Xiaoying Gao, Xiaoxia Zhang, Yaxuan Sun, Xueling Dai
Alzheimer’s disease (AD) is a common neurological disease in the elderly, and the major manifestations are cognitive dysfunction, neuronal loss, and neuropathic lesions in the brain. In the process of AD pathogenesis, the inflammatory response plays an indispensable role. The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome containing NOD, leucine-rich repeat (LRR), and pyran domains is a multi-molecular complex that can detect dangerous signals related to neurological diseases. The assembly of NLRP3 inflammasome promotes the maturation of interleukin-1beta (IL-1β) and IL-18 mediated by caspase-1 in microglia, which leads to neuroinflammation and finally contributes to the occurrence and development of AD. This review aimed to clarify the structure and activating mechanism of NLRP3 inflammasome and its key role in the pathogenesis of AD, summarize the latest findings on the suppression of NLRP3 inflammasome activation for the treatment of AD, as well as indicate that targeting regulation of NLRP3 inflammasome assembly may be a potential strategy for the treatment of AD, providing a theoretical basis for the research of AD.
{"title":"Mechanism of NLRP3 inflammasome activation and its role in Alzheimer’s disease","authors":"Xiaoying Gao, Xiaoxia Zhang, Yaxuan Sun, Xueling Dai","doi":"10.37349/ei.2022.00048","DOIUrl":"https://doi.org/10.37349/ei.2022.00048","url":null,"abstract":"Alzheimer’s disease (AD) is a common neurological disease in the elderly, and the major manifestations are cognitive dysfunction, neuronal loss, and neuropathic lesions in the brain. In the process of AD pathogenesis, the inflammatory response plays an indispensable role. The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome containing NOD, leucine-rich repeat (LRR), and pyran domains is a multi-molecular complex that can detect dangerous signals related to neurological diseases. The assembly of NLRP3 inflammasome promotes the maturation of interleukin-1beta (IL-1β) and IL-18 mediated by caspase-1 in microglia, which leads to neuroinflammation and finally contributes to the occurrence and development of AD. This review aimed to clarify the structure and activating mechanism of NLRP3 inflammasome and its key role in the pathogenesis of AD, summarize the latest findings on the suppression of NLRP3 inflammasome activation for the treatment of AD, as well as indicate that targeting regulation of NLRP3 inflammasome assembly may be a potential strategy for the treatment of AD, providing a theoretical basis for the research of AD.","PeriodicalId":93552,"journal":{"name":"Exploration of immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43166423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Until now, despite 30 years of intensive work, the RV144 human immunodeficiency virus (HIV) vaccine trial initiated in 2003 remains so far the most protective vaccine prototype of all those tested (32% reduction in the infection rate three years after the vaccination) and the HIV epidemic is still spreading worldwide. In addition, antiretroviral therapy (ART) for people living with HIV is given for life as no other pharmacological intervention has allowed to maintain an undetectable viral load after ART withdrawal. Pr Andrieu and colleagues discovered tolerogenic CD8+T-cells that suppress simian immunodeficiency virus (SIV) specific activation, ensuing SIV reverse transcription suppression and viral replication-defective in Chinese macaques vaccinated by intragastric route with inactivated SIV particles + Lactobacillus rhamnosus. Moreover, in HIV-infected elite controllers with specific genetic features (HLA-1-Bw4-80i and KIR3DL1 genes), Pr Andrieu found out that similar tolerogenic CD8+T-cells suppress in the same manner HIV-specific activation, HIV reverse transcription, and HIV replication. These data justify the development of a tolerogenic vaccine composed of inactivated HIV particles + Lactobacillus rhamnosus that could be used as a preventive or therapeutic vaccine.
