Clinical & Translational Immunology最新文献

{"title":"From delivery to integration: CRISPR-mediated large insert gene editing in primary human T cells.","authors":"Ben Buttle, Daniel Verdon, Hilary M Sheppard","doi":"10.1002/cti2.70124","DOIUrl":"https://doi.org/10.1002/cti2.70124","url":null,"abstract":"<p><p>Large insert gene editing in <i>ex vivo</i>, primary human T cells represents an important approach for engineering next-generation cellular immunotherapies. While CRISPR-based editing is well-established for small genetic modifications, large insert knock-in remains a technical bottleneck. This review examines current strategies for achieving efficient, precise and safe integration of large genetic elements. We compare delivery methods for CRISPR components, highlighting electroporation of Cas9 ribonucleoproteins as the most efficient but often cytotoxic approach; emerging alternatives such as cell-penetrating peptides and lipid nanoparticles offer improved cell viability at the expense of editing efficiency. The influence of genomic locus selection, guide RNA design and chromatin context on editing outcomes, as well as the role of homology-directed repair (HDR) template design is evaluated. Various template formats-including linear double- and single-stranded DNA, plasmids, circular single-stranded (css) DNA and recombinant adeno-associated virus (rAAV)-are assessed for their efficiency, toxicity and risk of off-target integration. Where possible, cross-study normalisation is used to enable meaningful comparisons. rAAV templates consistently achieve the highest insertion rates but come with concerns regarding cost, size limitations and insertional mutagenesis, whereas non-viral approaches such as cssDNA templates show promise. Additionally, we review the use of small-molecule modulators to enhance HDR efficiency, noting trade-offs between improved insertion rates and potential genomic instability. Overall, successful large insert editing requires balancing of editing efficiency, cell viability and genomic safety considerations. Continued optimisation of delivery systems, template design and repair pathway modulation will be critical for advancing scalable and clinically viable T-cell therapies.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 10","pages":"e70124"},"PeriodicalIF":3.4,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13677281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223041","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}

{"title":"Assessing CD8+ T cell cross-reactivity to influenza A, B and C virus-derived peptides presented by HLA-B*18:01","authors":"Lawton D Murdolo,&nbsp;Samuel Liwei Leong,&nbsp;Janesha C Maddumage,&nbsp;Lloyd D'Orsogna,&nbsp;Demetra SM Chatzileontiadou,&nbsp;Emma J Grant,&nbsp;Stephanie Gras","doi":"10.1002/cti2.70123","DOIUrl":"https://doi.org/10.1002/cti2.70123","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Despite the availability of vaccines, influenza viruses still cause substantial morbidity and mortality. This highlights the need for improved vaccines and novel therapeutics. CD8⁺ T cells recognise conserved viral epitopes and can provide broad protection, making them attractive targets for next-generation vaccine design. A key step in this process is to identify T cell epitopes across influenza viruses. Here, we characterised three homologous influenza Polymerase Basic 1 (PB1)-derived peptides from influenza viruses (PB1-A₃₁₀, PB1-B₃₁₀ and PB1-C₃₁₂, respectively) presented by the common, but understudied, HLA-B*18:01 molecule.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used a thermal melt assay and X-ray crystallography to assess the stability and structural features of each peptide. CD8⁺ T-cell responses were evaluated using intracellular cytokine staining with HLA-B*18:01⁺ samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The structures of HLA-B*18:01 presenting each peptide were solved, including the first structure of HLA-B*18:01 presenting a <i>Gammainfluenzavirus</i> (formerly influenza C virus) derived peptide. PB1-C₃₁₂ exhibited a higher thermal stability and a different conformation compared to PB1-A₃₁₀ and PB1-B₃₁₀. CD8⁺ T cell responses varied among samples, with PB1-A₃₁₀ eliciting the strongest activation. Minimal T cell cross-reactivity was observed and was mostly between PB1-A₃₁₀ and PB1-B₃₁₀ likely reflecting shared structural features.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings further expand knowledge on peptide presentation by the common HLA-B*18:01 molecule, and the limitations on CD8⁺ T cell cross-recognition of this PB1-derived epitope across influenza lineages. This highlights the importance of more research on cross-lineage T cell cross-reactivity that could inform the design of broadly protective T cell-based vaccines and therapeutics.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 10","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70123","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149177069","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}

