Lisa Denny, Katharina Robichon, Nikki Templeton, Mackenzie Kiernan, Thomas E Prisinzano, Bronwyn M Kivell, Anne Camille La Flamme
Objectives
Multiple sclerosis is an immune-mediated inflammatory disease of the central nervous system. Recently, kappa opioid receptor (KOR) agonists were found to promote remyelination and recovery in models of demyelination. However, the side effects of many full KOR agonists limit clinical use. Activation of KOR and mu opioid receptors (MOR) often has opposing effects. Therefore, it is plausible that activating KOR and antagonising MOR may confer a beneficial increase in therapeutic efficacy at lower doses.
Methods
This study investigated the hypothesis that combining the clinically available full KOR agonist nalfurafine (NalF) with a MOR antagonist/partial KOR agonist nalmefene (NalM) would provide greater than additive benefits in the murine model of immune-driven demyelination, experimental autoimmune encephalomyelitis (EAE).
Results
We found that NalM alone reduced EAE disease severity when administered therapeutically although NalM at the most effective doses did not enhance myelination or reduce lesions in the spinal cord. Moreover, a combination of NalF/NalM at suboptimal doses significantly reduced lesion size and promoted myelination in the spinal cord suggesting a better-than-additive effect on lesion resolution. This finding was supported by a bioinformatic analysis response that highlighted the myelination benefits of the suboptimal dose combination while the optimal dose combination of NalF/NalM stimulated increased immunomodulatory activity.
Conclusions
Findings from this study indicate that the remyelinating and immunomodulatory effects of the KOR agonist NalF can be significantly enhanced through interactions with the MOR antagonist NalM in a distinct dose-dependent manner.
{"title":"Nalmefene enhances the remyelinating ability of nalfurafine when administered therapeutically at very low doses during experimental autoimmune encephalomyelitis","authors":"Lisa Denny, Katharina Robichon, Nikki Templeton, Mackenzie Kiernan, Thomas E Prisinzano, Bronwyn M Kivell, Anne Camille La Flamme","doi":"10.1002/cti2.70069","DOIUrl":"https://doi.org/10.1002/cti2.70069","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Multiple sclerosis is an immune-mediated inflammatory disease of the central nervous system. Recently, kappa opioid receptor (KOR) agonists were found to promote remyelination and recovery in models of demyelination. However, the side effects of many full KOR agonists limit clinical use. Activation of KOR and mu opioid receptors (MOR) often has opposing effects. Therefore, it is plausible that activating KOR and antagonising MOR may confer a beneficial increase in therapeutic efficacy at lower doses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study investigated the hypothesis that combining the clinically available full KOR agonist nalfurafine (NalF) with a MOR antagonist/partial KOR agonist nalmefene (NalM) would provide greater than additive benefits in the murine model of immune-driven demyelination, experimental autoimmune encephalomyelitis (EAE).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that NalM alone reduced EAE disease severity when administered therapeutically although NalM at the most effective doses did not enhance myelination or reduce lesions in the spinal cord. Moreover, a combination of NalF/NalM at suboptimal doses significantly reduced lesion size and promoted myelination in the spinal cord suggesting a better-than-additive effect on lesion resolution. This finding was supported by a bioinformatic analysis response that highlighted the myelination benefits of the suboptimal dose combination while the optimal dose combination of NalF/NalM stimulated increased immunomodulatory activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Findings from this study indicate that the remyelinating and immunomodulatory effects of the KOR agonist NalF can be significantly enhanced through interactions with the MOR antagonist NalM in a distinct dose-dependent manner.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 12","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70069","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145739646","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}
Christopher A Gonelli, Marios Koutsakos, Robyn Esterbauer, Ming ZM Zheng, Yee-Chen Liu, Amanda Kyaw Zin, Lara SU Schwab, Aeron C Hurt, Stephen J Kent, Jennifer A Juno, Adam K Wheatley
Objectives
Immunisation remains the most cost-effective mechanism to combat influenza infection and is widely employed against seasonal influenza viruses. Zoonotic transmission of avian influenza A viruses represents a significant threat to human health given the lack of population-level immunity. Therefore, there is a need to better understand pre-existing cross-reactive human immunity against avian influenza strains, as highlighted by the recent global spread of avian H5Nx clade 2.3.4.4b variants.
Methods
Here, we quantified the frequencies and specificities of B and T cells recognising avian hemagglutinin (HA) within unexposed adults and characterised the ability of seasonal immunisation to boost cross-reactive immune responses to H5Nx strains, including from clade 2.3.4.4b.