{"title":"A proposed new paradigm for an anti-AIDS tolerogenic vaccine","authors":"C. Jacomet","doi":"10.37349/ei.2022.00046","DOIUrl":"https://doi.org/10.37349/ei.2022.00046","url":null,"abstract":"Until now, despite 30 years of intensive work, the RV144 human immunodeficiency virus (HIV) vaccine trial initiated in 2003 remains so far the most protective vaccine prototype of all those tested (32% reduction in the infection rate three years after the vaccination) and the HIV epidemic is still spreading worldwide. In addition, antiretroviral therapy (ART) for people living with HIV is given for life as no other pharmacological intervention has allowed to maintain an undetectable viral load after ART withdrawal. Pr Andrieu and colleagues discovered tolerogenic CD8+T-cells that suppress simian immunodeficiency virus (SIV) specific activation, ensuing SIV reverse transcription suppression and viral replication-defective in Chinese macaques vaccinated by intragastric route with inactivated SIV particles + Lactobacillus rhamnosus. Moreover, in HIV-infected elite controllers with specific genetic features (HLA-1-Bw4-80i and KIR3DL1 genes), Pr Andrieu found out that similar tolerogenic CD8+T-cells suppress in the same manner HIV-specific activation, HIV reverse transcription, and HIV replication. These data justify the development of a tolerogenic vaccine composed of inactivated HIV particles + Lactobacillus rhamnosus that could be used as a preventive or therapeutic vaccine.","PeriodicalId":93552,"journal":{"name":"Exploration of immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43749899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Fei, Yishan Liu, Lingyun Zuo, Bin-fang Gu, Liqun Liang, Luhao Wang, Y. Nie, Minying Chen, X. Guan, Jianfeng Wu
Aim: Thymosin alpha 1 (Tα1) is a promising treatment for the improvement of sepsis patients. Until now, its function in reducing acute organ damage of sepsis patients is still unclear. The aim of this study was to determine whether Tα1 can alleviate organ dysfunction in sepsis patients. Methods: This study retrospectively enrolled sepsis patients from a multicenter randomized controlled trial [efficacy of Tα1 for severe sepsis (ETASS)]. The sequential organ failure assessment (SOFA) score on day 0 (initial), day 3, and day 7 was collected. Absolute SOFAday07 was defined as initial SOFA score minus SOFA score on day 7 (initial SOFA–SOFA day7). Delta SOFA score (ΔSOFAday07) was provided by the formula: (initial SOFA–SOFA day7) × 100/initial SOFA, and it was expressed as a percentage. After propensity score matching (1:1 ratio), baseline characteristics were well-balanced between the Tα1 group and placebo group. The primary outcome was evaluated with a comparison of ΔSOFAday07 decline between patients treated with or without Tα1 therapy. Results: Among 288 enrolled patients, 149 patients received both Tα1 and standard therapy (Tα1 group), and 139 patients received both placebo and standard therapy (placebo group). Compared with the placebo group, the Tα1 group had significantly lower Absolute SOFAday07 [95% confidence interval (CI) 0.8 (0–1.7), P = 0.049]. Among 111 pairs of patients matched by propensity score, the Tα1 group still had lower Absolute SOFAday07 [95% CI 1.0 (0.1–1.9), P = 0.029]. Meanwhile, Tα1 treatment could significantly improve ΔSOFAday07. When the amplitude of ΔSOFAday07 was graded, one third of patients in the Tα1 group had an increase of more than 60%, compared with 22% in the placebo group. Subgroup analysis found that the ΔSOFAday07 improved significantly after Tα1 therapy in sepsis patients with no immunoparalysis at baseline, no complications, and early intervention. Conclusions: For sepsis patients, Tα1 treatment can alleviate organ dysfunction, and ΔSOFAday07 can be used as an indicator of its therapeutic effect (ClinicalTrials.gov identifier: NCT00711620).
