Pub Date : 2024-10-21DOI: 10.1038/s41551-024-01264-w
Fei Wang, Ran Li, Jing Yi Xu, Xiaoxia Bai, Ying Wang, Xu Ri Chen, Chen Pan, Shen Chen, Ke Zhou, Boon Chin Heng, Xuewei Wu, Wei Guo, Zhe Song, Shu Cheng Jin, Jing Zhou, Xiao Hui Zou, Hong Wei Ouyang, Hua Liu
Immune rejection caused by mismatches in human leucocyte antigens (HLAs) remains a major obstacle to the success of allogeneic cell therapies. Current strategies for the generation of ‘universal’ immune-compatible cells, particularly the editing of HLA class I (HLA-I) genes or the modulation of proteins that inhibit natural killer cells, often result in genomic instability or cellular cytotoxicity. Here we show that a β2-microglobulin super-enhancer (B2M-SE) that is responsive to interferon-γ is a critical regulator of the expression of HLA-I on mesenchymal stromal cells (MSCs). Targeted epigenetic repression of B2M-SE in MSCs reduced the surface expression of HLA-I below the threshold required to activate allogenic T cells while maintaining levels sufficient to evade cytotoxicity mediated by natural killer cells. In a humanized mouse model, the epigenetically edited MSCs demonstrated improved survival by evading the immune system, allowing them to exert enhanced therapeutic effects on LPS-induced acute lung injury. Targeted epigenetic repression of B2M-SE may facilitate the development of off-the-shelf cell sources for allogeneic cell therapy.
人类白细胞抗原(HLA)不匹配引起的免疫排斥仍是异体细胞疗法取得成功的主要障碍。目前生成 "通用 "免疫相容细胞的策略,特别是编辑 HLA I 类(HLA-I)基因或调节抑制自然杀伤细胞的蛋白质,往往会导致基因组不稳定或细胞毒性。在这里,我们发现对干扰素-γ有反应的β2-微球蛋白超级增强子(B2M-SE)是间充质基质细胞(MSCs)上HLA-I表达的关键调节因子。间充质干细胞中 B2M-SE 的靶向表观遗传抑制可将 HLA-I 的表面表达降低到激活异源 T 细胞所需的阈值以下,同时保持足够的水平以规避自然杀伤细胞介导的细胞毒性。在人源化小鼠模型中,经过表观遗传学编辑的间充质干细胞通过逃避免疫系统而提高了存活率,从而使它们对 LPS 诱导的急性肺损伤发挥了更强的治疗效果。对B2M-SE进行靶向表观遗传学抑制可能有助于开发用于异体细胞治疗的现成细胞来源。
{"title":"Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically repressing a β2-microglobulin super-enhancer","authors":"Fei Wang, Ran Li, Jing Yi Xu, Xiaoxia Bai, Ying Wang, Xu Ri Chen, Chen Pan, Shen Chen, Ke Zhou, Boon Chin Heng, Xuewei Wu, Wei Guo, Zhe Song, Shu Cheng Jin, Jing Zhou, Xiao Hui Zou, Hong Wei Ouyang, Hua Liu","doi":"10.1038/s41551-024-01264-w","DOIUrl":"https://doi.org/10.1038/s41551-024-01264-w","url":null,"abstract":"<p>Immune rejection caused by mismatches in human leucocyte antigens (HLAs) remains a major obstacle to the success of allogeneic cell therapies. Current strategies for the generation of ‘universal’ immune-compatible cells, particularly the editing of HLA class I (HLA-I) genes or the modulation of proteins that inhibit natural killer cells, often result in genomic instability or cellular cytotoxicity. Here we show that a β<sub>2</sub>-microglobulin super-enhancer (B2M-SE) that is responsive to interferon-γ is a critical regulator of the expression of HLA-I on mesenchymal stromal cells (MSCs). Targeted epigenetic repression of B2M-SE in MSCs reduced the surface expression of HLA-I below the threshold required to activate allogenic T cells while maintaining levels sufficient to evade cytotoxicity mediated by natural killer cells. In a humanized mouse model, the epigenetically edited MSCs demonstrated improved survival by evading the immune system, allowing them to exert enhanced therapeutic effects on LPS-induced acute lung injury. Targeted epigenetic repression of B2M-SE may facilitate the development of off-the-shelf cell sources for allogeneic cell therapy.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"57 11 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451816","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 : 2024-10-17DOI: 10.1038/s41551-024-01276-6
The design of implanted biomaterials and devices should involve strategies for the prevention of inflammation and fibrosis that enhance the functional lifespan of the implants.