Results
Low but detectable serum antibody titres against H5 and H7 avian influenza HA were observed in donors. The frequency of memory B cells with cross-reactive recognition of H5 and H7 HA was below 0.13% and two- to five-fold lower than populations of seasonal HA-specific B cells. Boosting of B-cell responses against clade 2.3.4.4b H5Nx HA following seasonal immunisation was sporadic with only three of 19 individuals showing an increased population of probe-positive cells. Cross-reactive B cells generally expressed immunoglobulins drawn from variable heavy chain genes associated with HA stem recognition. CD4+ T-cell responses towards H5 HA were weakly boosted with little increase in circulating T follicular helper cell populations.
Conclusion
These findings highlight the need for avian influenza-specific vaccine products to bolster immunity in human populations. Such vaccines could aid pre-pandemic preparedness by expanding baseline frequencies of avian influenza-specific memory lymphocytes.
{"title":"Low-level human memory T and B cells recognising avian influenza hemagglutinins are poorly responsive to existing seasonal influenza vaccines","authors":"Christopher A Gonelli, Marios Koutsakos, Robyn Esterbauer, Ming ZM Zheng, Yee-Chen Liu, Amanda Kyaw Zin, Lara SU Schwab, Aeron C Hurt, Stephen J Kent, Jennifer A Juno, Adam K Wheatley","doi":"10.1002/cti2.70067","DOIUrl":"https://doi.org/10.1002/cti2.70067","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Immunisation remains the most cost-effective mechanism to combat influenza infection and is widely employed against seasonal influenza viruses. Zoonotic transmission of avian influenza A viruses represents a significant threat to human health given the lack of population-level immunity. Therefore, there is a need to better understand pre-existing cross-reactive human immunity against avian influenza strains, as highlighted by the recent global spread of avian H5Nx clade 2.3.4.4b variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we quantified the frequencies and specificities of B and T cells recognising avian hemagglutinin (HA) within unexposed adults and characterised the ability of seasonal immunisation to boost cross-reactive immune responses to H5Nx strains, including from clade 2.3.4.4b.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Low but detectable serum antibody titres against H5 and H7 avian influenza HA were observed in donors. The frequency of memory B cells with cross-reactive recognition of H5 and H7 HA was below 0.13% and two- to five-fold lower than populations of seasonal HA-specific B cells. Boosting of B-cell responses against clade 2.3.4.4b H5Nx HA following seasonal immunisation was sporadic with only three of 19 individuals showing an increased population of probe-positive cells. Cross-reactive B cells generally expressed immunoglobulins drawn from variable heavy chain genes associated with HA stem recognition. CD4<sup>+</sup> T-cell responses towards H5 HA were weakly boosted with little increase in circulating T follicular helper cell populations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings highlight the need for avian influenza-specific vaccine products to bolster immunity in human populations. Such vaccines could aid pre-pandemic preparedness by expanding baseline frequencies of avian influenza-specific memory lymphocytes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 12","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145730370","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}
Olivia G Moscatelli, Amy K Russell, Lee M Henneken, Melinda Y Hardy, Jason A Tye-Din
Objectives
Detection of antigen-specific T cells has been crucial for the study of autoimmune illnesses such as coeliac disease (CD). In CD, an oral gluten challenge is required to expand the rare population of circulating gluten-specific T cells to detectable levels for IFN-γ ELISpot detection. We evaluated interleukin (IL)-2 detection as a simpler approach to identify gluten-specific T cells in CD.
Methods
HLA-DQ2.5+-treated CD adults (n = 10) were assessed before and 6–8 days after commencing a single-bolus gluten challenge. Serum IL-2 (GCIL-2), whole blood IL-2 (WBA) and peripheral blood mononuclear cell IFN-γ ELISpot responses were evaluated. Functional effects of peptides encompassing epitopes of varying immunogenicity and pan-HLA-DQ blocking were tested.
Results
GCIL-2 was 90% sensitive in detecting CD. Day 6 post challenge was the optimal day for assessment. In vitro IL-2 release showed higher sensitivity than IFN-γ or IL-10 release in the WBA. IL-2 WBA had 80% sensitivity prior to gluten challenge, and 90% sensitivity at Day 6 post gluten challenge. IFN-γ ELISpot was less sensitive: 20% at baseline and 40% at Day 6 after gluten challenge. Pan-HLA-DQ blocking reduced IL-2 WBA responses by 89–91%, and the assay accurately ranked gluten peptide immunogenicity consistent with published data.
Conclusions
The IL-2 WBA provides superior sensitivity over IFN-γ ELISpot for detecting gluten-specific T cells. It can measure the functional blockade of HLA and accurately reflects gluten peptide immunogenicity hierarchies. The IL-2 WBA supports immunomonitoring and T-cell epitope mapping in CD and offers broad research and clinical application beyond CD.
