Recent Advances in Immunological Landscape and Immunotherapeutic Agent of Nipah Virus Infection.

Over the last two decades, the Nipah virus (NiV) emerged as a highly lethal zoonotic pathogen to humans. Outbreaks occurred occasionally in South and Southeast Asia. Therefore, a safe and effective vaccine against the virus is needed to fight against the deadly virus. Understanding the immunological landscape during this lethal virus infection is necessary in this direction. However, we found scattered information on the immunological landscape of the virus's reservoir, as well as hosts such as humans and livestock. The review provides a recent understanding of the immunological landscape of the virus's reservoir, human hosts, monoclonal antibodies, and vaccines for NiV infection. To describe the immunological landscape, we divided our review article into some points. Firstly, we illustrated bats' immune response as a reservoir during the NiV infection. Secondly, we illustrated an overview of the molecular mechanisms underlying the immune response to the NiV infection, various immune cells, humans' innate immune response, adaptive immunity, and the landscape of cytokines and chemokines. We also discussed INF escape, NET evasion, the T cell landscape, and the B cell landscape during virus infection. Thirdly, we also demonstrated the potential monoclonal antibody therapeutics, and vaccines. Finally, neutralizing antibodies (nAbs) of NiV and potentially other therapeutic strategies were discussed. The review will help researchers for better understanding the immunological landscape, mAbs, and vaccines, enabling them to develop their next-generation versions.

Radiologic Abnormalities in Prolonged SARS-CoV-2 Infection: A Systematic Review.

We systematically reviewed radiological abnormalities in patients with prolonged SARS-CoV-2 infection, defined as persistently positive polymerase chain reaction (PCR) results for SARS-CoV-2 for > 21 days, with either persistent or relapsed symptoms. We extracted data from 24 patients (median age, 54.5 [interquartile range, 44-64 years]) reported in the literature and analyzed their representative CT images based on the timing of the CT scan relative to the initial PCR positivity. Our analysis focused on the patterns and distribution of CT findings, severity scores of lung involvement on a scale of 0-4, and the presence of migration. All patients were immunocompromised, including 62.5% (15/24) with underlying lymphoma and 83.3% (20/24) who had received anti-CD20 therapy within one year. Median duration of infection was 90 days. Most patients exhibited typical CT appearance of coronavirus disease 19 (COVID-19), including ground-glass opacities with or without consolidation, throughout the follow-up period. Notably, CT severity scores were significantly lower during ≤ 21 days than during > 21 days (P < 0.001). Migration was observed on CT in 22.7% (5/22) of patients at ≤ 21 days and in 68.2% (15/22) to 87.5% (14/16) of patients at > 21 days, with rare instances of parenchymal bands in previously affected areas. Prolonged SARS-CoV-2 infection usually presents as migrating typical COVID-19 pneumonia in immunocompromised patients, especially those with impaired B-cell immunity.

B cell responses to SARS-CoV-2.

This chapter provides an overview of B cell responses in COVID-19, highlighting the structure of SARS-CoV-2 and its impact on B cell immunity. It explores the production and maturation of SARS-CoV-2-specific B cells, with a focus on the two distinct phases of the humoral immune response: the extrafollicular (EF) phase and the germinal center (GC) phase. Furthermore, the interplay between B cells, follicular T helper cells, CD4+ T cells, and plasma cells is discussed, emphasizing their collaborative role in mounting an effective humoral immune response against SARS-CoV-2. The concept of immunological memory is explored, highlighting the roles of plasma cells and B memory cells in providing long-term protection. The chapter delves into the antibody response during SARS-CoV-2 infection, categorizing the types of antibodies generated. This includes a detailed analysis of neutralizing antibodies, such as those directed against the receptor-binding domain (RBD) and the N-terminal domain (NTD), as well as non-neutralizing antibodies. The role of mucosal antibodies, cross-reactive antibodies, and auto-reactive antibodies is also discussed. Factors influencing the dynamics of anti-SARS-CoV-2 antibodies are examined, including the duration and strength of the humoral response. Additionally, the chapter highlights the impact of the Omicron variant on humoral immune responses and its implications for vaccine efficacy and antibody-mediated protection.

