Kazushige Obata-Ninomiya, Tharmalingam Jayaraman, Steven F Ziegler
Type 2 epithelial cytokines, including thymic stromal lymphopoietin and IL-33, play central roles in modulation of type 2 immune cells, such as basophils. Basophils are a small subset of granulocytes within the leukocyte population that predominantly exist in the blood. They have non-redundant roles in allergic inflammation in peripheral tissues such as the lung, skin and gut, where they increase and accumulate at inflammatory lesions and exclusively produce large amounts of IL-4, a type 2 cytokine. These inflammatory reactions are known to be, to some extent, phenocopies of infectious diseases of ticks and helminths. Recently, biologics related to both type 2 epithelial cytokines and basophils have been approved by the US Food and Drug Administration for treatment of allergic diseases. We summarised the roles of Type 2 epithelial cytokines and basophils in basic science to translational medicine, including recent findings.
{"title":"From the bench to the clinic: basophils and type 2 epithelial cytokines of thymic stromal lymphopoietin and IL-33","authors":"Kazushige Obata-Ninomiya, Tharmalingam Jayaraman, Steven F Ziegler","doi":"10.1002/cti2.70020","DOIUrl":"10.1002/cti2.70020","url":null,"abstract":"<p>Type 2 epithelial cytokines, including thymic stromal lymphopoietin and IL-33, play central roles in modulation of type 2 immune cells, such as basophils. Basophils are a small subset of granulocytes within the leukocyte population that predominantly exist in the blood. They have non-redundant roles in allergic inflammation in peripheral tissues such as the lung, skin and gut, where they increase and accumulate at inflammatory lesions and exclusively produce large amounts of IL-4, a type 2 cytokine. These inflammatory reactions are known to be, to some extent, phenocopies of infectious diseases of ticks and helminths. Recently, biologics related to both type 2 epithelial cytokines and basophils have been approved by the US Food and Drug Administration for treatment of allergic diseases. We summarised the roles of Type 2 epithelial cytokines and basophils in basic science to translational medicine, including recent findings.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11626414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Palak H Mehta, Gemma S Trollope, Patrick Leung, Shivali Savita Chinni, Anna Iasinskaia, Aaron J Harrison, Hannah Hughes-Parry, Misty R Jenkins, Michael H Kershaw, Anthony Jaworowski, Clare Y Slaney, Rachel M Koldej, David S Ritchie, Kylie M Quinn
Objectives
In clinical chimeric antigen receptor (CAR) T cell therapy, one of the strongest correlates of favorable patient responses is lower levels of differentiation in T cells from the peripheral blood mononuclear cell (PBMC) starting material or the CAR T cell product. T cells from older patients are inherently more differentiated, but we hypothesised that specific activation protocols could be used to limit CAR T cell differentiation during manufacturing, particularly in older patients.
Methods
We used PBMCs from young (20–30 years old) and older (60+ years old) healthy donors to generate CAR T cells using two activation protocols: soluble anti-(α) CD3 monoclonal antibody (mAb) vs immune complexes of αCD3 and αCD28 mAbs. Products were assessed for yield, function and differentiation, which was used as a measure of CAR T cell quality. T cells in PBMCs were assessed for CD28 expression and correlative analyses were performed.
Results
Older samples generated fewer, more differentiated CAR T cells than young samples, and the αCD3/CD28 mAb protocol exacerbated this, further reducing yield and quality. CD28 expression by T cells correlated with CAR T cell differentiation, but T cell differentiation in PBMC starting material was a stronger correlate of CAR T cell differentiation.
Conclusions
Choice of activation protocol can substantially impact on the yield and quality of CAR T cells during manufacturing. This is a key consideration for older patients whose samples already generate a poorer yield and lower quality of CAR T cells.
{"title":"Choice of activation protocol impacts the yield and quality of CAR T cell product, particularly with older individuals","authors":"Palak H Mehta, Gemma S Trollope, Patrick Leung, Shivali Savita Chinni, Anna Iasinskaia, Aaron J Harrison, Hannah Hughes-Parry, Misty R Jenkins, Michael H Kershaw, Anthony Jaworowski, Clare Y Slaney, Rachel M Koldej, David S Ritchie, Kylie M Quinn","doi":"10.1002/cti2.70016","DOIUrl":"https://doi.org/10.1002/cti2.70016","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>In clinical chimeric antigen receptor (CAR) T cell therapy, one of the strongest correlates of favorable patient responses is lower levels of differentiation in T cells from the peripheral blood mononuclear cell (PBMC) starting material or the CAR T cell product. T cells from older patients are inherently more differentiated, but we hypothesised that specific activation protocols could be used to limit CAR T cell differentiation during manufacturing, particularly in older patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used PBMCs from young (20–30 years old) and older (60+ years old) healthy donors to generate CAR T cells using two activation protocols: soluble anti-(α) CD3 monoclonal antibody (mAb) <i>vs</i> immune complexes of αCD3 and αCD28 mAbs. Products were assessed for yield, function and differentiation, which was used as a measure of CAR T cell quality. T cells in PBMCs were assessed for CD28 expression and correlative analyses were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Older samples generated fewer, more differentiated CAR T cells than young samples, and the αCD3/CD28 mAb protocol exacerbated this, further reducing yield and quality. CD28 expression by T cells correlated with CAR T cell differentiation, but T cell differentiation in PBMC starting material was a stronger correlate of CAR T cell differentiation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Choice of activation protocol can substantially impact on the yield and quality of CAR T cells during manufacturing. This is a key consideration for older patients whose samples already generate a poorer yield and lower quality of CAR T cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thi Viet Trinh Dang, Kevin R Gillinder, Quan Nguyen, Onkar Mulay, Tuan Vo, Ahmed M Mehdi, Chenhao Zhou, Andrew J Brooks, Graham R Leggatt, David A Hume, Ian H Frazer, Janin Chandra
Objectives
Langerhans cells (LCs) are epithelial antigen-presenting cells (APC) contributing to immune surveillance. LCs depend on interleukin 34 (IL34) production by epithelial cells. This study aimed to uncover mechanisms of alteration of IL34 and LC function in squamous cell carcinoma (SCC).