植入式生物材料和设备的设计应包括预防炎症和纤维化的策略,以延长植入物的功能寿命。
{"title":"Overcoming immune hurdles to implant longevity","authors":"","doi":"10.1038/s41551-024-01276-6","DOIUrl":"10.1038/s41551-024-01276-6","url":null,"abstract":"The design of implanted biomaterials and devices should involve strategies for the prevention of inflammation and fibrosis that enhance the functional lifespan of the implants.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 10","pages":"1191-1192"},"PeriodicalIF":26.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01276-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447858","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}
Chimeric antigen receptor (CAR) T cells targeting receptors on tumour cells have had limited success in patients with glioblastoma. Here we report the development and therapeutic performance of CAR constructs leveraging protein binders computationally designed de novo to have high affinity for the epidermal growth factor receptor (EGFR) or the tumour-associated antigen CD276, which are overexpressed in glioblastoma. With respect to T cells with a CAR using an antibody-derived single-chain variable fragment as antigen-binding domain, the designed binders on CAR T cells promoted the proliferation of the cells, the secretion of cytotoxic cytokines and their resistance to cell exhaustion, and improved antitumour performance in vitro and in vivo. Moreover, CARs with the binders exhibited higher surface expression and greater resistance to degradation, as indicated by bulk and single-cell transcriptional profiling of the cells. The de novo design of binding domains for specific tumour antigens may potentiate the antitumour efficacy of CAR T cell therapies for other solid cancers.
以肿瘤细胞上的受体为靶点的嵌合抗原受体(CAR)T细胞在胶质母细胞瘤患者中的疗效有限。在这里,我们报告了利用通过计算重新设计的蛋白结合体的 CAR 构建物的开发和治疗效果,这种结合体对表皮生长因子受体(EGFR)或肿瘤相关抗原 CD276 具有高亲和力,而表皮生长因子受体或肿瘤相关抗原 CD276 在胶质母细胞瘤中过度表达。对于使用抗体衍生的单链可变片段作为抗原结合域的CAR T细胞,CAR T细胞上设计的结合剂促进了细胞的增殖、细胞毒性细胞因子的分泌和细胞衰竭的抵抗力,并提高了体外和体内的抗肿瘤性能。此外,细胞的大量和单细胞转录谱分析表明,带有结合域的 CAR 具有更高的表面表达能力和更强的抗降解能力。重新设计特定肿瘤抗原的结合域可能会增强CAR T细胞疗法对其他实体瘤的抗肿瘤疗效。
{"title":"Targeting overexpressed antigens in glioblastoma via CAR T cells with computationally designed high-affinity protein binders","authors":"Zhen Xia, Qihan Jin, Zhilin Long, Yexuan He, Fuyi Liu, Chengfang Sun, Jinyang Liao, Chun Wang, Chentong Wang, Jian Zheng, Weixi Zhao, Tianxin Zhang, Jeremy N. Rich, Yongdeng Zhang, Longxing Cao, Qi Xie","doi":"10.1038/s41551-024-01258-8","DOIUrl":"https://doi.org/10.1038/s41551-024-01258-8","url":null,"abstract":"<p>Chimeric antigen receptor (CAR) T cells targeting receptors on tumour cells have had limited success in patients with glioblastoma. Here we report the development and therapeutic performance of CAR constructs leveraging protein binders computationally designed de novo to have high affinity for the epidermal growth factor receptor (EGFR) or the tumour-associated antigen CD276, which are overexpressed in glioblastoma. With respect to T cells with a CAR using an antibody-derived single-chain variable fragment as antigen-binding domain, the designed binders on CAR T cells promoted the proliferation of the cells, the secretion of cytotoxic cytokines and their resistance to cell exhaustion, and improved antitumour performance in vitro and in vivo. Moreover, CARs with the binders exhibited higher surface expression and greater resistance to degradation, as indicated by bulk and single-cell transcriptional profiling of the cells. The de novo design of binding domains for specific tumour antigens may potentiate the antitumour efficacy of CAR T cell therapies for other solid cancers.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"13 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440823","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 : 2024-10-17DOI: 10.1038/s41551-024-01266-8