{"title":"An optimised whole blood interleukin-2 release assay is more sensitive than interferon-γ ELISpot for detecting and quantifying gluten-specific CD4+ T-cell responses in coeliac disease","authors":"Olivia G Moscatelli, Amy K Russell, Lee M Henneken, Melinda Y Hardy, Jason A Tye-Din","doi":"10.1002/cti2.70063","DOIUrl":"https://doi.org/10.1002/cti2.70063","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Detection of antigen-specific T cells has been crucial for the study of autoimmune illnesses such as coeliac disease (CD). In CD, an oral gluten challenge is required to expand the rare population of circulating gluten-specific T cells to detectable levels for IFN-γ ELISpot detection. We evaluated interleukin (IL)-2 detection as a simpler approach to identify gluten-specific T cells in CD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>HLA-DQ2.5+-treated CD adults (<i>n</i> = 10) were assessed before and 6–8 days after commencing a single-bolus gluten challenge. Serum IL-2 (GCIL-2), whole blood IL-2 (WBA) and peripheral blood mononuclear cell IFN-γ ELISpot responses were evaluated. Functional effects of peptides encompassing epitopes of varying immunogenicity and pan-HLA-DQ blocking were tested.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>GCIL-2 was 90% sensitive in detecting CD. Day 6 post challenge was the optimal day for assessment. <i>In vitro</i> IL-2 release showed higher sensitivity than IFN-γ or IL-10 release in the WBA. IL-2 WBA had 80% sensitivity prior to gluten challenge, and 90% sensitivity at Day 6 post gluten challenge. IFN-γ ELISpot was less sensitive: 20% at baseline and 40% at Day 6 after gluten challenge. Pan-HLA-DQ blocking reduced IL-2 WBA responses by 89–91%, and the assay accurately ranked gluten peptide immunogenicity consistent with published data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The IL-2 WBA provides superior sensitivity over IFN-γ ELISpot for detecting gluten-specific T cells. It can measure the functional blockade of HLA and accurately reflects gluten peptide immunogenicity hierarchies. The IL-2 WBA supports immunomonitoring and T-cell epitope mapping in CD and offers broad research and clinical application beyond CD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 12","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70063","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719431","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}
Hang Zhou, Xin Zhao, Ru Chen, Tianqi Wang, Yi Zhuang, Yanying Liu
Objectives
To describe the first reported case of coexisting Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) syndrome and IgG4-related disease (IgG4-RD) and to evaluate the therapeutic response to Upadacitinib.
Methods
We described the clinical course, investigations, treatments, and outcomes of a 45-year-old woman initially diagnosed with SAPHO syndrome who subsequently developed IgG4-RD. Laboratory tests, imaging findings, and therapeutic responses were analyzed.
Results
The patient developed IgG4-RD-related organ involvement during the course of SAPHO syndrome. Although glucocorticoid therapy was initially effective, disease flares occurred upon tapering. Upadacitinib was initiated as an escalation therapy, leading to rapid improvement in clinical symptoms and normalization of inflammatory and IgG4-related serological markers. Sustained remission was maintained with continued treatment.
Conclusion
This case demonstrates that Upadacitinib may be an effective therapeutic option for patients with concurrent SAPHO syndrome and IgG4-RD. The observed clinical response supports the potential role of JAK-STAT pathway modulation in managing overlapping immune-mediated disorders.
{"title":"Coexistence of SAPHO syndrome and IgG4-related disease with Upadacitinib","authors":"Hang Zhou, Xin Zhao, Ru Chen, Tianqi Wang, Yi Zhuang, Yanying Liu","doi":"10.1002/cti2.70065","DOIUrl":"10.1002/cti2.70065","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To describe the first reported case of coexisting Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) syndrome and IgG4-related disease (IgG4-RD) and to evaluate the therapeutic response to Upadacitinib.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We described the clinical course, investigations, treatments, and outcomes of a 45-year-old woman initially diagnosed with SAPHO syndrome who subsequently developed IgG4-RD. Laboratory tests, imaging findings, and therapeutic responses were analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The patient developed IgG4-RD-related organ involvement during the course of SAPHO syndrome. Although glucocorticoid therapy was initially effective, disease flares occurred upon tapering. Upadacitinib was initiated as an escalation therapy, leading to rapid improvement in clinical symptoms and normalization of inflammatory and IgG4-related serological markers. Sustained remission was maintained with continued treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This case demonstrates that Upadacitinib may be an effective therapeutic option for patients with concurrent SAPHO syndrome and IgG4-RD. The observed clinical response supports the potential role of JAK-STAT pathway modulation in managing overlapping immune-mediated disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12626648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555890","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}
Jonathan Garnier, Anaïs Palen, Xavier Durand, Jacques Ewald, Amira Ben Amara, Marie Sarah Rouvière, Samuel Granjeaud, Gregoire Bellan, Benjamin Choisy, Franck Verdonk, Brice Gaudilliere, Caroline Gouarne, Olivier Turrini, Daniel Olive, Anne Sophie Chretien
Objectives
Despite advancements in surgical techniques and perioperative care, pancreatic surgery remains a high-risk procedure with significant morbidity and mortality. Furthermore, understanding its impact on the immune system is essential for designing strategies that interact with it. The aim of this study was to elucidate the immunomodulation that occurs following pancreatectomy.