Methods
Cancer cohort data were used to identify associations between SCC and IL34. ATAC-seq of keratinocytes (KCs) and LCs from a murine model of epithelial hyperplasia, driven by HPV16 E7 oncoprotein (K14E7), was analysed. Transcriptomic data were used to validate findings. RNAscope, RT-qPCR, ELISA and confocal imaging was used to analyse IL34 expression and LCs in a spatial context.
Results
IL34 mRNA is downregulated in human SCCs of the head and neck, the cervix, the lung and the oesophagus, and low IL34 expression is associated with poor survival. We demonstrate that KCs of K14E7 mice have reduced Il34 gene accessibility, mRNA and protein, as well as broad changes in promotor accessibility associated with cell adhesion and immune responses. Chromatin accessibility was substantially changed in LCs, including increased accessibility of the Csf1r gene, and changes in promotors associated with cytoskeleton arrangement and antigen processing and presentation. We discovered altered spatial LC dendrite organisation in hyperproliferative epithelium.
Conclusion
Squamous cell carcinoma of the cervix, head and neck, oesophagus and lung demonstrate downregulation of IL34, which is associated with poor survival, and with alterations in LC spatial organisation and function. These findings suggest that reduced IL34 expression in SCC may contribute to impaired local immunity through LC dysregulation.
{"title":"Squamous cell carcinoma is associated with reduced IL34 expression, alterations in the Langerhans cell antigen-processing-presentation machinery and poor patient survival","authors":"Thi Viet Trinh Dang, Kevin R Gillinder, Quan Nguyen, Onkar Mulay, Tuan Vo, Ahmed M Mehdi, Chenhao Zhou, Andrew J Brooks, Graham R Leggatt, David A Hume, Ian H Frazer, Janin Chandra","doi":"10.1002/cti2.70018","DOIUrl":"https://doi.org/10.1002/cti2.70018","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Langerhans cells (LCs) are epithelial antigen-presenting cells (APC) contributing to immune surveillance. LCs depend on interleukin 34 (IL34) production by epithelial cells. This study aimed to uncover mechanisms of alteration of IL34 and LC function in squamous cell carcinoma (SCC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cancer cohort data were used to identify associations between SCC and IL34. ATAC-seq of keratinocytes (KCs) and LCs from a murine model of epithelial hyperplasia, driven by HPV16 E7 oncoprotein (K14E7), was analysed. Transcriptomic data were used to validate findings. RNAscope, RT-qPCR, ELISA and confocal imaging was used to analyse IL34 expression and LCs in a spatial context.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>IL34</i> mRNA is downregulated in human SCCs of the head and neck, the cervix, the lung and the oesophagus, and low <i>IL34</i> expression is associated with poor survival. We demonstrate that KCs of K14E7 mice have reduced <i>Il34</i> gene accessibility, mRNA and protein, as well as broad changes in promotor accessibility associated with cell adhesion and immune responses. Chromatin accessibility was substantially changed in LCs, including increased accessibility of the <i>Csf1r</i> gene, and changes in promotors associated with cytoskeleton arrangement and antigen processing and presentation. We discovered altered spatial LC dendrite organisation in hyperproliferative epithelium.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Squamous cell carcinoma of the cervix, head and neck, oesophagus and lung demonstrate downregulation of IL34, which is associated with poor survival, and with alterations in LC spatial organisation and function. These findings suggest that reduced IL34 expression in SCC may contribute to impaired local immunity through LC dysregulation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 12","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The recent H5N1 avian influenza outbreak in the USA has sparked fresh fears of avian viruses causing the next pandemic. To date, the H5N1 (clade 2.3.4.4b) outbreak in cattle has spread across several states in the USA, with several humans infected following exposure to cows. This H5N1 clade is also reportedly circulating across Europe, Africa and South America. H5N1 was also detected in a child returning to Australia following travel in India where H5N1 (clade 2.3.2.1a) is also reported to be circulating. There are no licenced vaccines against H5N1 avian influenza viruses for humans. Current vaccines aim to protect against seasonal H1N1 and H3N2 variants are unlikely to provide much protection against the different H5, or other avian viruses. CD8+ T cells are known to provide protection against influenza infection, enhancing viral control and decreasing disease severity.