目的:胸腺素α1 (Tα1)是一种很有希望改善脓毒症患者的治疗方法。迄今为止，其在减轻脓毒症患者急性器官损伤中的作用尚不清楚。本研究旨在探讨Tα1是否能减轻脓毒症患者的器官功能障碍。方法:本研究回顾性纳入了一项多中心随机对照试验[Tα1治疗严重脓毒症(ETASS)的疗效]的脓毒症患者。收集第0天(初始)、第3天和第7天的序贯器官衰竭评估(SOFA)评分。绝对SOFAday07定义为初始SOFA评分减去第7天的SOFA评分(初始SOFA - SOFA第7天)。Delta SOFA评分(ΔSOFAday07)的计算公式为:(initial SOFA - SOFA day7) × 100/initial SOFA，并以百分比表示。倾向评分匹配(1:1)后，Tα1组和安慰剂组的基线特征平衡良好。通过比较接受或不接受t - α1治疗的患者的ΔSOFAday07下降来评估主要结局。结果:288例入组患者中，同时接受Tα1和标准治疗的患者149例(Tα1组)，同时接受安慰剂和标准治疗的患者139例(安慰剂组)。与安慰剂组相比，Tα1组的绝对SOFAday07明显降低[95%置信区间(CI) 0.8 (0-1.7)， P = 0.049]。在倾向评分匹配的111对患者中，Tα1组的绝对SOFAday07仍较低[95% CI 1.0 (0.1 ~ 1.9)， P = 0.029]。同时t - α1处理可显著改善ΔSOFAday07。当ΔSOFAday07的振幅被分级时，Tα1组中三分之一的患者增加超过60%，而安慰剂组为22%。亚组分析发现，基线时无免疫瘫痪、无并发症、早期干预的败血症患者经Tα1治疗后ΔSOFAday07明显改善。结论:对于脓毒症患者，Tα1治疗可减轻器官功能障碍，ΔSOFAday07可作为其治疗效果的指标(ClinicalTrials.gov标识符:NCT00711620)。
{"title":"Thymosin alpha 1 therapy alleviates organ dysfunction of sepsis patients: a retrospective cohort study","authors":"P. Fei, Yishan Liu, Lingyun Zuo, Bin-fang Gu, Liqun Liang, Luhao Wang, Y. Nie, Minying Chen, X. Guan, Jianfeng Wu","doi":"10.37349/ei.2022.00045","DOIUrl":"https://doi.org/10.37349/ei.2022.00045","url":null,"abstract":"Aim:\u0000\u0000Thymosin alpha 1 (Tα1) is a promising treatment for the improvement of sepsis patients. Until now, its function in reducing acute organ damage of sepsis patients is still unclear. The aim of this study was to determine whether Tα1 can alleviate organ dysfunction in sepsis patients.\u0000Methods:\u0000\u0000This study retrospectively enrolled sepsis patients from a multicenter randomized controlled trial [efficacy of Tα1 for severe sepsis (ETASS)]. The sequential organ failure assessment (SOFA) score on day 0 (initial), day 3, and day 7 was collected. Absolute SOFAday07 was defined as initial SOFA score minus SOFA score on day 7 (initial SOFA–SOFA day7). Delta SOFA score (ΔSOFAday07) was provided by the formula: (initial SOFA–SOFA day7) × 100/initial SOFA, and it was expressed as a percentage. After propensity score matching (1:1 ratio), baseline characteristics were well-balanced between the Tα1 group and placebo group. The primary outcome was evaluated with a comparison of ΔSOFAday07 decline between patients treated with or without Tα1 therapy.\u0000Results:\u0000\u0000Among 288 enrolled patients, 149 patients received both Tα1 and standard therapy (Tα1 group), and 139 patients received both placebo and standard therapy (placebo group). Compared with the placebo group, the Tα1 group had significantly lower Absolute SOFAday07 [95% confidence interval (CI) 0.8 (0–1.7), P = 0.049]. Among 111 pairs of patients matched by propensity score, the Tα1 group still had lower Absolute SOFAday07 [95% CI 1.0 (0.1–1.9), P = 0.029]. Meanwhile, Tα1 treatment could significantly improve ΔSOFAday07. When the amplitude of ΔSOFAday07 was graded, one third of patients in the Tα1 group had an increase of more than 60%, compared with 22% in the placebo group. Subgroup analysis found that the ΔSOFAday07 improved significantly after Tα1 therapy in sepsis patients with no immunoparalysis at baseline, no complications, and early intervention.\u0000Conclusions:\u0000\u0000For sepsis patients, Tα1 treatment can alleviate organ dysfunction, and ΔSOFAday07 can be used as an indicator of its therapeutic effect (ClinicalTrials.gov identifier: NCT00711620).","PeriodicalId":93552,"journal":{"name":"Exploration of immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41666070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Cerapio, M. Perrier, F. Pont, C. Laurent, Stéphane Bertani, J. Fournié
Aim: The aim of this article is to characterize in detail the γδ T lymphocytes from an adult patient with primary cutaneous T-cell lymphoma of γδ subtype (γδ CTCL). Methods: Here this article reports trajectory mapping on high-resolution differentiation trajectories of γδ T lymphocytes digitally extracted from a scRNAseq dataset. Results: In the patch-to-plaque progression of CTCL, the TCRVγnon9 subset of γδ T cells differentiated from naive T cells (Tn) and central memory T cells (Tcm) to abundant effector memory T cells (Tem) while other cutaneous γδ T and CD8 T cells remained unchanged. Conclusions: This transcriptomic switch underlies the emergence of a CTCL-like progression of the TCRVγnon9 γδ T subtype and suggests new routes for treating these diseases.
