiveness in predicting the tumour accumulation of liposomal doxorubicin. Biomarkers of the tumour accumulation of nanomedicines may aid the stratification of patients in clinical trials of cancer nanomedicines. The densities of blood vessels and of tumour-associated macrophages are key predictive features of the degree of accumulation of polymeric and liposomal nanomedicines, as shown for specimens of mouse and human tumours.
{"title":"Histopathological biomarkers for predicting the tumour accumulation of nanomedicines","authors":"Jan-Niklas May, Jennifer I. Moss, Florian Mueller, Susanne K. Golombek, Ilaria Biancacci, Larissa Rizzo, Asmaa Said Elshafei, Felix Gremse, Robert Pola, Michal Pechar, Tomáš Etrych, Svea Becker, Christian Trautwein, Roman D. Bülow, Peter Boor, Ruth Knuechel, Saskia von Stillfried, Gert Storm, Sanyogitta Puri, Simon T. Barry, Volkmar Schulz, Fabian Kiessling, Marianne B. Ashford, Twan Lammers","doi":"10.1038/s41551-024-01197-4","DOIUrl":"10.1038/s41551-024-01197-4","url":null,"abstract":"The clinical prospects of cancer nanomedicines depend on effective patient stratification. Here we report the identification of predictive biomarkers of the accumulation of nanomedicines in tumour tissue. By using supervised machine learning on data of the accumulation of nanomedicines in tumour models in mice, we identified the densities of blood vessels and of tumour-associated macrophages as key predictive features. On the basis of these two features, we derived a biomarker score correlating with the concentration of liposomal doxorubicin in tumours and validated it in three syngeneic tumour models in immunocompetent mice and in four cell-line-derived and six patient-derived tumour xenografts in mice. The score effectively discriminated tumours according to the accumulation of nanomedicines (high versus low), with an area under the receiver operating characteristic curve of 0.91. Histopathological assessment of 30 tumour specimens from patients and of 28 corresponding primary tumour biopsies confirmed the score’s effectiveness in predicting the tumour accumulation of liposomal doxorubicin. Biomarkers of the tumour accumulation of nanomedicines may aid the stratification of patients in clinical trials of cancer nanomedicines. The densities of blood vessels and of tumour-associated macrophages are key predictive features of the degree of accumulation of polymeric and liposomal nanomedicines, as shown for specimens of mouse and human tumours.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 11","pages":"1366-1378"},"PeriodicalIF":26.8,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01197-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1038/s41551-024-01190-x
Shijie Cao, Erica Budina, Michal M. Raczy, Ani Solanki, Mindy Nguyen, Taryn N. Beckman, Joseph W. Reda, Kevin Hultgren, Phillip S. Ang, Anna J. Slezak, Lauren A. Hesser, Aaron T. Alpar, Kirsten C. Refvik, Lucas S. Shores, Ishita Pillai, Rachel P. Wallace, Arjun Dhar, Elyse A. Watkins, Jeffrey A. Hubbell
Butyrate—a metabolite produced by commensal bacteria—has been extensively studied for its immunomodulatory effects on immune cells, including regulatory T cells, macrophages and dendritic cells. However, the development of butyrate as a drug has been hindered by butyrate’s poor oral bioavailability, owing to its rapid metabolism in the gut, its low potency (hence, necessitating high dosing), and its foul smell and taste. Here we report that the oral bioavailability of butyrate can be increased by esterifying it to serine, an amino acid transporter that aids the escape of the resulting odourless and tasteless prodrug (O-butyryl-l-serine, which we named SerBut) from the gut, enhancing its systemic uptake. In mice with collagen-antibody-induced arthritis (a model of rheumatoid arthritis) and with experimental autoimmune encephalomyelitis (a model of multiple sclerosis), we show that SerBut substantially ameliorated disease severity, modulated key immune cell populations systemically and in disease-associated tissues, and reduced inflammatory responses without compromising the global immune response to vaccination. SerBut may become a promising therapeutic for autoimmune and inflammatory diseases. The esterification of butyrate to serine makes for an odourless and tasteless oral prodrug that ameliorated disease severity and reduced inflammatory responses in mouse models of rheumatoid arthritis and multiple sclerosis.