Methods
We recently compiled and published a list of the known immunogenic influenza-derived CD8+ T cell epitopes restricted to the most prevalent 10 HLA-A, -B and -C molecules worldwide. We assessed the conservation of a curated list of these influenza A virus-derived CD8+ T cell epitopes in H5N1 viruses' sequences at the heart of the outbreak.
Results
We identified that > 64% of the CD8+ T cell epitopes are highly conserved (> 90% sequence identity) in the H5N1 viruses, with 60% (18/30) of the most prevalent HLA-I molecules have at least one immunogenic CD8+ T cell epitope conserved in H5N1 viruses. Together these HLA-I molecules with conserved epitopes have a cumulative total of > 100% global coverage. Epitopes derived from the NP, M1, PB2, NS1 and PB1 proteins displayed the highest level of conservation.
Conclusions
Together, this analysis highlights that globally there is the potential for T cell cross-recognition against the H5N1 viruses that may provide some protection in humans towards the current avian flu outbreak.
{"title":"CD8+ T cell epitope conservation in emerging H5N1 viruses suggests global protection","authors":"Emma J Grant, Stephanie Gras","doi":"10.1002/cti2.70017","DOIUrl":"https://doi.org/10.1002/cti2.70017","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The recent H5N1 avian influenza outbreak in the USA has sparked fresh fears of avian viruses causing the next pandemic. To date, the H5N1 (clade 2.3.4.4b) outbreak in cattle has spread across several states in the USA, with several humans infected following exposure to cows. This H5N1 clade is also reportedly circulating across Europe, Africa and South America. H5N1 was also detected in a child returning to Australia following travel in India where H5N1 (clade 2.3.2.1a) is also reported to be circulating. There are no licenced vaccines against H5N1 avian influenza viruses for humans. Current vaccines aim to protect against seasonal H1N1 and H3N2 variants are unlikely to provide much protection against the different H5, or other avian viruses. CD8<sup>+</sup> T cells are known to provide protection against influenza infection, enhancing viral control and decreasing disease severity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We recently compiled and published a list of the known immunogenic influenza-derived CD8<sup>+</sup> T cell epitopes restricted to the most prevalent 10 HLA-A, -B and -C molecules worldwide. We assessed the conservation of a curated list of these influenza A virus-derived CD8<sup>+</sup> T cell epitopes in H5N1 viruses' sequences at the heart of the outbreak.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified that > 64% of the CD8<sup>+</sup> T cell epitopes are highly conserved (> 90% sequence identity) in the H5N1 viruses, with 60% (18/30) of the most prevalent HLA-I molecules have at least one immunogenic CD8<sup>+</sup> T cell epitope conserved in H5N1 viruses. Together these HLA-I molecules with conserved epitopes have a cumulative total of > 100% global coverage. Epitopes derived from the NP, M1, PB2, NS1 and PB1 proteins displayed the highest level of conservation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Together, this analysis highlights that globally there is the potential for T cell cross-recognition against the H5N1 viruses that may provide some protection in humans towards the current avian flu outbreak.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142707677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Susan N Christo, Keely M McDonald, Thomas N Burn, Nadia Kurd, Jessica Stanfield, Megan M Kaneda, Ruth Seelige, Christopher P Dillon, Timothy S Fisher, Bas Baaten, Laura K Mackay
Objectives
Bispecific antibodies targeting CD47 and PD-L1 (CD47 × PD-L1 BisAb) demonstrate efficacy against a range of solid cancers. While dual blockade negates anti-CD47-mediated toxicity, the effect of combined innate and adaptive immune activation on protective tumor-resident CD8+ T cells has yet to be fully elucidated.
Methods
CD8+ T cell populations were tracked upon CD47 × PD-L1 BisAb treatment in an orthotopic model of murine breast cancer where anti-tumor immunity is mediated by CD8+ T cells. Immune responses were also compared with anti-PD-L1 monotherapy to assess the advantage of dual checkpoint targeting.
Results
We found that CD47 × PD-L1 BisAb treatment augmented CD8+ T cell responses in tumors, which resulted in enhanced tumor control. Compared with anti-PD-L1 treatment, dual CD47 and PD-L1 blockade promoted greater numbers of antigen-specific tumor-resident CD8+ T cells that exhibited increased cytokine production.
Conclusions
Engagement of innate and adaptive immune checkpoint molecules via CD47 × PD-L1 BisAb treatment resulted in robust CD8+ T cell responses, including the induction of tumor-resident CD8+ T cells that exhibited functionally superior anti-tumor immunity. These results demonstrate that innate immune activation potentiates anti-tumor adaptive responses, highlighting the use of dual checkpoint blockade as an optimal strategy for promoting CD8+ T cell-mediated protection.