Julia Garcia Mancebo, Kristen Sack, Jay Hartford, Saffron Dominguez, Michelle Balcarcel-Monzon, Elizabeth Chartier, Tien Nguyen, Alexis R. Cole, Francesca Sperotto, David M. Harrild, Brian D. Polizzotti, Allen D. Everett, Alan B. Packard, Jason Dearling, Arthur G. Nedder, Simon Warfield, Edward Yang, Hart G. W. Lidov, John N. Kheir, Yifeng Peng
Acute respiratory failure can cause profound hypoxaemia that leads to organ injury or death within minutes. When conventional interventions are ineffective, the intravenous administration of oxygen can rescue patients from severe hypoxaemia, but at the risk of microvascular obstruction and of toxicity of the carrier material. Here we describe polymeric microbubbles as carriers of high volumes of oxygen (350–500 ml of oxygen per litre of foam) that are stable in storage yet quickly dissolve following intravenous injection, reverting to their soluble and excretable molecular constituents. In swine with profound hypoxaemia owing to acute and temporary (12 min) upper-airway obstruction, the microbubble-mediated delivery of oxygen led to: the maintenance of critical oxygenation, lowered burdens of cardiac arrest, improved survival, and substantially improved neurologic and kidney function in surviving animals. Our findings underscore the importance of maintaining a critical threshold of oxygenation and the promise of injectable oxygen as a viable therapy in acute and temporary hypoxaemic crises. The intravenous injection of oxygen via polymeric microbubbles that are stable in storage yet quickly dissolve following intravenous injection led to the maintenance of critical oxygenation and to improved survival in swine with profound hypoxaemia.
{"title":"Systemically injected oxygen within rapidly dissolving microbubbles improves the outcomes of severe hypoxaemia in swine","authors":"Julia Garcia Mancebo, Kristen Sack, Jay Hartford, Saffron Dominguez, Michelle Balcarcel-Monzon, Elizabeth Chartier, Tien Nguyen, Alexis R. Cole, Francesca Sperotto, David M. Harrild, Brian D. Polizzotti, Allen D. Everett, Alan B. Packard, Jason Dearling, Arthur G. Nedder, Simon Warfield, Edward Yang, Hart G. W. Lidov, John N. Kheir, Yifeng Peng","doi":"10.1038/s41551-024-01266-8","DOIUrl":"10.1038/s41551-024-01266-8","url":null,"abstract":"Acute respiratory failure can cause profound hypoxaemia that leads to organ injury or death within minutes. When conventional interventions are ineffective, the intravenous administration of oxygen can rescue patients from severe hypoxaemia, but at the risk of microvascular obstruction and of toxicity of the carrier material. Here we describe polymeric microbubbles as carriers of high volumes of oxygen (350–500 ml of oxygen per litre of foam) that are stable in storage yet quickly dissolve following intravenous injection, reverting to their soluble and excretable molecular constituents. In swine with profound hypoxaemia owing to acute and temporary (12 min) upper-airway obstruction, the microbubble-mediated delivery of oxygen led to: the maintenance of critical oxygenation, lowered burdens of cardiac arrest, improved survival, and substantially improved neurologic and kidney function in surviving animals. Our findings underscore the importance of maintaining a critical threshold of oxygenation and the promise of injectable oxygen as a viable therapy in acute and temporary hypoxaemic crises. The intravenous injection of oxygen via polymeric microbubbles that are stable in storage yet quickly dissolve following intravenous injection led to the maintenance of critical oxygenation and to improved survival in swine with profound hypoxaemia.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 11","pages":"1396-1411"},"PeriodicalIF":26.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01266-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440824","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 : 2024-10-15DOI: 10.1038/s41551-024-01268-6