Antibody and B-cell Immune Responses Against Bordetella Pertussis Following Infection and Immunization.

Neither immunization nor recovery from natural infection provides life-long protection against Bordetella pertussis. Replacement of a whole-cell pertussis (wP) vaccine with an acellular pertussis (aP) vaccine, mutations in B. pertussis strains, and better diagnostic techniques, contribute to resurgence of number of cases especially in young infants. Development of new immunization strategies relies on a comprehensive understanding of immune system responses to infection and immunization and how triggering these immune components would ensure protective immunity. In this review, we assess how B cells, and their secretory products, antibodies, respond to B. pertussis infection, current and novel vaccines and highlight similarities and differences in these responses. We first focus on antibody-mediated immunity. We discuss antibody (sub)classes, elaborate on antibody avidity, ability to neutralize pertussis toxin, and summarize different effector functions, i.e. ability to activate complement, promote phagocytosis and activate NK cells. We then discuss challenges and opportunities in studying B-cell immunity. We highlight shared and unique aspects of B-cell and plasma cell responses to infection and immunization, and discuss how responses to novel immunization strategies better resemble those triggered by a natural infection (i.e., by triggering responses in mucosa and production of IgA). With this comprehensive review, we aim to shed some new light on the role of B cells and antibodies in the pertussis immunity to guide new vaccine development.

Permafrost viremia and immune tweening.

The immune system, an exquisitely regulated physiological system, utilizes a wide spectrum of soluble factors and multiple cell populations and subpopulations at diverse states of maturation to monitor and protect the organism against foreign organisms. Immune surveillance is ensured by distinguishing self-antigens from self-associated with non-self (e.g., viral) peptides presented by major histocompatibility complexes (MHC). Pathology is often identified as unregulated inflammatory responses (e.g., cytokine storm), or recognizing self as a non-self entity (i.e., auto-immunity). Artificial intelligence (AI), and in particular specific machine learning (ML) paradigms (e.g., Deep Learning [DL]) proffer powerful algorithms to better understand and more accurately predict immune responses, immune regulation and homeostasis, and immune reactivity to challenges (i.e., immune allostasis) by their intrinsic ability to interpret immune parameters, pathways and events by analyzing large amounts of complex data and drawing predictive inferences (i.e., immune tweening). We propose here that DL models play an increasingly significant role in better defining and characterizing immunological surveillance to ancient and novel virus species released by thawing permafrost.

Hybrid and SARS-CoV-2-vaccine immunity in kidney transplant recipients.

BACKGROUND: Kidney transplant recipients (KTR) are at high risk for severe COVID-19 and have demonstrated poor response to vaccination, making it unclear whether successive vaccinations offer immunity and protection. METHODS: We conducted a serologically guided interventional study where KTR patients that failed to seroconvert were revaccinated and also monitored seroconversion of KTR following the Norwegian vaccination program. We analysed IgG anti-RBD Spike responses from dose 2 (n = 432) up to after the 6th (n = 37) mRNA vaccine dose. The frequency and phenotype of Spike-specific T and B cell responses were assessed in the interventional cohort after 3-4 vaccine doses (n = 30). Additionally, we evaluated the Specific T and B cell response to breakthrough infection (n = 32), measured inflammatory cytokines and broadly cross-neutralizing antibodies, and defined the incidence of COVID-19-related hospitalizations and deaths. The Norwegian KTR cohort has a male dominance (2323 males, 1297 females), PBMC were collected from 114 male and 78 female donors. FINDINGS: After vaccine dose 3, most KTR developed Spike-specific T cell responses but had significantly reduced Spike-binding B cells and few memory cells. The B cell response included a cross-reactive subset that could bind Omicron VOC, which expanded after breakthrough infection (BTI) and gave rise to a memory IgG+ B cell response. After BTI, KTR had increased Spike-specific T cells, emergent non-Spike T and B cell responses, and a systemic inflammatory signature. Late seroconversion occurred after doses 5-6, but 38% (14/37) of KTR had no detectable immunity even after multiple vaccine doses. INTERPRETATION: Boosting vaccination can induce Spike-specific immunity that may expand in breakthrough infections highlighting the benefit of vaccination to protect this vulnerable population. FUNDING: CEPI and internal funds.