丁酸盐是一种由共生细菌产生的代谢产物，因其对免疫细胞（包括调节性 T 细胞、巨噬细胞和树突状细胞）的免疫调节作用而被广泛研究。然而，由于丁酸盐在肠道中的代谢速度快、效力低（因此必须加大剂量）以及气味和味道难闻，丁酸盐的口服生物利用度较低，这阻碍了丁酸盐作为药物的开发。我们在此报告，通过将丁酸酯酯化为丝氨酸，可以提高丁酸酯的口服生物利用度。丝氨酸是一种氨基酸转运体，可以帮助产生的无味无臭原药（O-丁酰-L-丝氨酸，我们将其命名为 SerBut）从肠道中排出，从而提高其全身吸收率。在胶原抗体诱导的关节炎（类风湿性关节炎的一种模型）和实验性自身免疫性脑脊髓炎（多发性硬化症的一种模型）小鼠中，我们发现 SerBut 能显著改善疾病的严重程度，调节全身和疾病相关组织中的关键免疫细胞群，并在不影响疫苗接种的整体免疫反应的情况下减少炎症反应。SerBut可能成为治疗自身免疫性疾病和炎症性疾病的一种有前途的疗法。
{"title":"A serine-conjugated butyrate prodrug with high oral bioavailability suppresses autoimmune arthritis and neuroinflammation in mice","authors":"Shijie Cao, Erica Budina, Michal M. Raczy, Ani Solanki, Mindy Nguyen, Taryn N. Beckman, Joseph W. Reda, Kevin Hultgren, Phillip S. Ang, Anna J. Slezak, Lauren A. Hesser, Aaron T. Alpar, Kirsten C. Refvik, Lucas S. Shores, Ishita Pillai, Rachel P. Wallace, Arjun Dhar, Elyse A. Watkins, Jeffrey A. Hubbell","doi":"10.1038/s41551-024-01190-x","DOIUrl":"10.1038/s41551-024-01190-x","url":null,"abstract":"Butyrate—a metabolite produced by commensal bacteria—has been extensively studied for its immunomodulatory effects on immune cells, including regulatory T cells, macrophages and dendritic cells. However, the development of butyrate as a drug has been hindered by butyrate’s poor oral bioavailability, owing to its rapid metabolism in the gut, its low potency (hence, necessitating high dosing), and its foul smell and taste. Here we report that the oral bioavailability of butyrate can be increased by esterifying it to serine, an amino acid transporter that aids the escape of the resulting odourless and tasteless prodrug (O-butyryl-l-serine, which we named SerBut) from the gut, enhancing its systemic uptake. In mice with collagen-antibody-induced arthritis (a model of rheumatoid arthritis) and with experimental autoimmune encephalomyelitis (a model of multiple sclerosis), we show that SerBut substantially ameliorated disease severity, modulated key immune cell populations systemically and in disease-associated tissues, and reduced inflammatory responses without compromising the global immune response to vaccination. SerBut may become a promising therapeutic for autoimmune and inflammatory diseases. The esterification of butyrate to serine makes for an odourless and tasteless oral prodrug that ameliorated disease severity and reduced inflammatory responses in mouse models of rheumatoid arthritis and multiple sclerosis.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 5","pages":"611-627"},"PeriodicalIF":28.1,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01190-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140336298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1038/s41551-024-01195-6
Olivia Sirpilla, R. Leo Sakemura, Mehrdad Hefazi, Truc N. Huynh, Ismail Can, James H. Girsch, Erin E. Tapper, Michelle J. Cox, Kendall J. Schick, Claudia Manriquez-Roman, Kun Yun, Carli M. Stewart, Ekene J. Ogbodo, Brooke L. Kimball, Long K. Mai, Omar L. Gutierrez-Ruiz, Makena L. Rodriguez, Martina Gluscevic, Daniel P. Larson, Alex M. Abel, Wesley A. Wierson, Gloria Olivier, Elizabeth L. Siegler, Saad S. Kenderian
Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals’ symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression. Antigen-specific immunosuppression can be enhanced by genetically modifying mesenchymal stromal cells with chimaeric antigen receptors, as shown for the treatment of graft-versus-host disease in mice.
{"title":"Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression","authors":"Olivia Sirpilla, R. Leo Sakemura, Mehrdad Hefazi, Truc N. Huynh, Ismail Can, James H. Girsch, Erin E. Tapper, Michelle J. Cox, Kendall J. Schick, Claudia Manriquez-Roman, Kun Yun, Carli M. Stewart, Ekene J. Ogbodo, Brooke L. Kimball, Long K. Mai, Omar L. Gutierrez-Ruiz, Makena L. Rodriguez, Martina Gluscevic, Daniel P. Larson, Alex M. Abel, Wesley A. Wierson, Gloria Olivier, Elizabeth L. Siegler, Saad S. Kenderian","doi":"10.1038/s41551-024-01195-6","DOIUrl":"10.1038/s41551-024-01195-6","url":null,"abstract":"Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals’ symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression. Antigen-specific immunosuppression can be enhanced by genetically modifying mesenchymal stromal cells with chimaeric antigen receptors, as shown for the treatment of graft-versus-host disease in mice.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 4","pages":"443-460"},"PeriodicalIF":28.1,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140336299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-27DOI: 10.1038/s41551-024-01192-9
By coating manganese dioxide on the surface of fixed bacteria, we obtained mineralized bacteria with the ability to potently activate multiple immune signalling pathways. Immunotherapy with mineralized bacteria suppressed various types of cancer in multiple animal models, eliciting both immune memory and abscopal antitumour effects.
{"title":"Mineralized bacteria as an immunotherapy agent against various cancer types","authors":"","doi":"10.1038/s41551-024-01192-9","DOIUrl":"10.1038/s41551-024-01192-9","url":null,"abstract":"By coating manganese dioxide on the surface of fixed bacteria, we obtained mineralized bacteria with the ability to potently activate multiple immune signalling pathways. Immunotherapy with mineralized bacteria suppressed various types of cancer in multiple animal models, eliciting both immune memory and abscopal antitumour effects.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 5","pages":"497-498"},"PeriodicalIF":28.1,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140303785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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