{"title":"Prolonged molecular control during intermittent reduced-intensity blinatumomab maintenance in a transplant-ineligible patient with Philadelphia chromosome-positive acute lymphoblastic leukaemia and IKZF1 deletion","authors":"Xiaoqian Duan,&nbsp;Jinjun Yang,&nbsp;Yufei Yang,&nbsp;Shuwen Guo,&nbsp;Yu Wu","doi":"10.1002/cti2.70121","DOIUrl":"10.1002/cti2.70121","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Long-term disease control in transplant-ineligible patients with high-risk Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph⁺ ALL) remains difficult, particularly when adverse genetic lesions and acquired kinase domain mutations coexist.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical, cytogenetic and molecular records were retrospectively reviewed. <i>BCR::ABL1</i> transcripts were monitored by quantitative PCR, and peripheral lymphocyte subsets were followed longitudinally. Public transcriptomic data (GSE196463) were analysed to compare T-cell expression profiles under continuous versus intermittent bispecific antibody exposure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A 64-year-old man with Ph⁺ ALL harbouring a heterozygous <i>IKZF1</i> deletion relapsed while receiving dasatinib, with emergence of an ABL1 E255K/V mutation. Although this P-loop mutant retains sensitivity to dasatinib, relapse suggested kinase-independent escape; treatment was redirected towards immune-mediated clearance with one cycle of continuous blinatumomab plus dasatinib, achieving deep molecular remission. Allogeneic transplantation was deferred because of advanced age, prior cardiac dysfunction and cumulative infectious burden, and outpatient maintenance was initiated with monthly 24-h blinatumomab infusions (35 μg) plus dasatinib (100 mg daily) and subcutaneous interferon alfa-2b (3 MIU thrice weekly). Morphologic remission was sustained for over 3.5 years with no unplanned hospitalizations and no grade ≥3 neurotoxicity. <i>BCR::ABL1</i> transcripts remained undetectable for nearly 3 years before a transient low-level fluctuation (0.0024% IS) appeared and stabilized without treatment escalation. Peripheral monitoring showed persistent CD8⁺ predominance and sustained B-cell depletion (&lt;20 cells/μL), indicating ongoing target engagement. Public transcriptomic data supported that intermittent bispecific exposure preserves progenitor/memory T-cell programmes while limiting exhaustion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Intermittent reduced-intensity blinatumomab maintenance guided by serial MRD monitoring was feasible and associated with durable molecular control in a transplant-ineligible patient with high-risk Ph⁺ ALL. This strategy merits prospective evaluation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 9","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023344","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}

{"title":"Manufacturing cost analysis and exploratory economic evaluation of natural killer cell immunotherapy for paediatric solid tumors","authors":"Sabera Tabassum Wahid,&nbsp;Melissa Elliott,&nbsp;Yufan Wang,&nbsp;Wayne Nicholls,&nbsp;Natacha Omer,&nbsp;Fernando Souza-Fonseca-Guimaraes,&nbsp;Haitham Tuffaha","doi":"10.1002/cti2.70122","DOIUrl":"10.1002/cti2.70122","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Natural killer (NK) cell therapy is a promising allogeneic, off-the-shelf immunotherapy for solid tumors, yet economic evidence to guide its clinical translation is absent. This study aimed to conduct a micro-costing analysis of their manufacturing and perform an exploratory economic evaluation of NK cell therapy for paediatric solid tumors from an Australian health system perspective.