{"title":"Single-cell differentiation trajectories define early stages of a human cutaneous T-cell lymphoma","authors":"J. Cerapio, M. Perrier, F. Pont, C. Laurent, Stéphane Bertani, J. Fournié","doi":"10.37349/ei.2022.00044","DOIUrl":"https://doi.org/10.37349/ei.2022.00044","url":null,"abstract":"Aim: The aim of this article is to characterize in detail the γδ T lymphocytes from an adult patient with primary cutaneous T-cell lymphoma of γδ subtype (γδ CTCL).\u0000Methods: Here this article reports trajectory mapping on high-resolution differentiation trajectories of γδ T lymphocytes digitally extracted from a scRNAseq dataset.\u0000Results: In the patch-to-plaque progression of CTCL, the TCRVγnon9 subset of γδ T cells differentiated from naive T cells (Tn) and central memory T cells (Tcm) to abundant effector memory T cells (Tem) while other cutaneous γδ T and CD8 T cells remained unchanged.\u0000Conclusions: This transcriptomic switch underlies the emergence of a CTCL-like progression of the TCRVγnon9 γδ T subtype and suggests new routes for treating these diseases.","PeriodicalId":93552,"journal":{"name":"Exploration of immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43272979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although a large number of preventative human immunodeficiency virus (HIV) vaccine trials have been carried out during the last 30 years, it is remarkable that an effective HIV vaccine has not yet been developed. Research paradigms correspond to theoretical assumptions and particular strategies that scientists use when they try to solve a particular problem. Many paradigms used successfully in vaccinology were ineffective with HIV. For instance: 1) The structure-based reverse vaccinology approach failed because investigators tried to generate a vaccine starting with the antigenic structure of HIV-envelope (Env) epitopes bound to neutralizing monoclonal antibodies (mAbs) derived from HIV-infected individuals. They assumed that this antigenic structure would also possess the immunogenic capacity of inducing in vaccinees a polyclonal antibody (Ab) response with the same neutralizing capacity as the mAb. 2) The structures observed in epitope-paratope crystallographic complexes result from mutually induced fit between the two partners and do not correspond to the structures present in the free molecules before they had interacted. 3) The affinity-matured neutralizing mAbs obtained from chronically infected individuals did not recognize the germline predecessors of these Abs present in vaccinees. 4) The HIV p17 matrix protein that lines the inner surface of the viral membrane is one of the most disordered proteins identified on our planet and this prevents the induced Abs from binding to the glycosylated HIV gp120 protein. 5) Vaccinologists need to solve so-called inverse problems, for instance, guessing what are the multiple causes that produced an earlier wanted beneficial effect such as the absence of deleterious HIV infection in elite controllers. Since the immune system consists of numerous subsystems that have not yet been elucidated, it is impossible to solve the inverse problems posed by each subsystem. 6) Vaccinology is an empirical science that only sometimes succeeds because we do not understand the complex mechanisms that lead to protective immune responses.