Methods
Patients were recruited for the IMMUNOPANC trial (NCT03978702). We performed mass cytometry to analyse the circulating immune subpopulations and integrated the data using the hierarchical-stochastic neighbour embedding clustering analysis and Stabl algorithm.
Results
Among the enrolled 39 patients, 33 (84.5%) had undergone pancreatectomy for neoplasia including 13 (39%) with pancreatic ductal adenocarcinoma. Twelve (32%) patients developed pancreatic fistula with a 90-day mortality rate of 2.5%. We phenotyped 156 samples and observed a significant increase in myeloid cells (26% vs. 34%, P = 0.018) after pancreatectomy. Natural killer cell proportions decreased on postoperative day one (POD1) compared with the preoperative levels (7% vs. 12%, P < 0.001). Similarly, both CD8+ and CD4+ T-cell proportions decreased significantly post-surgery (25% and 40%, respectively, P < 0.001). During a narrow window, we observed the alteration of NK cells, contraction of CD8+ T cells, and increase in the proportion of naive CD4+ T cells. These changes may be a result of the immune response to surgery but could also reflect lymphoid organ demargination.
Conclusion
This study presents the first analysis of peripheral immune system trajectories following pancreatic surgery. Understanding these dynamics would facilitate the restoration of postoperative immunity, which is potentially crucial for recovery.
{"title":"Immediate variations in high-dimensional circulating immune cells following pancreatectomy","authors":"Jonathan Garnier, Anaïs Palen, Xavier Durand, Jacques Ewald, Amira Ben Amara, Marie Sarah Rouvière, Samuel Granjeaud, Gregoire Bellan, Benjamin Choisy, Franck Verdonk, Brice Gaudilliere, Caroline Gouarne, Olivier Turrini, Daniel Olive, Anne Sophie Chretien","doi":"10.1002/cti2.70059","DOIUrl":"10.1002/cti2.70059","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Despite advancements in surgical techniques and perioperative care, pancreatic surgery remains a high-risk procedure with significant morbidity and mortality. Furthermore, understanding its impact on the immune system is essential for designing strategies that interact with it. The aim of this study was to elucidate the immunomodulation that occurs following pancreatectomy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients were recruited for the IMMUNOPANC trial (NCT03978702). We performed mass cytometry to analyse the circulating immune subpopulations and integrated the data using the hierarchical-stochastic neighbour embedding clustering analysis and Stabl algorithm.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among the enrolled 39 patients, 33 (84.5%) had undergone pancreatectomy for neoplasia including 13 (39%) with pancreatic ductal adenocarcinoma. Twelve (32%) patients developed pancreatic fistula with a 90-day mortality rate of 2.5%. We phenotyped 156 samples and observed a significant increase in myeloid cells (26% vs. 34%, <i>P</i> = 0.018) after pancreatectomy. Natural killer cell proportions decreased on postoperative day one (POD1) compared with the preoperative levels (7% vs. 12%, <i>P <</i> 0.001). Similarly, both CD8<sup>+</sup> and CD4<sup>+</sup> T-cell proportions decreased significantly post-surgery (25% and 40%, respectively, <i>P <</i> 0.001). During a narrow window, we observed the alteration of NK cells, contraction of CD8<sup>+</sup> T cells, and increase in the proportion of naive CD4<sup>+</sup> T cells. These changes may be a result of the immune response to surgery but could also reflect lymphoid organ demargination.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study presents the first analysis of peripheral immune system trajectories following pancreatic surgery. Understanding these dynamics would facilitate the restoration of postoperative immunity, which is potentially crucial for recovery.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12620249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145547337","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}
Amal Elhage, Janna H Hadaya, Chloe Sligar, Debbie Watson, Sahil Adriouch, Ronald Sluyter
Objectives
Graft-versus-host disease (GVHD) is an inflammatory disorder that arises following allogeneic haematopoietic stem cell transplantation. P2X7 is an extracellular ATP-gated cation channel present on immune cells. P2X7 blockade with small molecule inhibitors impairs GVHD development in a humanised mouse model. This study investigated whether adeno-associated viral (AAV) vectors encoding nanobodies (Nbs) that block mouse P2X7 (mP2X7) or both mP2X7 and human P2X7 (m/hP2X7) impair GVHD development in this model.