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A micro-costing analysis was conducted using primary laboratory production data across six manufacturing steps and categories. Hospitalisation costs were estimated by expert opinion. Effectiveness estimates were drawn from chimeric antigen receptor (CAR)-T cell therapy economic evaluations. Analyses included incremental cost-effectiveness ratios (ICERs), headroom analysis, net monetary benefit (NMB) and probabilistic sensitivity analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Manufacturing cost was AUD 58 681 (USD 38 143) per batch (AUD 9780; USD 6357 per dose). Eighty-eight per cent of costs were concentrated in three steps: NK cell expansion (50.8%), mRNA transfection (25.1%) and T-cell depletion (11.7%), with consumables/reagents comprising 85% of the total production cost. Combining manufacturing (AUD 58 681) and hospitalisation (AUD 75 000; USD 48 750) costs, the total NK cell therapy cost was AUD 133 681 (USD 86 893) per patient, yielding an illustrative ICER of AUD 35 167 (USD 22 859) per QALY gained, based on a proxy effectiveness estimate. Economic headroom was AUD 56 386 (USD 36 651) per patient. Probabilistic analysis showed 51.7% probability of cost-effectiveness at AUD 50 000/QALY, with a minimum of 2.67 QALYs required.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>NK cell therapy shows indicative early economic signals warranting further clinical and economic investigation. Micro-costing identifies actionable manufacturing cost drivers to inform process optimisation, and these exploratory estimates provide a foundation for iterative economic evaluation as clinical evidence develops.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 9","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13590241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015113","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}

{"title":"Parallel processing of T cells and natural killer cells to enhance in vivo CAR T cell activity against blood and solid cancers","authors":"Lachlan J Dobson,&nbsp;Patrick W Marron,&nbsp;Ariana HT Drabble,&nbsp;Thiloma D Liyanage,&nbsp;Kristine C Pe,&nbsp;Clare Y Slaney,&nbsp;Barry D Hock,&nbsp;Alexander D McLellan","doi":"10.1002/cti2.70120","DOIUrl":"https://doi.org/10.1002/cti2.70120","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Despite their anti-cancer properties, natural killer (NK) cells are discarded during CAR T cell manufacturing. NK cells display promising responses as a cell therapy, exhibiting remarkable safety at high doses. Moreover, NK cells have complementary cytokine profiles and distinct antigen-recognition pathways to supplement CAR T cell therapies. We demonstrate parallel expansion of NK cells from the normally discarded PBMC of CAR T cell production for downstream combination therapies against solid and blood-borne malignancies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CAR T cells were manufactured from buffy coats with initial isolation of T cells from PBMC. NK cells were rapidly expanded in parallel by stimulating the remaining PBMC with membrane-bound (mb)IL-21 + mbIL-15 feeder cells. Expanded NK cells were assessed through spectral flow cytometry and applied as a pretreatment prior to CAR Tcell infusion against xenograft tumor models in NOD-<i>scid</i> IL2Rgamma^null (NSG) mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Applying feeder cells to residual PBMC stimulated 5000-fold expansions of pure NK cells. Expanded NK cells expressed various activation receptors and displayed strong <i>in vitro</i> cytotoxicity, which was further improved in CAR T-conditioned medium. A pretreatment of NK cells enhanced existing CAR T cell therapies, improving <i>in vivo</i> tumor clearance and survival against breast cancer, acute lymphoblastic leukaemia and non-Hodgkin's lymphoma. While NK cells eliminated CD19^−/− variants <i>in vitro</i>, they were unable to suppress antigen-escape relapse <i>in vivo</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study encourages the optimal use of leukapheresis product. By recycling discarded PBMC into NK cells, CAR T cell therapies can be effectively enhanced, improving tumor clearance and survival.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 9","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862188","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}