{"title":"Paradigms in HIV vaccine research","authors":"M. V. van Regenmortel","doi":"10.37349/ei.2022.00043","DOIUrl":"https://doi.org/10.37349/ei.2022.00043","url":null,"abstract":"Although a large number of preventative human immunodeficiency virus (HIV) vaccine trials have been carried out during the last 30 years, it is remarkable that an effective HIV vaccine has not yet been developed. Research paradigms correspond to theoretical assumptions and particular strategies that scientists use when they try to solve a particular problem. Many paradigms used successfully in vaccinology were ineffective with HIV. For instance: 1) The structure-based reverse vaccinology approach failed because investigators tried to generate a vaccine starting with the antigenic structure of HIV-envelope (Env) epitopes bound to neutralizing monoclonal antibodies (mAbs) derived from HIV-infected individuals. They assumed that this antigenic structure would also possess the immunogenic capacity of inducing in vaccinees a polyclonal antibody (Ab) response with the same neutralizing capacity as the mAb. 2) The structures observed in epitope-paratope crystallographic complexes result from mutually induced fit between the two partners and do not correspond to the structures present in the free molecules before they had interacted. 3) The affinity-matured neutralizing mAbs obtained from chronically infected individuals did not recognize the germline predecessors of these Abs present in vaccinees. 4) The HIV p17 matrix protein that lines the inner surface of the viral membrane is one of the most disordered proteins identified on our planet and this prevents the induced Abs from binding to the glycosylated HIV gp120 protein. 5) Vaccinologists need to solve so-called inverse problems, for instance, guessing what are the multiple causes that produced an earlier wanted beneficial effect such as the absence of deleterious HIV infection in elite controllers. Since the immune system consists of numerous subsystems that have not yet been elucidated, it is impossible to solve the inverse problems posed by each subsystem. 6) Vaccinology is an empirical science that only sometimes succeeds because we do not understand the complex mechanisms that lead to protective immune responses.","PeriodicalId":93552,"journal":{"name":"Exploration of immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45768538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Allogeneic stem cell transplantation is currently the only curative approach for a variety of malignant and non-malignant diseases. In the early transplant era, the intent of this treatment was to apply an intensive myeloablative regimen to eliminate residual malignant cells followed by the hematopoietic rescue of the patients with donor hematopoietic stem cells. However, the focus has shifted over time and allogeneic transplantation is nowadays seen as a cellular therapy in which the donor-derived immune system mounts an anti-infectious and especially an anti-tumor effect in the posttransplant phase. In order to further augment the anti-tumor effect, various approaches have been developed, including the manipulation of the donor-derived immune system in vivo or the adoptive transfer of ex vivo-expanded donor-derived effector cells. Based on their lack of alloreactivity, γδ+ T cells are shifting into the spotlight of research in the context of allogeneic transplantation. Their exploitation with regard to their anti-infectious and anti-tumor properties and their in vivo and ex vivo manipulation will lead to new therapeutic approaches to improve the outcome of patients after allogeneic stem cell transplantation. In this review, the important role of γδ+ T cells in allogeneic matched and mismatched transplantation is summarized and an outlook is discussed on how to best make use of this unique cell population.
{"title":"The role of γδ T cells in the context of allogeneic stem cell transplantation","authors":"R. Handgretinger, P. Lang, M. Queudeville","doi":"10.37349/ei.2022.00041","DOIUrl":"https://doi.org/10.37349/ei.2022.00041","url":null,"abstract":"Allogeneic stem cell transplantation is currently the only curative approach for a variety of malignant and non-malignant diseases. In the early transplant era, the intent of this treatment was to apply an intensive myeloablative regimen to eliminate residual malignant cells followed by the hematopoietic rescue of the patients with donor hematopoietic stem cells. However, the focus has shifted over time and allogeneic transplantation is nowadays seen as a cellular therapy in which the donor-derived immune system mounts an anti-infectious and especially an anti-tumor effect in the posttransplant phase. In order to further augment the anti-tumor effect, various approaches have been developed, including the manipulation of the donor-derived immune system in vivo or the adoptive transfer of ex vivo-expanded donor-derived effector cells. Based on their lack of alloreactivity, γδ+ T cells are shifting into the spotlight of research in the context of allogeneic transplantation. Their exploitation with regard to their anti-infectious and anti-tumor properties and their in vivo and ex vivo manipulation will lead to new therapeutic approaches to improve the outcome of patients after allogeneic stem cell transplantation. In this review, the important role of γδ+ T cells in allogeneic matched and mismatched transplantation is summarized and an outlook is discussed on how to best make use of this unique cell population.","PeriodicalId":93552,"journal":{"name":"Exploration of immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47821172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Avidity of immunoglobulin G (IgG) is defined as its binding strength to its target antigen. As a consequence of affinity maturation of the IgG response, avidity is maturing as well. Therefore, acute infections are characterized by low-avidity IgG, whereas past infections are usually associated with high-avidity IgG. Avidity maturation is also observed as a consequence of optimal vaccination. Avidity has been shown to play a significant role in protective humoral immunity in many microbial systems. After severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the situation is different compared to other viral infections, as the moderate degree of avidity reached in most cases of infection is similar to that reached after only one vaccination step. In contrast, two vaccination steps lead to a much higher avidity of IgG directed towards viral spike protein S1 (S1) in the majority of vaccinated individuals. Therefore, it seems that two vaccination steps allow for a more extended affinity/avidity maturation than natural infection. The degree of avidity maturation after two vaccination steps is heterogeneous. It can be further enhanced by a third vaccination step. Complete avidity maturation seems to depend on sustained availability of antigen during the maturation process. Variants of concern seem to increase the affinity of their receptor-binding domain (RBD) to angiotensin-converting enzyme-2 (ACE2) and/or to decrease the susceptibility for neutralizing antibodies. Classical neutralization tests do not necessarily reflect the avidity of neutralizing IgG, as they operationally dissect the binding reaction between S1 and IgG from the binding of the S1 to ACE2. This approach fades out critical competition reactions between IgG and ACE for RBD of the S1. Quantitative avidity determination might be an essential tool to define individuals that only possess suboptimal protective immunity after vaccination and therefore might benefit from an additional booster immunization.