Methods
On Day −21, NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice were injected intramuscularly with 10 × 1010 viral genomes encoding either green fluorescent protein (GFP), an anti-mP2X7 Nb or an anti-m/hP2X7 Nb, or with saline. On Day 0, mice were euthanised or injected intraperitoneally with 10 × 106 human peripheral blood mononuclear cells and monitored thrice weekly for signs of GVHD until the experiment or disease endpoint.
Results
The anti-m/hP2X7 and anti-mP2X7 Nbs reduced clinical GVHD and time to disease onset, as well as liver and lung GVHD. Both Nbs reduced liver human T helper (Th)17 cells. Sera collected at Day 0 and disease endpoint from treated mice, but not from control mice, completely blocked P2X7 activity in human RPMI 8226 and/or murine J774 cells, confirming circulating anti-P2X7 Nbs in mice from Day 0 to disease endpoint.
Conclusion
This study indicates that P2X7 blockade with an anti-m/hP2X7 and to a lesser extent an anti-mP2X7 Nb reduces GVHD progression in humanised mice. This supports the future testing of these P2X7 biologics as a prophylactic therapy for GVHD.
{"title":"Adeno-associated viral vectors encoding anti-P2X7 nanobodies reduce graft-versus-host disease in a humanised mouse model","authors":"Amal Elhage, Janna H Hadaya, Chloe Sligar, Debbie Watson, Sahil Adriouch, Ronald Sluyter","doi":"10.1002/cti2.70061","DOIUrl":"https://doi.org/10.1002/cti2.70061","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Graft-versus-host disease (GVHD) is an inflammatory disorder that arises following allogeneic haematopoietic stem cell transplantation. P2X7 is an extracellular ATP-gated cation channel present on immune cells. P2X7 blockade with small molecule inhibitors impairs GVHD development in a humanised mouse model. This study investigated whether adeno-associated viral (AAV) vectors encoding nanobodies (Nbs) that block mouse P2X7 (mP2X7) or both mP2X7 and human P2X7 (m/hP2X7) impair GVHD development in this model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>On Day −21, NOD.Cg-<i>Prkdc</i><sup><i>scid</i></sup><i>Il2rg</i><sup><i>tm1Wjl</i></sup>/SzJ (NSG) mice were injected intramuscularly with 10 × 10<sup>10</sup> viral genomes encoding either green fluorescent protein (GFP), an anti-mP2X7 Nb or an anti-m/hP2X7 Nb, or with saline. On Day 0, mice were euthanised or injected intraperitoneally with 10 × 10<sup>6</sup> human peripheral blood mononuclear cells and monitored thrice weekly for signs of GVHD until the experiment or disease endpoint.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The anti-m/hP2X7 and anti-mP2X7 Nbs reduced clinical GVHD and time to disease onset, as well as liver and lung GVHD. Both Nbs reduced liver human T helper (Th)17 cells. Sera collected at Day 0 and disease endpoint from treated mice, but not from control mice, completely blocked P2X7 activity in human RPMI 8226 and/or murine J774 cells, confirming circulating anti-P2X7 Nbs in mice from Day 0 to disease endpoint.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study indicates that P2X7 blockade with an anti-m/hP2X7 and to a lesser extent an anti-mP2X7 Nb reduces GVHD progression in humanised mice. This supports the future testing of these P2X7 biologics as a prophylactic therapy for GVHD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469775","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}
Yunus Kuijpers, M Liset Rietman, H Susan J Picavet, Peter Engelfriet, W M Monique Verschuren, Anne-Marie Buisman
Objectives
Older persons generally have weaker antibody responses to vaccines than younger individuals, but heterogeneity is large. We aimed to identify genetic variants associated with primary SARS-CoV-2 vaccine-induced antibody responses in older persons that might contribute to this heterogeneity.
Methods
Demographic and genotype data were collected in the Doetinchem Cohort Study prior to the COVID-19 pandemic. Antibody responses were measured 1 month after the first and second SARS-CoV-2 vaccinations, and genome-wide association analysis was performed in 842 and 890 individuals respectively. Polygenic scores were calculated and tested in an independent sample, and the variance explained by the scores was estimated using a bootstrap procedure. Genes were mapped to genome-wide suggestive (P < 1 × 10−5) loci, and gene set enrichment was performed using the hypergeometric test.