目的 针对 CD47 和 PD-L1 的双特异性抗体（CD47 × PD-L1 双抗体）对一系列实体瘤具有疗效。虽然双重阻断否定了抗 CD47 介导的毒性，但先天性免疫和适应性免疫联合激活对保护性肿瘤驻留 CD8+ T 细胞的影响尚未完全阐明。 方法 在 CD47 × PD-L1 BisAb 治疗小鼠乳腺癌的正位模型中，跟踪 CD8+ T 细胞群，该模型中的抗肿瘤免疫由 CD8+ T 细胞介导。免疫反应还与抗 PD-L1 单一疗法进行了比较，以评估双重检查点靶向的优势。 结果 我们发现，CD47 × PD-L1 BisAb 治疗增强了肿瘤中的 CD8+ T 细胞反应，从而提高了肿瘤控制率。与抗-PD-L1治疗相比，CD47和PD-L1双重阻断促进了更多的抗原特异性肿瘤驻留CD8+ T细胞，这些细胞产生的细胞因子也有所增加。 结论 通过 CD47 × PD-L1 BisAb 处理先天性和适应性免疫检查点分子的参与可产生强大的 CD8+ T 细胞反应，包括诱导肿瘤驻留的 CD8+ T 细胞，这些细胞表现出卓越的抗肿瘤免疫功能。这些结果表明，先天性免疫激活可增强抗肿瘤适应性反应，突出表明使用双重检查点阻断是促进 CD8+ T 细胞介导的保护的最佳策略。
{"title":"Dual CD47 and PD-L1 blockade elicits anti-tumor immunity by intratumoral CD8+ T cells","authors":"Susan N Christo, Keely M McDonald, Thomas N Burn, Nadia Kurd, Jessica Stanfield, Megan M Kaneda, Ruth Seelige, Christopher P Dillon, Timothy S Fisher, Bas Baaten, Laura K Mackay","doi":"10.1002/cti2.70014","DOIUrl":"https://doi.org/10.1002/cti2.70014","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Bispecific antibodies targeting CD47 and PD-L1 (CD47 × PD-L1 BisAb) demonstrate efficacy against a range of solid cancers. While dual blockade negates anti-CD47-mediated toxicity, the effect of combined innate and adaptive immune activation on protective tumor-resident CD8<sup>+</sup> T cells has yet to be fully elucidated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CD8<sup>+</sup> T cell populations were tracked upon CD47 × PD-L1 BisAb treatment in an orthotopic model of murine breast cancer where anti-tumor immunity is mediated by CD8<sup>+</sup> T cells. Immune responses were also compared with anti-PD-L1 monotherapy to assess the advantage of dual checkpoint targeting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that CD47 × PD-L1 BisAb treatment augmented CD8<sup>+</sup> T cell responses in tumors, which resulted in enhanced tumor control. Compared with anti-PD-L1 treatment, dual CD47 and PD-L1 blockade promoted greater numbers of antigen-specific tumor-resident CD8<sup>+</sup> T cells that exhibited increased cytokine production.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Engagement of innate and adaptive immune checkpoint molecules via CD47 × PD-L1 BisAb treatment resulted in robust CD8<sup>+</sup> T cell responses, including the induction of tumor-resident CD8<sup>+</sup> T cells that exhibited functionally superior anti-tumor immunity. These results demonstrate that innate immune activation potentiates anti-tumor adaptive responses, highlighting the use of dual checkpoint blockade as an optimal strategy for promoting CD8<sup>+</sup> T cell-mediated protection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142707678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dwarakanathan Ranganathan, Saskia Leibowitz, George T John, Michelle A Neller, George R Ambalathingal, Leone Beagley, Archana Panikkar, Shannon Best, Jyothy Raju, Hilary Reddiex, Sharad Ratanjee, Monica Suet Ying Ng, Corey Smith, Rajiv Khanna
Objectives
Dysregulation of Epstein–Barr virus (EBV)-specific cellular immunity has been hypothesised as one of the contributing factors in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis is a major risk factor for overall morbidity in SLE. Immune-based strategies directed to EBV have been proposed as potential therapeutic strategy for SLE and lupus nephritis.
Methods
Autologous EBV latent antigen-specific CD4+ and CD8+ T cells were expanded in vitro and adoptively transferred to a lupus nephritis patient.
Results
This adoptive immunotherapy had no immediate adverse effects, and the patient was subsequently treated with the anti-CD20 antibody, obinutuzumab. The patient showed a reduction in anti-dsDNA antibodies and improved glomerular filtration rate but remained nephrotic. These observations were coincident with a reduction in anti-viral and global T-cell activation.
Conclusion
To our knowledge, this is the first report of the use of EBV-specific adoptive immunotherapy to treat a patient with lupus nephritis.