{"title":"Peripheral immune dynamics during treatment predict prognosis in HCC receiving TACE plus ICIs and anti-VEGF/TKIs","authors":"Lihao Qin,&nbsp;Linzhou Zhu,&nbsp;Hao Yang,&nbsp;Wanci Li,&nbsp;Shuai Zhang,&nbsp;Jian Shen,&nbsp;Xiaoli Zhu","doi":"10.1002/cti2.70115","DOIUrl":"https://doi.org/10.1002/cti2.70115","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objectives&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;To evaluate the prognostic value of peripheral immune markers and their static and dynamic changes during different treatment stages in patients with hepatitis B virus (HBV)-related unresectable hepatocellula carcinoma (uHCC) receiving transarterial chemoembolisation (TACE) combined with immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor (anti-VEGF) antibodies or tyrosine kinase inhibitors (TKIs).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This single-centre retrospective study included patients with HBV-related uHCC treated with TACE combined with ICls and anti-VEGF antibodies or TKIs between July 2019 and July 2024. Peripheral blood immune indicators were collected at baseline (Cycle 0), the second treatment cycle (Cycle 2) and the fourth treatment cycle (Cycle 4). The primary outcome was overall survival (OS), while secondary outcomes included progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR), with tumour response assessed at the first treatment evaluation (at the end of the fourth treatment cycle) based on mRECIST criteria. Longitudinal changes between adjacent time points were calculated (Δ: Cycle 2 - Cycle 0; Δ2: Cycle 4 - Cycle 2). Both static values and dynamic changes in immune markers were subjected to LASSO-Cox and stepwise multivariate Cox regression analyses to identify independent predictors of OS. Based on the significant variables, a prognostic nomogram and an immune-based risk score model were developed. To further assess prognostic heterogeneity, patients were stratified by K-means clustering according to the temporal patterns of the most predictive immune marker, and survival outcomes were compared across the resulting subgroups.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A total of 67 HBV-related uHCC patients treated with TACE plus ICIs and anti-VEGF antibodies/TKIs were included. The cohort had a median follow-up of 18.2 months, with a median overall survival (mOS) of 30.4 months and a median progression-free survival (mPFS) of 11.0 months. At the first evaluation, the objective response rate (ORR) was 53.7%, and the disease control rate (DCR) was 86.6%. LASSO-Cox regression identified several static and dynamic immune markers associated with OS. Ultimately, CD4⁺/CD8⁺ ratio at Cycle 4 (HR = 0.58, &lt;i&gt;p&lt;/i&gt; = 0.035), Δ2 NLR (HR = 1.66, &lt;i&gt;p&lt;/i&gt; = 0.014), and Δ2 CD3⁺CD4⁺ (HR = 0.04, &lt;i&gt;p&lt;/i&gt; = 0.007) were confirmed by stepwise multivariate Cox regression. A prognostic nomogram incorporating these variables demonstrated favourable predictive performance (C-index = 0.72; AUCs = 0.750, 0.722 and 0.854 for 1-, 2- and","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70115","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753852","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}

{"title":"Sustained response to rituximab in an ANCA-negative necrotizing vasculitis with initial detection of Corynebacterium kroppenstedtii","authors":"Nadine Al-Azem,&nbsp;Anna Knothe,&nbsp;Jan-Dirk Raguse,&nbsp;Inga Nierkamp,&nbsp;Achim Georg Beule,&nbsp;Claudia Rudack,&nbsp;Friedericke Müller,&nbsp;Anne Kerlikowki,&nbsp;Eva Wardelmann,&nbsp;Hermann Pavenstädt,&nbsp;Martin A Kriegel,&nbsp;Rebecca Hasseli","doi":"10.1002/cti2.70119","DOIUrl":"10.1002/cti2.70119","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>In this case, we present a patient with rapidly progressive unilateral destructive orbital and midface inflammation. Initial detection of <i>Corynebacterium kroppenstedtii</i> was followed by a consistent course of localised necrotizing small-vessel vasculitis, which was responsive to B-cell depletion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A 79-year-old woman presented with acute left periorbital pain, tearing and purulent discharge. The workup included serial microbiological cultures, fungal and mycobacterial testing, molecular diagnostics, CT/MRI/PET-CT imaging, multiple surgical biopsies with histopathology and special stains, ANCA testing, and multidisciplinary treatments (antimicrobials, glucocorticoids, methotrexate and rituximab). The clinical course, laboratory work, imaging studies, histological analysis and response to treatment were thoroughly reviewed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Initial conjunctival culture revealed <i>C</i>. <i>kroppenstedtii</i> and clindamycin and vancomycin was initiated. Despite escalating antimicrobials, the patient developed progressive inflammation with sinus destruction, cutaneous fistula and cheek abscess, requiring orbital exenteration. The biopsies revealed