Results
Antibody responses 1 month after the first and second SARS-CoV-2 vaccinations were linked to genome-wide significant (P < 5 × 10−8) loci on Chromosome 5. Polygenic scores related to these antibody responses could explain 9% (95% CI P1: [−4% to 21%], 95% CI P2: [−4% to 24%]) of the variance. Genome-wide suggestive loci related to the responses after two vaccinations could be mapped to several genes in the human leukocyte antigen (HLA) region on chromosome 6p21.
Conclusion
Genetic variation is suggested to play a role in the primary vaccine-induced IgG antibody responses to SARS-CoV-2 in older persons. The most prominent source of variation was found to lie in HLA genes, which are enriched in several immune pathways and immune-mediated diseases.
目的：老年人对疫苗的抗体反应通常比年轻人弱，但异质性很大。我们的目的是确定与老年人原发性SARS-CoV-2疫苗诱导的抗体反应相关的遗传变异，这些变异可能导致这种异质性。方法：收集COVID-19大流行前Doetinchem队列研究的人口统计学和基因型数据。在第一次和第二次SARS-CoV-2疫苗接种1个月后测量抗体应答，并分别对842和890例个体进行全基因组关联分析。在独立样本中计算和测试多基因分数，并使用自举程序估计分数解释的方差。基因被定位到全基因组暗示（P -5）位点，并使用超几何测试进行基因集富集。结果：第一次和第二次SARS-CoV-2疫苗接种1个月后的抗体应答与5号染色体上全基因组显著（P -8）位点相关。与这些抗体反应相关的多基因评分可以解释9%的方差（95% CI P1:[-4%至21%]，95% CI P2:[-4%至24%]）。在全基因组范围内，与两次接种后的应答相关的暗示性位点可以定位到6p21染色体上人类白细胞抗原（HLA）区域的几个基因。结论：遗传变异可能在老年人一次疫苗诱导的SARS-CoV-2 IgG抗体应答中起作用。最突出的变异来源是HLA基因，它在几种免疫途径和免疫介导的疾病中富集。
{"title":"Genetic differences in the HLA region contribute to the variability in SARS-CoV-2 vaccine responsiveness of older persons: the Doetinchem Cohort Study","authors":"Yunus Kuijpers, M Liset Rietman, H Susan J Picavet, Peter Engelfriet, W M Monique Verschuren, Anne-Marie Buisman","doi":"10.1002/cti2.70058","DOIUrl":"10.1002/cti2.70058","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Older persons generally have weaker antibody responses to vaccines than younger individuals, but heterogeneity is large. We aimed to identify genetic variants associated with primary SARS-CoV-2 vaccine-induced antibody responses in older persons that might contribute to this heterogeneity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Demographic and genotype data were collected in the Doetinchem Cohort Study prior to the COVID-19 pandemic. Antibody responses were measured 1 month after the first and second SARS-CoV-2 vaccinations, and genome-wide association analysis was performed in 842 and 890 individuals respectively. Polygenic scores were calculated and tested in an independent sample, and the variance explained by the scores was estimated using a bootstrap procedure. Genes were mapped to genome-wide suggestive (<i>P</i> < 1 × 10<sup>−5</sup>) loci, and gene set enrichment was performed using the hypergeometric test.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Antibody responses 1 month after the first and second SARS-CoV-2 vaccinations were linked to genome-wide significant (<i>P</i> < 5 × 10<sup>−8</sup>) loci on Chromosome 5. Polygenic scores related to these antibody responses could explain 9% (95% CI P1: [−4% to 21%], 95% CI P2: [−4% to 24%]) of the variance. Genome-wide suggestive loci related to the responses after two vaccinations could be mapped to several genes in the human leukocyte antigen (HLA) region on chromosome 6p21.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Genetic variation is suggested to play a role in the primary vaccine-induced IgG antibody responses to SARS-CoV-2 in older persons. The most prominent source of variation was found to lie in HLA genes, which are enriched in several immune pathways and immune-mediated diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12588338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457273","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 skin is a vital organ that protects organisms from external insults, providing a barrier to the outside environment. The cellular system of the skin consists of highly specialised immune and non-immune cells, which are equipped to respond promptly, providing effective immunity and restoring tissue homeostasis. Well-coordinated cellular communication involves cells and soluble factors, which are essential for maintaining the balance and protecting the skin from inflammatory skin diseases, impaired tissue repair and recurring infections. In this review, we will focus on the recent development of understanding how cellular networks orchestrate skin immunity via a coordinated communication system of soluble factors and their signalling pathways, with a focus on psoriasis as a model of inflammatory skin disease.