Rui Yan, Md Tauhidual Islam, Lei Xing
Tabular data—rows of samples and columns of sample features—are ubiquitously used across disciplines. Yet the tabular representation makes it difficult to discover underlying associations in the data and thus hinders their analysis and the discovery of useful patterns. Here we report a broadly applicable strategy for unravelling intertwined relationships in tabular data by reconfiguring each data sample into a spatially semantic 2D topographic map, which we refer to as TabMap. A TabMap preserves the original feature values as pixel intensities, with the relationships among the features spatially encoded in the map (the strength of two inter-related features correlates with their distance on the map). TabMap makes it possible to apply 2D convolutional neural networks to extract association patterns in the data to aid data analysis, and offers interpretability by ranking features according to importance. We show the superior predictive performance of TabMap by applying it to 12 datasets across a wide range of biomedical applications, including disease diagnosis, human activity recognition, microbial identification and the analysis of quantitative structure–activity relationships.
{"title":"Interpretable discovery of patterns in tabular data via spatially semantic topographic maps","authors":"Rui Yan, Md Tauhidual Islam, Lei Xing","doi":"10.1038/s41551-024-01268-6","DOIUrl":"https://doi.org/10.1038/s41551-024-01268-6","url":null,"abstract":"<p>Tabular data—rows of samples and columns of sample features—are ubiquitously used across disciplines. Yet the tabular representation makes it difficult to discover underlying associations in the data and thus hinders their analysis and the discovery of useful patterns. Here we report a broadly applicable strategy for unravelling intertwined relationships in tabular data by reconfiguring each data sample into a spatially semantic 2D topographic map, which we refer to as TabMap. A TabMap preserves the original feature values as pixel intensities, with the relationships among the features spatially encoded in the map (the strength of two inter-related features correlates with their distance on the map). TabMap makes it possible to apply 2D convolutional neural networks to extract association patterns in the data to aid data analysis, and offers interpretability by ranking features according to importance. We show the superior predictive performance of TabMap by applying it to 12 datasets across a wide range of biomedical applications, including disease diagnosis, human activity recognition, microbial identification and the analysis of quantitative structure–activity relationships.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"64 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436341","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 : 2024-10-07DOI: 10.1038/s41551-024-01261-z
Daniel Truhn, Jakob Nikolas Kather
A latent diffusion model pre-trained on pairs of natural images and text descriptors can be adapted to generate realistic chest radiographs that are controlled by free-form medical text prompts.