{"title":"High avidity of vaccine-induced immunoglobulin G against SARS-CoV-2: potential relevance for protective humoral immunity","authors":"G. Bauer","doi":"10.37349/ei.2022.00040","DOIUrl":"https://doi.org/10.37349/ei.2022.00040","url":null,"abstract":"Avidity of immunoglobulin G (IgG) is defined as its binding strength to its target antigen. As a consequence of affinity maturation of the IgG response, avidity is maturing as well. Therefore, acute infections are characterized by low-avidity IgG, whereas past infections are usually associated with high-avidity IgG. Avidity maturation is also observed as a consequence of optimal vaccination. Avidity has been shown to play a significant role in protective humoral immunity in many microbial systems. After severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the situation is different compared to other viral infections, as the moderate degree of avidity reached in most cases of infection is similar to that reached after only one vaccination step. In contrast, two vaccination steps lead to a much higher avidity of IgG directed towards viral spike protein S1 (S1) in the majority of vaccinated individuals. Therefore, it seems that two vaccination steps allow for a more extended affinity/avidity maturation than natural infection. The degree of avidity maturation after two vaccination steps is heterogeneous. It can be further enhanced by a third vaccination step. Complete avidity maturation seems to depend on sustained availability of antigen during the maturation process. Variants of concern seem to increase the affinity of their receptor-binding domain (RBD) to angiotensin-converting enzyme-2 (ACE2) and/or to decrease the susceptibility for neutralizing antibodies. Classical neutralization tests do not necessarily reflect the avidity of neutralizing IgG, as they operationally dissect the binding reaction between S1 and IgG from the binding of the S1 to ACE2. This approach fades out critical competition reactions between IgG and ACE for RBD of the S1. Quantitative avidity determination might be an essential tool to define individuals that only possess suboptimal protective immunity after vaccination and therefore might benefit from an additional booster immunization.","PeriodicalId":93552,"journal":{"name":"Exploration of immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42487738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antitumor immunity relies on the ability of T cells to recognize and kill tumor targets. γδ T cells are a specialized subset of T cells that predominantly localizes to non-lymphoid tissue such as the skin, gut, and lung where they are actively involved in tumor immunosurveillance. γδ T cells respond to self-stress ligands that are increased on many tumor cells, and these interactions provide costimulatory signals that promote their activation and cytotoxicity. This review will cover costimulatory molecules that are known to be critical for the function of γδ T cells with a specific focus on mouse dendritic epidermal T cells (DETC). DETC are a prototypic tissue-resident γδ T cell population with known roles in antitumor immunity and are therefore useful for identifying mechanisms that may control activation of other γδ T cell subsets within non-lymphoid tissues. This review concludes with a brief discussion on how γδ T cell costimulatory molecules can be targeted for improved cancer immunotherapy.