{"title":"Skin immunity and inflammation: cellular interactions and communication","authors":"Divyaa Narayanan, Seen Ling Sim, Snehlata Kumari","doi":"10.1002/cti2.70053","DOIUrl":"10.1002/cti2.70053","url":null,"abstract":"<p>The skin is a vital organ that protects organisms from external insults, providing a barrier to the outside environment. The cellular system of the skin consists of highly specialised immune and non-immune cells, which are equipped to respond promptly, providing effective immunity and restoring tissue homeostasis. Well-coordinated cellular communication involves cells and soluble factors, which are essential for maintaining the balance and protecting the skin from inflammatory skin diseases, impaired tissue repair and recurring infections. In this review, we will focus on the recent development of understanding how cellular networks orchestrate skin immunity via a coordinated communication system of soluble factors and their signalling pathways, with a focus on psoriasis as a model of inflammatory skin disease.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12581170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443571","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}
Alba Díaz Herrero, Phuong-Ha Le, Loic Renaud, Véronique Meignin, Catherine Thieblemont, Véronique Blanc, Vassili Soumelis, Pierre Tonnerre
Objectives
Diffuse large B-cell lymphoma (DLBCL) constitutes 30–40% of non-Hodgkin lymphoma cases. Despite therapeutic advances, persistence of relapsed cases has been linked to the complex tumor microenvironment (TME) and its interactions with lymphoma cells. In particular, characterising T-cell subsets, including rare cell types, and their interplay with the remaining TME is crucial for unravelling DLBCL pathogenesis and refining therapeutic strategies.
Methods
Using flow and spectral cytometry with unsupervised analysis, we investigated T-cell subpopulations across DLBCL biopsies and control lymph nodes (LN). We also inferred communication pathways between T cells and other immune cells in the TME based on the correlation of ligand–receptor expression.
Results
Our analysis revealed a higher frequency of CD8+ follicular regulatory T (Tfr) cells in DLBCL biopsies compared to control LN. These cells exhibited an effector-memory phenotype (CD45RA− CCR7−), expressed follicular markers (PD-1+ CXCR5+) and had a regulatory profile (CD127− CD25+) along with an activation/co-stimulatory signature (HLA-DR+, ICOS+, CD95+). Correlation analysis highlighted a co-stimulatory interaction between lymphoma B cells and CD8+ Tfr cells through the ICOS/ICOSL pathway, which may contribute to a protumor effect. Validation in independent scRNAseq and flow cytometry datasets confirmed the notable prevalence of CD8+ Tfr cells in DLBCL biopsies.
Conclusions
Our study highlights the utility of high-dimensional computational cytometry in elucidating T-cell subpopulations, including an increased frequency of CD8+ follicular regulatory T cells and their communication patterns within the DLBCL TME. This unbiased approach sheds light on novel cellular mechanisms in DLBCL, uncovering potential targets and biomarkers for immunotherapy.
{"title":"High-dimensional spectral cytometry identifies follicular regulatory CD8+ T cells in diffuse large B-cell lymphoma","authors":"Alba Díaz Herrero, Phuong-Ha Le, Loic Renaud, Véronique Meignin, Catherine Thieblemont, Véronique Blanc, Vassili Soumelis, Pierre Tonnerre","doi":"10.1002/cti2.70062","DOIUrl":"10.1002/cti2.70062","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Diffuse large B-cell lymphoma (DLBCL) constitutes 30–40% of non-Hodgkin lymphoma cases. Despite therapeutic advances, persistence of relapsed cases has been linked to the complex tumor microenvironment (TME) and its interactions with lymphoma cells. In particular, characterising T-cell subsets, including rare cell types, and their interplay with the remaining TME is crucial for unravelling DLBCL pathogenesis and refining therapeutic strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using flow and spectral cytometry with unsupervised analysis, we investigated T-cell subpopulations across DLBCL biopsies and control lymph nodes (LN). We also inferred communication pathways between T cells and other immune cells in the TME based on the correlation of ligand–receptor expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our analysis revealed a higher frequency of CD8<sup>+</sup> follicular regulatory T (Tfr) cells in DLBCL biopsies compared to control LN. These cells exhibited an effector-memory phenotype (CD45RA<sup>−</sup> CCR7<sup>−</sup>), expressed follicular markers (PD-1<sup>+</sup> CXCR5<sup>+</sup>) and had a regulatory profile (CD127<sup>−</sup> CD25<sup>+</sup>) along with an activation/co-stimulatory signature (HLA-DR<sup>+</sup>, ICOS<sup>+</sup>, CD95<sup>+</sup>). Correlation analysis highlighted a co-stimulatory interaction between lymphoma B cells and CD8<sup>+</sup> Tfr cells through the ICOS/ICOSL pathway, which may contribute to a protumor effect. Validation in independent scRNAseq and flow cytometry datasets confirmed the notable prevalence of CD8<sup>+</sup> Tfr cells in DLBCL biopsies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study highlights the utility of high-dimensional computational cytometry in elucidating T-cell subpopulations, including an increased frequency of CD8<sup>+</sup> follicular regulatory T cells and their communication patterns within the DLBCL TME. This unbiased approach sheds light on novel cellular mechanisms in DLBCL, uncovering potential targets and biomarkers for immunotherapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12581182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443425","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}
Romy Böttcher-Loschinski, Franziska Karl, Diana Drettwan, Johannes Wittmann, Benedikt Jacobs, Simon Völkl, Heiko Bruns, Andreas Mackensen, Dimitrios Mougiakakos
Objectives
Allogeneic stem cell transplantation (allo-SCT) is the only curative treatment option for several haematologic malignancies. Its therapeutic principle is based on the donor T cells' ability to eliminate any residual malignant cells. Despite its success, challenges such as graft-versus-host disease (GvHD) and disease relapse persist. Recent studies emphasise the role of the metabolic environment in shaping T-cell responses. This study investigates the impact of serum metabolites on T-cell responses following allo-SCT.