在自然图像和文本描述符对上预先训练的潜在扩散模型可用于生成由自由格式医学文本提示控制的逼真胸片。
{"title":"Synthetic chest X-ray images from text prompts","authors":"Daniel Truhn, Jakob Nikolas Kather","doi":"10.1038/s41551-024-01261-z","DOIUrl":"https://doi.org/10.1038/s41551-024-01261-z","url":null,"abstract":"A latent diffusion model pre-trained on pairs of natural images and text descriptors can be adapted to generate realistic chest radiographs that are controlled by free-form medical text prompts.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"19 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383746","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 : 2024-10-04DOI: 10.1038/s41551-024-01260-0
Chima V. Maduka, Axel D. Schmitter-Sánchez, Ashley V. Makela, Evran Ural, Katlin B. Stivers, Hunter Pope, Maxwell M. Kuhnert, Oluwatosin M. Habeeb, Anthony Tundo, Mohammed Alhaj, Artem Kiselev, Shoue Chen, Alexis Donneys, Wade P. Winton, Jenelle Stauff, Peter J. H. Scott, Andrew J. Olive, Kurt D. Hankenson, Ramani Narayan, Sangbum Park, Jennifer H. Elisseeff, Christopher H. Contag
Circulating monocytes infiltrate and coordinate immune responses in tissues surrounding implanted biomaterials and in other inflamed tissues. Here we show that immunometabolic cues in the biomaterial microenvironment govern the trafficking of immune cells, including neutrophils and monocytes, in a manner dependent on the chemokine receptor 2 (CCR2) and the C-X3-C motif chemokine receptor 1 (CX3CR1). This affects the composition and activation states of macrophage and dendritic cell populations, ultimately orchestrating the relative composition of pro-inflammatory, transitory and anti-inflammatory CCR2+, CX3CR1+ and CCR2+ CX3CR1+ immune cell populations. In amorphous polylactide implants, modifying immunometabolism by glycolytic inhibition drives a pro-regenerative microenvironment principally by myeloid cells. In crystalline polylactide implants, together with arginase-1-expressing myeloid cells, T helper 2 cells and γδ+ T cells producing interleukin-4 substantially contribute to shaping the metabolically reprogrammed pro-regenerative microenvironment. Our findings inform the premise that local metabolic states regulate inflammatory processes in the biomaterial microenvironment. Immunometabolic cues surrounding implanted biomaterials govern the trafficking of subsets of neutrophils, monocytes and other immune cells, and determine the relative composition of pro-inflammatory and anti-inflammatory immune cell populations.
{"title":"Immunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials","authors":"Chima V. Maduka, Axel D. Schmitter-Sánchez, Ashley V. Makela, Evran Ural, Katlin B. Stivers, Hunter Pope, Maxwell M. Kuhnert, Oluwatosin M. Habeeb, Anthony Tundo, Mohammed Alhaj, Artem Kiselev, Shoue Chen, Alexis Donneys, Wade P. Winton, Jenelle Stauff, Peter J. H. Scott, Andrew J. Olive, Kurt D. Hankenson, Ramani Narayan, Sangbum Park, Jennifer H. Elisseeff, Christopher H. Contag","doi":"10.1038/s41551-024-01260-0","DOIUrl":"10.1038/s41551-024-01260-0","url":null,"abstract":"Circulating monocytes infiltrate and coordinate immune responses in tissues surrounding implanted biomaterials and in other inflamed tissues. Here we show that immunometabolic cues in the biomaterial microenvironment govern the trafficking of immune cells, including neutrophils and monocytes, in a manner dependent on the chemokine receptor 2 (CCR2) and the C-X3-C motif chemokine receptor 1 (CX3CR1). This affects the composition and activation states of macrophage and dendritic cell populations, ultimately orchestrating the relative composition of pro-inflammatory, transitory and anti-inflammatory CCR2+, CX3CR1+ and CCR2+ CX3CR1+ immune cell populations. In amorphous polylactide implants, modifying immunometabolism by glycolytic inhibition drives a pro-regenerative microenvironment principally by myeloid cells. In crystalline polylactide implants, together with arginase-1-expressing myeloid cells, T helper 2 cells and γδ+ T cells producing interleukin-4 substantially contribute to shaping the metabolically reprogrammed pro-regenerative microenvironment. Our findings inform the premise that local metabolic states regulate inflammatory processes in the biomaterial microenvironment. Immunometabolic cues surrounding implanted biomaterials govern the trafficking of subsets of neutrophils, monocytes and other immune cells, and determine the relative composition of pro-inflammatory and anti-inflammatory immune cell populations.