{"title":"γδ T cell costimulatory ligands in antitumor immunity","authors":"J. M. McGraw, D. Witherden","doi":"10.37349/ei.2022.00038","DOIUrl":"https://doi.org/10.37349/ei.2022.00038","url":null,"abstract":"Antitumor immunity relies on the ability of T cells to recognize and kill tumor targets. γδ T cells are a specialized subset of T cells that predominantly localizes to non-lymphoid tissue such as the skin, gut, and lung where they are actively involved in tumor immunosurveillance. γδ T cells respond to self-stress ligands that are increased on many tumor cells, and these interactions provide costimulatory signals that promote their activation and cytotoxicity. This review will cover costimulatory molecules that are known to be critical for the function of γδ T cells with a specific focus on mouse dendritic epidermal T cells (DETC). DETC are a prototypic tissue-resident γδ T cell population with known roles in antitumor immunity and are therefore useful for identifying mechanisms that may control activation of other γδ T cell subsets within non-lymphoid tissues. This review concludes with a brief discussion on how γδ T cell costimulatory molecules can be targeted for improved cancer immunotherapy.","PeriodicalId":93552,"journal":{"name":"Exploration of immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47111872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yue-Zhong Wang, Yi Xu, Hui Chen, Jianmin Zhang, Wei He
γδ T cells express unique T cell receptor (TCR) γ and TCR δ chains, with structural and functional heterogeneity. Taking advantage of the diverse γδ TCR repertoire or other ligand-receptor interactions, γδ T cells can recognize a broad spectrum of tumor-associated antigens (TAAs) in a major histocompatibility complex (MHC)-independent manner, thereby activating downstream pleiotropic effects. γδ T cells recruited into the tumor microenvironment can act as effector cells to mediate cancer immune surveillance. Their advantage lies in the ability to perceive tumors with a low mutation load, thus establishing the first line of defense against pathogens. Activated γδ T cells exhibit strong cytotoxic activity and cytokine secretion functions and are effective antitumor lymphocytes with simple and direct recognition modes and rapid responses. However, the clinical application of tumor-infiltrating γδ T cells has certain limitations. First, γδ T cells exposed to complicated cytokine networks are potentially affected by multiple inhibitory mechanisms. Additionally, these cells show highly flexible and dynamic plasticity and are extremely easily polarized into regulatory phenotypes. This review further emphasizes the diversified cross-talk between γδ T cells and other immune cells. Effective immunity of the body is often manifested by counterbalance under mutual restriction. Therefore, an in-depth understanding of γδ T cells that play conflicting roles in the tumor microenvironment is necessary. These cells may be a key factor ultimately mediating the deviation of the antagonistic response between tumor inhibition and tumor promotion. Finally, it retrospectively analyze the activation strategies and clinical relevance of existing γδ T cell adoptive immunotherapies. According to current challenges, there is a need to explore innovative immunotherapies, maximize the tumor-killing efficacy of γδ T cells, and attenuate or eliminate tumor immunosuppression. It is hoped that the host immune status can be accurately predicted and gradually advance γδ T cell precise individualized medicine.
{"title":"Novel insights based on the plasticity of γδ T cells in the tumor microenvironment","authors":"Yue-Zhong Wang, Yi Xu, Hui Chen, Jianmin Zhang, Wei He","doi":"10.37349/ei.2022.00039","DOIUrl":"https://doi.org/10.37349/ei.2022.00039","url":null,"abstract":"γδ T cells express unique T cell receptor (TCR) γ and TCR δ chains, with structural and functional heterogeneity. Taking advantage of the diverse γδ TCR repertoire or other ligand-receptor interactions, γδ T cells can recognize a broad spectrum of tumor-associated antigens (TAAs) in a major histocompatibility complex (MHC)-independent manner, thereby activating downstream pleiotropic effects. γδ T cells recruited into the tumor microenvironment can act as effector cells to mediate cancer immune surveillance. Their advantage lies in the ability to perceive tumors with a low mutation load, thus establishing the first line of defense against pathogens. Activated γδ T cells exhibit strong cytotoxic activity and cytokine secretion functions and are effective antitumor lymphocytes with simple and direct recognition modes and rapid responses. However, the clinical application of tumor-infiltrating γδ T cells has certain limitations. First, γδ T cells exposed to complicated cytokine networks are potentially affected by multiple inhibitory mechanisms. Additionally, these cells show highly flexible and dynamic plasticity and are extremely easily polarized into regulatory phenotypes. This review further emphasizes the diversified cross-talk between γδ T cells and other immune cells. Effective immunity of the body is often manifested by counterbalance under mutual restriction. Therefore, an