目的：爱泼斯坦-巴氏病毒（EBV）特异性细胞免疫失调被认为是系统性红斑狼疮（SLE）发病机制的诱因之一。狼疮性肾炎是系统性红斑狼疮总体发病率的主要风险因素。针对EB病毒的免疫策略已被提出作为系统性红斑狼疮和狼疮性肾炎的潜在治疗策略：方法：在体外扩增自体EB病毒潜伏抗原特异性CD4+和CD8+T细胞，并将其收养性转移给狼疮肾炎患者：结果：这种采纳性免疫疗法没有立即产生不良反应，患者随后接受了抗CD20抗体--奥比妥珠单抗的治疗。患者体内的抗dsDNA抗体有所减少，肾小球滤过率也有所改善，但仍然存在肾病。这些观察结果与抗病毒和整体 T 细胞活化的减少相吻合：据我们所知，这是首次报道使用 EBV 特异性免疫疗法治疗狼疮肾炎患者。
{"title":"Autologous Epstein–Barr virus-specific adoptive T-cell therapy in a patient with lupus nephritis","authors":"Dwarakanathan Ranganathan, Saskia Leibowitz, George T John, Michelle A Neller, George R Ambalathingal, Leone Beagley, Archana Panikkar, Shannon Best, Jyothy Raju, Hilary Reddiex, Sharad Ratanjee, Monica Suet Ying Ng, Corey Smith, Rajiv Khanna","doi":"10.1002/cti2.70015","DOIUrl":"10.1002/cti2.70015","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Dysregulation of Epstein–Barr virus (EBV)-specific cellular immunity has been hypothesised as one of the contributing factors in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis is a major risk factor for overall morbidity in SLE. Immune-based strategies directed to EBV have been proposed as potential therapeutic strategy for SLE and lupus nephritis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Autologous EBV latent antigen-specific CD4<sup>+</sup> and CD8<sup>+</sup> T cells were expanded <i>in vitro</i> and adoptively transferred to a lupus nephritis patient.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This adoptive immunotherapy had no immediate adverse effects, and the patient was subsequently treated with the anti-CD20 antibody, obinutuzumab. The patient showed a reduction in anti-dsDNA antibodies and improved glomerular filtration rate but remained nephrotic. These observations were coincident with a reduction in anti-viral and global T-cell activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>To our knowledge, this is the first report of the use of EBV-specific adoptive immunotherapy to treat a patient with lupus nephritis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C-reactive protein (CRP) is a well-known acute-phase protein that increases remarkably under various inflammatory conditions and is elevated in patients with malignant tumors. In this study, we investigated the influence of CRP on the tumor microenvironment in clear cell renal cell carcinoma (ccRCC).
Methods
This study explored CRP's role in ccRCC by co-culturing human macrophages with ccRCC cells and employing antibody blocking, RNA sequencing and in vitro experiments for functional insights. We also analysed The Cancer Genome Atlas Program (TCGA) data to link CD64 expression with ccRCC prognosis and used immunohistochemistry to associate CD64+ macrophages with tumor severity and systemic CRP levels.
Results
A co-culture study using human macrophages and RCC cell lines showed that CRP-stimulated macrophages secrete IL-6, which induces RCC proliferation via STAT3 activation. CRP-induced protumor activation of macrophages was suppressed by CD64 blocking antibodies. Furthermore, CRP elevates PD-L1 expression in macrophages via the CD64-STAT1 signalling pathway. Statistical analysis of TCGA data indicated that increased CD64 expression was associated with a worse clinical course in ccRCC. Immunohistochemical analysis of pathological specimens revealed that high CD64 expression in tumor-associated macrophages (TAMs), and a high density of CD64+ TAMs, was linked to high nuclear grade and stage. High CD64 expression was also correlated with increased serum CRP levels.
Conclusions
The CRP-CD64 signal was linked to the protumor activation of TAMs and could be a promising target for anticancer immunotherapy in ccRCC.
{"title":"The contribution of the CRP/CD64 axis to renal cancer progression by inducing protumor activation of tumor-associated macrophages","authors":"Cheng Pan, Yukio Fujiwara, Hiromu Yano, Toshiki Anami, Yuki Ibe, Lianbo Li, Yuji Miura, Takanobu Motoshima, Shigeyuki Esumi, Junji Yatsuda, Taizo Hibi, Tomomi Kamba, Yoshihiro Komohara","doi":"10.1002/cti2.70013","DOIUrl":"10.1002/cti2.70013","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>C-reactive protein (CRP) is a well-known acute-phase protein that increases remarkably under various inflammatory conditions and is elevated in patients with malignant tumors. In this study, we investigated the influence of CRP on the tumor microenvironment in clear cell renal cell carcinoma (ccRCC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study explored CRP's role in ccRCC by co-culturing human macrophages with ccRCC cells and employing antibody blocking, RNA sequencing and <i>in vitro</i> experiments for functional insights. We also analysed The Cancer Genome Atlas Program (TCGA) data to link CD64 expression with ccRCC prognosis and used immunohistochemistry to associate CD64<sup>+</sup> macrophages with tumor severity and systemic CRP levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A co-culture study using human macrophages and RCC cell lines showed that CRP-stimulated macrophages secrete IL-6, which induces RCC proliferation via STAT3 activation. CRP-induced protumor activation of macrophages was suppressed by CD64 blocking antibodies. Furthermore, CRP elevates PD-L1 expression in macrophages via the CD64-STAT1 signalling pathway. Statistical analysis of TCGA data indicated that increased CD64 expression was associated with a worse clinical course in ccRCC. Immunohistochemical analysis of pathological specimens revealed that high CD64 expression in tumor-associated macrophages (TAMs), and a high density of CD64<sup>+</sup> TAMs, was linked to high nuclear grade and stage. High CD64 expression was also correlated with increased serum CRP levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The CRP-CD64 signal was linked to the protumor activation of TAMs and could be a promising target for anticancer immunotherapy in ccRCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stephen Tukwasibwe, Savannah Nicole Lewis, Yoweri Taremwa, Kattria van der Ploeg, Kathleen D Press, Maureen Ty, Felistas Namirimu Nankya, Kenneth Musinguzi, Evelyn Nansubuga, Florian Bach, Martin Chamai, Martin Okitwi, Gerald Tumusiime, Annettee Nakimuli, Francesco Colucci, Moses R Kamya, Joaniter I Nankabirwa, Emmanuel Arinaitwe, Bryan Greenhouse, Grant Dorsey, Philip J Rosenthal, Isaac Ssewanyana, Prasanna Jagannathan
Objectives
Natural killer (NK) cells make important contributions to anti-malarial immunity through antibody-dependent cellular cytotoxicity (ADCC), but the role of different components of this pathway in promoting NK cell activation remains unclear.