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 10","pages":"1308-1321"},"PeriodicalIF":26.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370071","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 : 2024-10-03DOI: 10.1038/s41551-024-01256-w
Namit Chaudhary, Lisa N. Kasiewicz, Alexandra N. Newby, Mariah L. Arral, Saigopalakrishna S. Yerneni, Jilian R. Melamed, Samuel T. LoPresti, Katherine C. Fein, Daria M. Strelkova Petersen, Sushant Kumar, Rahul Purwar, Kathryn A. Whitehead
Lipid nanoparticles (LNPs) are the most clinically advanced delivery vehicle for RNA therapeutics, partly because of established lipid structure–activity relationships focused on formulation potency. Yet such knowledge has not extended to LNP immunogenicity. Here we show that the innate and adaptive immune responses elicited by LNPs are linked to their ionizable lipid chemistry. Specifically, we show that the amine headgroups in ionizable lipids drive LNP immunogenicity by binding to Toll-like receptor 4 and CD1d and by promoting lipid-raft formation. Immunogenic LNPs favour a type-1 T-helper-cell-biased immune response marked by increases in the immunoglobulins IgG2c and IgG1 and in the pro-inflammatory cytokines tumour necrosis factor, interferon γ and the interleukins IL-6 and IL-2. Notably, the inflammatory signals originating from these receptors inhibit the production of anti-poly(ethylene glycol) IgM antibodies, preventing the often-observed loss of efficacy in the LNP-mediated delivery of siRNA and mRNA. Moreover, we identified computational methods for the prediction of the structure-dependent innate and adaptive responses of LNPs. Our findings may help accelerate the discovery of well-tolerated ionizable lipids suitable for repeated dosing. Amine headgroups in ionizable lipids drive the immunogenicity of lipid nanoparticles by binding to Toll-like receptor 4 and CD1d and by promoting lipid-raft formation.
{"title":"Amine headgroups in ionizable lipids drive immune responses to lipid nanoparticles by binding to the receptors TLR4 and CD1d","authors":"Namit Chaudhary, Lisa N. Kasiewicz, Alexandra N. Newby, Mariah L. Arral, Saigopalakrishna S. Yerneni, Jilian R. Melamed, Samuel T. LoPresti, Katherine C. Fein, Daria M. Strelkova Petersen, Sushant Kumar, Rahul Purwar, Kathryn A. Whitehead","doi":"10.1038/s41551-024-01256-w","DOIUrl":"10.1038/s41551-024-01256-w","url":null,"abstract":"Lipid nanoparticles (LNPs) are the most clinically advanced delivery vehicle for RNA therapeutics, partly because of established lipid structure–activity relationships focused on formulation potency. Yet such knowledge has not extended to LNP immunogenicity. Here we show that the innate and adaptive immune responses elicited by LNPs are linked to their ionizable lipid chemistry. Specifically, we show that the amine headgroups in ionizable lipids drive LNP immunogenicity by binding to Toll-like receptor 4 and CD1d and by promoting lipid-raft formation. Immunogenic LNPs favour a type-1 T-helper-cell-biased immune response marked by increases in the immunoglobulins IgG2c and IgG1 and in the pro-inflammatory cytokines tumour necrosis factor, interferon γ and the interleukins IL-6 and IL-2. Notably, the inflammatory signals originating from these receptors inhibit the production of anti-poly(ethylene glycol) IgM antibodies, preventing the often-observed loss of efficacy in the LNP-mediated delivery of siRNA and mRNA. Moreover, we identified computational methods for the prediction of the structure-dependent innate and adaptive responses of LNPs. Our findings may help accelerate the discovery of well-tolerated ionizable lipids suitable for repeated dosing. Amine headgroups in ionizable lipids drive the immunogenicity of lipid nanoparticles by binding to Toll-like receptor 4 and CD1d and by promoting lipid-raft formation.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 11","pages":"1483-1498"},"PeriodicalIF":26.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142368957","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 : 2024-10-01DOI: 10.1038/s41551-024-01257-9