in-depth understanding of γδ T cells that play conflicting roles in the tumor microenvironment is necessary. These cells may be a key factor ultimately mediating the deviation of the antagonistic response between tumor inhibition and tumor promotion. Finally, it retrospectively analyze the activation strategies and clinical relevance of existing γδ T cell adoptive immunotherapies. According to current challenges, there is a need to explore innovative immunotherapies, maximize the tumor-killing efficacy of γδ T cells, and attenuate or eliminate tumor immunosuppression. It is hoped that the host immune status can be accurately predicted and gradually advance γδ T cell precise individualized medicine.","PeriodicalId":93552,"journal":{"name":"Exploration of immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41735035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In recent years, immunologists have been working to utilize the functional mechanism of the immune system to research new tumor treatment methods and achieved a major breakthrough in 2013, which was listed as one of the top 10 scientific breakthroughs of 2013 by Science magazine (see “Cancer immunotherapy”. Science. 2013;342:1417. doi: 10.1126/science.1249481). Currently, two main methods are used in clinical tumor immunotherapy: immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Clinical responses to checkpoint inhibitors rely on blockade of the target neoantigens expressed on the surfaces of tumor cells, which can inhibit T cell activity and prevent the T cell immune response; therefore, the therapeutic effect is limited by the tumor antigen expression level. While CAR-T cell therapy can partly enhance neoantigen recognition of T cells, problems remain in the current treatment for solid tumors, such as restricted transport of adoptively transferred cells to the tumor site and off-targets. Immunologists have therefore turned their attention to γδ T cells, which are not restricted by the major histocompatibility complex (MHC) for neoantigen recognition and are able to initiate a rapid immune response at an early stage. However, due to the lack of an understanding of the antigens that γδ T cells recognize, the role of γδ T cells in tumorigenesis and tumor development is not clearly understood. In the past few years, extensive data identifying antigen ligands recognized by γδ T cells have been obtained, mainly focusing on bisphosphonates and small-molecule polypeptides, but few studies have focused on protein ligands recognized by γδ T cells. In this paper, it is reviewed and analyzed that the tumor-associated protein ligands of γδ T cells that have been discovered thus far, hoping to provide new ideas for the comprehensive application of γδ T cells in tumor immunotherapy.
{"title":"Tumor-associated protein ligands recognized by human γδ T cell receptor and their implications in cancer therapy","authors":"Chang Liu, Yi Xu, Jianmin Zhang, Wei He","doi":"10.37349/ei.2022.00037","DOIUrl":"https://doi.org/10.37349/ei.2022.00037","url":null,"abstract":"In recent years, immunologists have been working to utilize the functional mechanism of the immune system to research new tumor treatment methods and achieved a major breakthrough in 2013, which was listed as one of the top 10 scientific breakthroughs of 2013 by Science magazine (see “Cancer immunotherapy”. Science. 2013;342:1417. doi: 10.1126/science.1249481). Currently, two main methods are used in clinical tumor immunotherapy: immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Clinical responses to checkpoint inhibitors rely on blockade of the target neoantigens expressed on the surfaces of tumor cells, which can inhibit T cell activity and prevent the T cell immune response; therefore, the therapeutic effect is limited by the tumor antigen expression level. While CAR-T cell therapy can partly enhance neoantigen recognition of T cells, problems remain in the current treatment for solid tumors, such as restricted transport of adoptively transferred cells to the tumor site and off-targets. Immunologists have therefore turned their attention to γδ T cells, which are not restricted by the major histocompatibility complex (MHC) for neoantigen recognition and are able to initiate a rapid immune response at an early stage. However, due to the lack of an understanding of the antigens that γδ T cells recognize, the role of γδ T cells in tumorigenesis and tumor development is not clearly understood. In the past few years, extensive data identifying antigen ligands recognized by γδ T cells have been obtained, mainly focusing on bisphosphonates and small-molecule polypeptides, but few studies have focused on protein ligands recognized by γδ T cells. In this paper, it is reviewed and analyzed that the tumor-associated protein ligands of γδ T cells that have been discovered thus far, hoping to provide new ideas for the comprehensive application of γδ T cells in tumor immunotherapy.","PeriodicalId":93552,"journal":{"name":"Exploration of immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41249709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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