Methods
We compared the functions and phenotypes of NK cells from malaria-exposed and malaria-naive donors, and then varied the erythrocyte genetic background, Plasmodium falciparum strain and opsonising plasma used in ADCC to observe their impacts on NK cell degranulation as measured by CD107a mobilisation.
Results
Natural killer cells from malaria-exposed adult Ugandan donors had enhanced ADCC, but an impaired pro-inflammatory response to cytokine stimulation, compared to NK cells obtained from malaria-naive adult North American donors. Cellular phenotypes from malaria-exposed donors reflected this specialisation for ADCC, with a compartment-wide downregulation of the Fc receptor γ-chain and enrichment of highly differentiated CD56dim and CD56neg populations. NK cell degranulation was enhanced in response to opsonised P. falciparum schizonts cultured in sickle cell heterozygous erythrocytes relative to wild-type erythrocytes, and when using opsonising plasma collected from donors living in a high transmission area compared to a lower transmission area despite similar levels of 3D7 schizont-specific IgG levels. However, degranulation was lowered in response to opsonised field isolate P. falciparum schizonts isolated from clinical malaria infections, compared to the 3D7 laboratory strain typically used in these assays.
Conclusion
This work highlights important host and parasite factors that contribute to ADCC efficacy that should be considered in the design of ADCC assays.
目的 自然杀伤（NK）细胞通过抗体依赖性细胞毒性（ADCC）对抗疟免疫做出了重要贡献，但这一途径的不同成分在促进 NK 细胞活化方面的作用仍不清楚。 方法 我们比较了来自疟疾暴露供体和疟疾免疫供体的 NK 细胞的功能和表型，然后改变了 ADCC 中使用的红细胞遗传背景、恶性疟原虫菌株和疏松血浆，以观察它们对 NK 细胞脱颗粒的影响（通过 CD107a 动员测量）。 结果 与来自对疟疾免疫的北美成年供体的 NK 细胞相比，来自疟疾暴露的乌干达成年供体的自然杀伤细胞的 ADCC 增强，但对细胞因子刺激的促炎反应减弱。疟疾暴露供体的细胞表型反映了这种ADCC特化，Fc受体γ-链在整个区段范围内下调，高度分化的CD56dim和CD56neg种群富集。与野生型红细胞相比，在镰状细胞杂合子红细胞中培养的恶性疟原虫裂殖体的疏松化过程中，NK细胞的脱颗粒反应增强；尽管3D7裂殖体特异性IgG水平相似，但与低传播地区相比，当使用从高传播地区捐献者处收集的疏松化血浆时，NK细胞的脱颗粒反应也增强。然而，与这些试验中通常使用的 3D7 实验室菌株相比，对从临床疟疾感染中分离出来的野外分离的恶性疟原虫裂殖体的去颗粒化反应较低。 结论 这项工作强调了促进 ADCC 效能的重要宿主和寄生虫因素，在设计 ADCC 试验时应考虑到这些因素。
{"title":"Natural killer cell antibody-dependent cellular cytotoxicity to Plasmodium falciparum is impacted by cellular phenotypes, erythrocyte polymorphisms, parasite diversity and intensity of transmission","authors":"Stephen Tukwasibwe, Savannah Nicole Lewis, Yoweri Taremwa, Kattria van der Ploeg, Kathleen D Press, Maureen Ty, Felistas Namirimu Nankya, Kenneth Musinguzi, Evelyn Nansubuga, Florian Bach, Martin Chamai, Martin Okitwi, Gerald Tumusiime, Annettee Nakimuli, Francesco Colucci, Moses R Kamya, Joaniter I Nankabirwa, Emmanuel Arinaitwe, Bryan Greenhouse, Grant Dorsey, Philip J Rosenthal, Isaac Ssewanyana, Prasanna Jagannathan","doi":"10.1002/cti2.70005","DOIUrl":"https://doi.org/10.1002/cti2.70005","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Natural killer (NK) cells make important contributions to anti-malarial immunity through antibody-dependent cellular cytotoxicity (ADCC), but the role of different components of this pathway in promoting NK cell activation remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We compared the functions and phenotypes of NK cells from malaria-exposed and malaria-naive donors, and then varied the erythrocyte genetic background, <i>Plasmodium falciparum</i> strain and opsonising plasma used in ADCC to observe their impacts on NK cell degranulation as measured by CD107a mobilisation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Natural killer cells from malaria-exposed adult Ugandan donors had enhanced ADCC, but an impaired pro-inflammatory response to cytokine stimulation, compared to NK cells obtained from malaria-naive adult North American donors. Cellular phenotypes from malaria-exposed donors reflected this specialisation for ADCC, with a compartment-wide downregulation of the Fc receptor γ-chain and enrichment of highly differentiated CD56<sup>dim</sup> and CD56<sup>neg</sup> populations. NK cell degranulation was enhanced in response to opsonised <i>P. falciparum</i> schizonts cultured in sickle cell heterozygous erythrocytes relative to wild-type erythrocytes, and when using opsonising plasma collected from donors living in a high transmission area compared to a lower transmission area despite similar levels of 3D7 schizont-specific IgG levels. However, degranulation was lowered in response to opsonised field isolate <i>P. falciparum</i> schizonts isolated from clinical malaria infections, compared to the 3D7 laboratory strain typically used in these assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This work highlights important host and parasite factors that contribute to ADCC efficacy that should be considered in the design of ADCC assays.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 11","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giuseppe Ercoli, Hugh Selway-Clarke, Dena Truijen, Milda Folkmanaite, Tate Oulton, Caitlin Norris-Grey, Rie Nakajima, Philip Felgner, Brendan W Wren, Kevin Tetteh, Nicholas J Croucher, Maria Leandro, Geraldine Cambridge, Jeremy S Brown