Oren Avram, Berkin Durmus, Nadav Rakocz, Giulia Corradetti, Ulzee An, Muneeswar G. Nittala, Prerit Terway, Akos Rudas, Zeyuan Johnson Chen, Yu Wakatsuki, Kazutaka Hirabayashi, Swetha Velaga, Liran Tiosano, Federico Corvi, Aditya Verma, Ayesha Karamat, Sophiana Lindenberg, Deniz Oncel, Louay Almidani, Victoria Hull, Sohaib Fasih-Ahmad, Houri Esmaeilkhanian, Maxime Cannesson, Charles C. Wykoff, Elior Rahmani, Corey W. Arnold, Bolei Zhou, Noah Zaitlen, Ilan Gronau, Sriram Sankararaman, Jeffrey N. Chiang, Srinivas R. Sadda, Eran Halperin
The application of machine learning to tasks involving volumetric biomedical imaging is constrained by the limited availability of annotated datasets of three-dimensional (3D) scans for model training. Here we report a deep-learning model pre-trained on 2D scans (for which annotated data are relatively abundant) that accurately predicts disease-risk factors from 3D medical-scan modalities. The model, which we named SLIViT (for ‘slice integration by vision transformer’), preprocesses a given volumetric scan into 2D images, extracts their feature map and integrates it into a single prediction. We evaluated the model in eight different learning tasks, including classification and regression for six datasets involving four volumetric imaging modalities (computed tomography, magnetic resonance imaging, optical coherence tomography and ultrasound). SLIViT consistently outperformed domain-specific state-of-the-art models and was typically as accurate as clinical specialists who had spent considerable time manually annotating the analysed scans. Automating diagnosis tasks involving volumetric scans may save valuable clinician hours, reduce data acquisition costs and duration, and help expedite medical research and clinical applications.
{"title":"Accurate prediction of disease-risk factors from volumetric medical scans by a deep vision model pre-trained with 2D scans","authors":"Oren Avram, Berkin Durmus, Nadav Rakocz, Giulia Corradetti, Ulzee An, Muneeswar G. Nittala, Prerit Terway, Akos Rudas, Zeyuan Johnson Chen, Yu Wakatsuki, Kazutaka Hirabayashi, Swetha Velaga, Liran Tiosano, Federico Corvi, Aditya Verma, Ayesha Karamat, Sophiana Lindenberg, Deniz Oncel, Louay Almidani, Victoria Hull, Sohaib Fasih-Ahmad, Houri Esmaeilkhanian, Maxime Cannesson, Charles C. Wykoff, Elior Rahmani, Corey W. Arnold, Bolei Zhou, Noah Zaitlen, Ilan Gronau, Sriram Sankararaman, Jeffrey N. Chiang, Srinivas R. Sadda, Eran Halperin","doi":"10.1038/s41551-024-01257-9","DOIUrl":"https://doi.org/10.1038/s41551-024-01257-9","url":null,"abstract":"<p>The application of machine learning to tasks involving volumetric biomedical imaging is constrained by the limited availability of annotated datasets of three-dimensional (3D) scans for model training. Here we report a deep-learning model pre-trained on 2D scans (for which annotated data are relatively abundant) that accurately predicts disease-risk factors from 3D medical-scan modalities. The model, which we named SLIViT (for ‘slice integration by vision transformer’), preprocesses a given volumetric scan into 2D images, extracts their feature map and integrates it into a single prediction. We evaluated the model in eight different learning tasks, including classification and regression for six datasets involving four volumetric imaging modalities (computed tomography, magnetic resonance imaging, optical coherence tomography and ultrasound). SLIViT consistently outperformed domain-specific state-of-the-art models and was typically as accurate as clinical specialists who had spent considerable time manually annotating the analysed scans. Automating diagnosis tasks involving volumetric scans may save valuable clinician hours, reduce data acquisition costs and duration, and help expedite medical research and clinical applications.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"17 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330387","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 : 2024-09-30DOI: 10.1038/s41551-024-01247-x