Methods
Metabolite levels in serum samples from 55 allo-SCT patients transplanted between November 2015 and October 2018 were analysed by nuclear magnetic resonance (NMR) spectroscopy for six time points after transplantation. These metabolite profiles were correlated with clinical data and T-cell characteristics obtained by flow cytometry-based immunomonitoring. High-density lipoprotein (HDL) emerged as a key factor of interest. To explore the potential relationship between T-cell-related differences and HDL levels, healthy donor T-cell cultures supplemented with HDL were performed.
Results
Elevated HDL levels were associated with acute GvHD (aGvHD) and relapse. Patients with high HDL serum levels exhibited a delayed normalisation of T-cell frequencies and increased effector-memory CD8+ T-cell frequencies. In vitro experiments revealed reduced proliferation and expression of activation/effector molecules after exposure to HDL. Effects of HDL on memory T-cell subset formation resembled the in situ findings in patients.
Conclusions
AGvHD was linked to elevated HDL levels, potentially affecting T-cell-mediated graft-versus-leukaemia (GvL) activity and promoting relapse. HDL could therefore be a potential biomarker for the success of allo-SCT and a lever for improving patients' outcomes.
{"title":"Elevated high-density lipoprotein levels following acute graft-versus-host disease onset: a potential link to T-cell dysfunction and increased relapse risk","authors":"Romy Böttcher-Loschinski, Franziska Karl, Diana Drettwan, Johannes Wittmann, Benedikt Jacobs, Simon Völkl, Heiko Bruns, Andreas Mackensen, Dimitrios Mougiakakos","doi":"10.1002/cti2.70060","DOIUrl":"10.1002/cti2.70060","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Allogeneic stem cell transplantation (allo-SCT) is the only curative treatment option for several haematologic malignancies. Its therapeutic principle is based on the donor T cells' ability to eliminate any residual malignant cells. Despite its success, challenges such as graft-versus-host disease (GvHD) and disease relapse persist. Recent studies emphasise the role of the metabolic environment in shaping T-cell responses. This study investigates the impact of serum metabolites on T-cell responses following allo-SCT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Metabolite levels in serum samples from 55 allo-SCT patients transplanted between November 2015 and October 2018 were analysed by nuclear magnetic resonance (NMR) spectroscopy for six time points after transplantation. These metabolite profiles were correlated with clinical data and T-cell characteristics obtained by flow cytometry-based immunomonitoring. High-density lipoprotein (HDL) emerged as a key factor of interest. To explore the potential relationship between T-cell-related differences and HDL levels, healthy donor T-cell cultures supplemented with HDL were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Elevated HDL levels were associated with acute GvHD (aGvHD) and relapse. Patients with high HDL serum levels exhibited a delayed normalisation of T-cell frequencies and increased effector-memory CD8<sup>+</sup> T-cell frequencies. <i>In vitro</i> experiments revealed reduced proliferation and expression of activation/effector molecules after exposure to HDL. Effects of HDL on memory T-cell subset formation resembled the <i>in situ</i> findings in patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>AGvHD was linked to elevated HDL levels, potentially affecting T-cell-mediated graft-versus-leukaemia (GvL) activity and promoting relapse. HDL could therefore be a potential biomarker for the success of allo-SCT and a lever for improving patients' outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"14 11","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12581179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443464","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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