chronic inflammation with multinucleated giant cells, focal necrosis and small-vessel vasculitis. ANCA remained negative, and subsequent testing was negative. High-dose prednisolone improved the patient, prompting the discontinuation of methotrexate because of pancytopenia. Rituximab-induced remission allowed for steroid tapering and rituximab maintenance, which controlled the disease without complications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This case illustrates a rare, localised ANCA-negative necrotizing small-vessel vasculitis with destructive orbital involvement and initial detection of <i>C. kroppenstedtii</i>. Although the pathogenic significance of this finding remains uncertain, the case highlights the importance of comprehensive microbiological and immunological evaluation in atypical destructive inflammatory disease. Sustained disease control was achieved with immunosuppressive therapy including rituximab after persistent infection had been excluded.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13458720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148710772","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}

{"title":"Humoral and cellular responses to SARS-CoV-2 variants after ancestral COVID-19 vaccines in people with HIV and lung transplant recipients","authors":"David WJ Griffin,&nbsp;Paul A Gill,&nbsp;Irene Boo,&nbsp;Shir Sun,&nbsp;Raffi Gugasyan,&nbsp;Alina Wang,&nbsp;Scott J Bornheimer,&nbsp;Stuart Turville,&nbsp;Anupriya Aggarwal,&nbsp;Greg I Snell,&nbsp;Glen P Westall,&nbsp;Emily SJ Edwards,&nbsp;Anna Coldham,&nbsp;Menno C van Zelm,&nbsp;Heidi E Drummer,&nbsp;James H McMahon","doi":"10.1002/cti2.70117","DOIUrl":"10.1002/cti2.70117","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Immunocompromised hosts have reduced immune responses to COVID-19 vaccination, and more severe disease. Antibody responses correlate with protection but markers of immunity vary across a spectrum of immunocompromise. We compared serologic and cellular responses following Ancestral COVID-19 vaccines in healthy controls (HC), people with HIV (PWH) and lung transplant (LTx) recipients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Anti-spike receptor binding domain (RBD) IgG, neutralising antibodies (nAb) and T-cell responses were assessed one-month post-dose 2 and dose 3 of Ancestral COVID-19 vaccination in HC, PWH and LTx. NAb responses to Ancestral, Delta and Omicron BA.2 and BA.5 variants were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Twenty-nine HC, 21 PWH and 12 LTx recipients were included. PWH demonstrated lower anti-RBD-IgG responses (median post-dose 3: 80.3 μg mL⁻¹ vs 43.3 μg mL⁻¹, <i>P</i> = 0.03) to mRNA COVID-19 vaccination than HC, while LTx recipients displayed diminished responses following any vaccine (15.3 μg mL⁻¹ vs 74.0 μg mL⁻¹, <i>P</i> = 0.01). Dose 3 increased anti-RBD-IgG concentrations and nAb responses in HC and PWH, though Omicron variant neutralisation was attenuated. LTx recipients mounted limited nAb responses. PWH and HC had no difference in nAb responses for Ancestral (median 1738 vs 486.2, <i>P</i> &gt; 0.99) or BA.5 variants (median 34.0 vs 67.9, <i>P</i> &gt; 0.99). Compared with HC, PWH and LTx demonstrated reduced frequencies of SARS-CoV-2-specific memory T cells and a reduced functional memory T-cell response in LTx.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Although Dose 3 was beneficial, LTx recipients demonstrated lower serological responses than HC, while reductions were modest in PWH. Immunocompromised groups had reduced but detectable SARS-CoV-2-specific T-cell responses, demonstrating the utility of COVID-19 vaccination despite poorer serological responses.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148672713","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}

{"title":"CD4+ T-cell responses directed towards A/H5N1-derived haemagglutinin peptides increase in patients with seasonal influenza A virus infection","authors":"Lilith F Allen,&nbsp;Louise C Rowntree,&nbsp;Mitchell Jenzen,&nbsp;Ruth R Hagen,&nbsp;Nathan P Croft,&nbsp;Fiona James,&nbsp;Genevieve E Martin,&nbsp;Anthony W Purcell,&nbsp;Patricia T Illing,&nbsp;Steven Y C Tong,&nbsp;Allen C Cheng,&nbsp;Tom C Kotsimbos,&nbsp;Jason A Trubiano,&nbsp;Katherine Kedzierska,&nbsp;Thi H O Nguyen","doi":"10.1002/cti2.70118","DOIUrl":"https://doi.org/10.1002/cti2.70118","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Recent outbreak of influenza A/H5N1 viral infections in birds and mammals worldwide prompted renewed concerns over an