Objectives
Patients with rheumatoid arthritis (RA) have an increased susceptibility to infections, including those caused by Streptococcus pneumoniae. Why RA is associated with increased susceptibility to S. pneumoniae is poorly understood. This study aims to assess the effects of RA and B-cell depletion therapy on naturally acquired antibody responses to 289 S. pneumoniae protein antigens using a novel protein array.
Methods
IgG responses to S. pneumoniae were characterised in serum from RA patients and disease controls (myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)) using whole-cell ELISA, a flow cytometry opsonisation assay and an S. pneumoniae protein array. For the RA patients, results were compared before and after B-cell depletion therapy.
Results
Compared to a well-characterised disease control group of ME/CFS patients, RA patients had reduced antibody responses to multiple S. pneumoniae protein antigens, with significant IgG recognition of approximately half the number of antigens along with reduced median strengths of these responses. Reduction in multiple array antigen-specific responses also correlated with reduced IgG opsonisation of S. pneumoniae. Although B-cell depletion therapy with rituximab did not reduce overall IgG recognition of S. pneumoniae in the RA group, it was associated with marked disruption of pre-existing IgG repertoire to protein antigens in individual patients.
Conclusion
These data show RA is associated with major disruption of naturally acquired adaptive immunity to S. pneumoniae, which can be assessed rapidly using a protein antigen array and is likely to contribute towards the increased incidence of pneumonia in patients with RA.
目的 类风湿性关节炎（RA）患者对感染的易感性增加，其中包括由肺炎链球菌引起的感染。目前尚不清楚 RA 为什么会增加对肺炎链球菌的易感性。本研究旨在使用新型蛋白质阵列评估 RA 和 B 细胞耗竭疗法对 289 种肺炎链球菌蛋白质抗原的天然抗体反应的影响。 方法 采用全细胞酶联免疫吸附试验、流式细胞仪抗溶血试验和肺炎双球菌蛋白阵列分析 RA 患者和疾病对照组（肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS））血清中肺炎双球菌 IgG 反应的特征。对 RA 患者进行了 B 细胞耗竭治疗前后的结果比较。 结果 与特征明确的疾病对照组 ME/CFS 患者相比，RA 患者对多种肺炎双球菌蛋白抗原的抗体反应减弱，对大约一半抗原的 IgG 识别率明显下降，同时这些反应的中位强度也有所降低。多种阵列抗原特异性反应的降低还与肺炎双球菌的IgG蛋白溶解度降低有关。虽然使用利妥昔单抗的 B 细胞耗竭疗法并未降低 RA 组对肺炎双球菌的总体 IgG 识别率，但却明显破坏了个别患者对蛋白质抗原的原有 IgG 反应谱系。 结论 这些数据表明，RA 与对肺炎双球菌的自然获得性适应性免疫的严重破坏有关，这种破坏可通过蛋白抗原阵列进行快速评估，并可能导致 RA 患者肺炎发病率的增加。
{"title":"Naturally acquired adaptive immunity to Streptococcus pneumoniae is impaired in rheumatoid arthritis patients","authors":"Giuseppe Ercoli, Hugh Selway-Clarke, Dena Truijen, Milda Folkmanaite, Tate Oulton, Caitlin Norris-Grey, Rie Nakajima, Philip Felgner, Brendan W Wren, Kevin Tetteh, Nicholas J Croucher, Maria Leandro, Geraldine Cambridge, Jeremy S Brown","doi":"10.1002/cti2.70012","DOIUrl":"https://doi.org/10.1002/cti2.70012","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Patients with rheumatoid arthritis (RA) have an increased susceptibility to infections, including those caused by <i>Streptococcus pneumoniae</i>. Why RA is associated with increased susceptibility to <i>S. pneumoniae</i> is poorly understood. This study aims to assess the effects of RA and B-cell depletion therapy on naturally acquired antibody responses to 289 <i>S. pneumoniae</i> protein antigens using a novel protein array.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>IgG responses to <i>S. pneumoniae</i> were characterised in serum from RA patients and disease controls (myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)) using whole-cell ELISA, a flow cytometry opsonisation assay and an <i>S. pneumoniae</i> protein array. For the RA patients, results were compared before and after B-cell depletion therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared to a well-characterised disease control group of ME/CFS patients, RA patients had reduced antibody responses to multiple <i>S. pneumoniae</i> protein antigens, with significant IgG recognition of approximately half the number of antigens along with reduced median strengths of these responses. Reduction in multiple array antigen-specific responses also correlated with reduced IgG opsonisation of <i>S. pneumoniae</i>. Although B-cell depletion therapy with rituximab did not reduce overall IgG recognition of <i>S. pneumoniae</i> in the RA group, it was associated with marked disruption of pre-existing IgG repertoire to protein antigens in individual patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data show RA is associated with major disruption of naturally acquired adaptive immunity to <i>S. pneumoniae</i>, which can be assessed rapidly using a protein antigen array and is likely to contribute towards the increased incidence of pneumonia in patients with RA.