N. T. Huynh, E. Zhang, O. Francies, F. Kuklis, T. Allen, J. Zhu, O. Abeyakoon, F. Lucka, M. Betcke, J. Jaros, S. Arridge, B. Cox, A. A. Plumb, P. Beard
The clinical assessment of microvascular pathologies (in diabetes and in inflammatory skin diseases, for example) requires the visualization of superficial vascular anatomy. Photoacoustic tomography (PAT) scanners based on an all-optical Fabry–Perot ultrasound sensor can provide highly detailed 3D microvascular images, but minutes-long acquisition times have precluded their clinical use. Here we show that scan times can be reduced to a few seconds and even hundreds of milliseconds by parallelizing the optical architecture of the sensor readout, by using excitation lasers with high pulse-repetition frequencies and by exploiting compressed sensing. A PAT scanner with such fast acquisition minimizes motion-related artefacts and allows for the volumetric visualization of individual arterioles, venules, venous valves and millimetre-scale arteries and veins to depths approaching 15 mm, as well as for dynamic 3D images of time-varying tissue perfusion and other haemodynamic events. In exploratory case studies, we used the scanner to visualize and quantify microvascular changes associated with peripheral vascular disease, skin inflammation and rheumatoid arthritis. Fast all-optical PAT may prove useful in cardiovascular medicine, oncology, dermatology and rheumatology.
微血管病变(例如糖尿病和炎症性皮肤病)的临床评估需要表层血管解剖的可视化。基于全光学法布里-珀罗超声传感器的光声层析(PAT)扫描仪可以提供非常详细的三维微血管图像,但长达几分钟的采集时间使其无法用于临床。在这里,我们展示了通过并行化传感器读出的光学结构、使用高脉冲重复频率的激发激光器以及利用压缩传感技术,扫描时间可以缩短到几秒甚至几百毫秒。具有这种快速采集功能的 PAT 扫描仪能最大限度地减少与运动相关的伪影,并能对单个动脉血管、静脉、静脉瓣膜和毫米级的动脉和静脉(深度接近 15 毫米)进行容积可视化,以及对随时间变化的组织灌注和其他血流动力学事件进行动态三维成像。在探索性案例研究中,我们使用该扫描仪对与外周血管疾病、皮肤炎症和类风湿性关节炎相关的微血管变化进行了可视化和量化。快速全光 PAT 可能会在心血管医学、肿瘤学、皮肤病学和风湿病学领域大有用武之地。
{"title":"A fast all-optical 3D photoacoustic scanner for clinical vascular imaging","authors":"N. T. Huynh, E. Zhang, O. Francies, F. Kuklis, T. Allen, J. Zhu, O. Abeyakoon, F. Lucka, M. Betcke, J. Jaros, S. Arridge, B. Cox, A. A. Plumb, P. Beard","doi":"10.1038/s41551-024-01247-x","DOIUrl":"https://doi.org/10.1038/s41551-024-01247-x","url":null,"abstract":"<p>The clinical assessment of microvascular pathologies (in diabetes and in inflammatory skin diseases, for example) requires the visualization of superficial vascular anatomy. Photoacoustic tomography (PAT) scanners based on an all-optical Fabry–Perot ultrasound sensor can provide highly detailed 3D microvascular images, but minutes-long acquisition times have precluded their clinical use. Here we show that scan times can be reduced to a few seconds and even hundreds of milliseconds by parallelizing the optical architecture of the sensor readout, by using excitation lasers with high pulse-repetition frequencies and by exploiting compressed sensing. A PAT scanner with such fast acquisition minimizes motion-related artefacts and allows for the volumetric visualization of individual arterioles, venules, venous valves and millimetre-scale arteries and veins to depths approaching 15 mm, as well as for dynamic 3D images of time-varying tissue perfusion and other haemodynamic events. In exploratory case studies, we used the scanner to visualize and quantify microvascular changes associated with peripheral vascular disease, skin inflammation and rheumatoid arthritis. Fast all-optical PAT may prove useful in cardiovascular medicine, oncology, dermatology and rheumatology.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"54 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329617","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}