emerging H5N1-related influenza pandemic in the generally immunologically-naive global population. Cross-reactive CD4⁺ T cells between A/H1N1 and A/H5N1 subtypes targeting internal and surface influenza proteins have been identified in humans, indicating some protection against severe and fatal A/H5N1 infection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To detect T-cell responses towards H1 and H5 viruses, we stimulated PBMCs from patients hospitalised with seasonal influenza A viruses, alongside healthy individuals, with overlapping peptide pools spanning hemagglutinin (HA) and neuraminidase (NA) of A/Vietnam/1203/2004 (H5N1) and A/New York/18/2009 (H1N1-pdm09-like) viruses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Majority of acutely infected and healthy participants (100% and 75%, respectively) had detectable CD4⁺ and CD8⁺ T-cell responses towards H1-HA and H5-HA, whereas 30–80% of individuals had detectable H5-NA responses. H1 and H5 HA-specific CD4⁺ T-cell responses highly correlated, suggesting some level of cross-reactivity between T-cell responses directed against H1 and H5 subtypes. HA-specific CD4⁺ T-cell responses were increased in influenza patients compared to healthy participants. We found no differences in H1- and H5-specific T cell responses between those born pre- and post-1968, irrespective of infection status. Sequence alignment of H1 and H5 viruses identified high conservation in the HA2 stalk subunit (81.53%). CD4⁺ T-cell immunity towards immunodominant HA_306–318 epitope, restricted by several HLA-DRB1 molecules, revealed limited cross-reactivity between Group 1 and Group 2 HA-subtypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We define correlative H1- and H5-specific CD4⁺ T-cell responses during seasonal influenza A virus infection, likely reflecting some level of H1/H5 T cell cross-reactivity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148652461","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}

{"title":"High IL-10 levels during CRS are negatively associated with NK-cell recovery after CAR-T cell therapy","authors":"Xindi Wang,&nbsp;Wenjing Luo,&nbsp;Yingying Li,&nbsp;Jianghua Wu,&nbsp;Lu Tang,&nbsp;Chenggong Li,&nbsp;Qiaolin Liu,&nbsp;Zhihan Chen,&nbsp;Yu Hu,&nbsp;Heng Mei","doi":"10.1002/cti2.70116","DOIUrl":"10.1002/cti2.70116","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Immune reconstitution following chimeric antigen receptor (CAR)-T cell therapy remains a critical clinical challenge, and the determinants of natural killer (NK)-cell recovery are not fully understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We longitudinally monitored natural killer (NK)-cell recovery in 64 patients during the first year after CD19-directed CAR-T cell therapy, analysing NK-cell counts and surface receptor expression. Associations between cytokine release syndrome (CRS), cytokine profiles, and NK-cell numerical reconstitution were evaluated, and mechanistic insights were explored using <i>in vitro</i> NK-cell assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NK-cell numerical and phenotypic recovery was impaired within the first month after CAR-T cell infusion. Notably, NK-cell numerical recovery was significantly delayed in patients who developed CRS. A reduced NK-to-T cell ratio at one-month post-infusion was associated with a markedly increased risk of viral infection (hazard ratio = 4.512). Elevated interleukin (IL)-10 levels during CRS were inversely associated with NK-cell recovery. Patients with high IL-10 levels exhibited delayed NK-cell reconstitution, which was independently validated in two external cohorts. Mechanistically, <i>in vitro</i> exposure of NK cells to IL-10 promoted caspase-3 activation, increased apoptosis, and enhanced reactive oxygen species accumulation and lipid peroxidation. Rescue experiments using ferrostatin-1 and Z-VAD-FMK further supported the involvement of IL-10 in apoptosis and ferroptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings highlight a previously underappreciated role of IL-10 in shaping NK-cell reconstitution post-CAR-T cell therapy, particularly in the setting of CRS. Patients with CRS accompanied by elevated IL-10 levels may benefit from anti-inflammatory interventions or therapeutic strategies aimed at promoting NK-cell recovery.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 7","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13396887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583234","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}