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenlin Qiu, Xiaoxiao Han, Tong Yu, Lijuan Jiang, Xuefei Wang, Ruizhi Feng, Xiaoru Duan, Yao Teng, Haifeng Yin, Maria I Bokarewa, Guo-Min Deng
Objectives
Systemic lupus erythematosus (SLE) is a chronic and severe autoimmune disease characterised by persistent inflammation. Hydroxychloroquine (HCQ) and glucocorticoids (GCs) are the primary agents commonly used in combination as the first-line treatment for SLE. Nevertheless, the specific mechanisms responsible for the effectiveness of this combined therapy with HCQ and GCs have not been fully elucidated. This study aimed to reveal the mechanism behind combined HCQ and GC treatment in lupus.
Methods
An SLE IgG-induced inflammation model was used to investigate the anti-inflammatory effects of HCQ and dexamethasone (DXM). A glucocorticoid-induced osteoporosis (GIOP) model was used to investigate the inhibitory effect of HCQ on osteoclastogenesis. Inflammation was assessed by haematoxylin and eosin staining. Bone metabolism was determined structurally via microcomputer tomography and in bone marrow-derived osteoclast cultures.
Results
An SLE IgG-induced inflammation model demonstrated that HCQ could not ameliorate inflammation alone but could enhance the anti-inflammatory effect of GCs by decreasing the expression of FcγRI on macrophages. HCQ inhibited osteoclastogenesis induced by GCs and RANKL by upregulating nuclear factor erythroid 2-related factor 2 and limiting reactive oxygen species formation, which mitigated GC-induced bone loss.
Conclusion
The results indicate that HCQ improved the anti-inflammatory effects of GCs and inhibits the osteoclastogenesis in experimental lupus. This study offers valuable insights into the mechanisms underlying the combined treatment of lupus with HCQ and GCs.
{"title":"Inhibitory effect of hydroxychloroquine on glucocorticoid-induced osteoporosis in lupus therapy","authors":"Wenlin Qiu, Xiaoxiao Han, Tong Yu, Lijuan Jiang, Xuefei Wang, Ruizhi Feng, Xiaoru Duan, Yao Teng, Haifeng Yin, Maria I Bokarewa, Guo-Min Deng","doi":"10.1002/cti2.70010","DOIUrl":"https://doi.org/10.1002/cti2.70010","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Systemic lupus erythematosus (SLE) is a chronic and severe autoimmune disease characterised by persistent inflammation. Hydroxychloroquine (HCQ) and glucocorticoids (GCs) are the primary agents commonly used in combination as the first-line treatment for SLE. Nevertheless, the specific mechanisms responsible for the effectiveness of this combined therapy with HCQ and GCs have not been fully elucidated. This study aimed to reveal the mechanism behind combined HCQ and GC treatment in lupus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>An SLE IgG-induced inflammation model was used to investigate the anti-inflammatory effects of HCQ and dexamethasone (DXM). A glucocorticoid-induced osteoporosis (GIOP) model was used to investigate the inhibitory effect of HCQ on osteoclastogenesis. Inflammation was assessed by haematoxylin and eosin staining. Bone metabolism was determined structurally via microcomputer tomography and in bone marrow-derived osteoclast cultures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>An SLE IgG-induced inflammation model demonstrated that HCQ could not ameliorate inflammation alone but could enhance the anti-inflammatory effect of GCs by decreasing the expression of FcγRI on macrophages. HCQ inhibited osteoclastogenesis induced by GCs and RANKL by upregulating nuclear factor erythroid 2-related factor 2 and limiting reactive oxygen species formation, which mitigated GC-induced bone loss.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The results indicate that HCQ improved the anti-inflammatory effects of GCs and inhibits the osteoclastogenesis in experimental lupus. This study offers valuable insights into the mechanisms underlying the combined treatment of lupus with HCQ and GCs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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