B cell-intrinsic TLR7 signaling is required for neutralizing antibody responses to SARS-CoV-2 and pathogen-like COVID-19 vaccines.

Toll-like receptor 7 (TLR7) triggers antiviral immune responses through its capacity to recognize single-stranded RNA. TLR7 loss-of-function mutants are associated with life-threatening pneumonia in severe COVID-19 patients. Whereas TLR7-driven innate induction of type I IFN appears central to control SARS-CoV2 virus spreading during the first days of infection, the impact of TLR7-deficiency on adaptive B-cell immunity is less clear. In the present study, we examined the role of TLR7 in the adaptive B cells response to various pathogen-like antigens (PLAs). We used inactivated SARS-CoV2 and a PLA-based COVID-19 vaccine candidate designed to mimic SARS-CoV2 with encapsulated bacterial ssRNA as TLR7 ligands and conjugated with the RBD of the SARS-CoV2 Spike protein. Upon repeated immunization with inactivated SARS-CoV2 or PLA COVID-19 vaccine, we show that Tlr7-deficiency abolished the germinal center (GC)-dependent production of RBD-specific class-switched IgG2b and IgG2c, and neutralizing antibodies to SARS-CoV2. We also provide evidence for a non-redundant role for B-cell-intrinsic TLR7 in the promotion of RBD-specific IgG2b/IgG2c and memory B cells. Together, these data demonstrate that the GC reaction and class-switch recombination to the Myd88-dependent IgG2b/IgG2c in response to SARS-CoV2 or PLAs is strictly dependent on cell-intrinsic activation of TLR7 in B cells.

A third SARS-CoV-2 mRNA vaccine dose in people receiving hemodialysis overcomes B cell defects but elicits a skewed CD4+ T cell profile.

Cellular immune defects associated with suboptimal responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination in people receiving hemodialysis (HD) are poorly understood. We longitudinally analyze antibody, B cell, CD4+, and CD8+ T cell vaccine responses in 27 HD patients and 26 low-risk control individuals (CIs). The first two doses elicit weaker B cell and CD8+ T cell responses in HD than in CI, while CD4+ T cell responses are quantitatively similar. In HD, a third dose robustly boosts B cell responses, leads to convergent CD8+ T cell responses, and enhances comparatively more T helper (TH) immunity. Unsupervised clustering of single-cell features reveals phenotypic and functional shifts over time and between cohorts. The third dose attenuates some features of TH cells in HD (tumor necrosis factor alpha [TNFα]/interleukin [IL]-2 skewing), while others (CCR6, CXCR6, programmed cell death protein 1 [PD-1], and HLA-DR overexpression) persist. Therefore, a third vaccine dose is critical to achieving robust multifaceted immunity in hemodialysis patients, although some distinct TH characteristics endure.

Immunological Findings in a Group of Individuals Who Were Poor or Non-Responders to Standard Two-Dose SARS-CoV-2 Vaccines.

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a pandemic. However, data on the poor or non-responders to SARS-CoV-2 vaccines in the general population are limited. The objective of this study was to comprehensively compare the immunological characteristics of poor or non-responders to SARS-CoV-2 vaccines in the 18-59-year group with those in the ≥60-year group using internationally recognized cut-off values. The main outcome was effective seroconversion characterized by an anti-SARS-CoV-2 spike IgG level of at least a four-fold increase from baseline. Profiling of naïve immune cells was analyzed prior to vaccination to demonstrate baseline immunity. The outcomes of effective seroconversion in patients aged 18-59 years with those in patients aged ≥60 years were compared. The quantitative level of anti-spike IgG was significantly lower in individuals aged ≥60 and men aged 18-59 years. There were 7.5% of poor or non-responders among the 18-59 years and 11.7% of poor or non-responders in the ≥60 years using a four-fold increase parameter. There were 37.0-58.1% with low lymphocyte count (<1000/mm3), 33.3-45.2% with low CD4 cell counts (<500/mm3), and 74.1-96.8% with low B cell counts (<100/mm3) in the non-seroconversion group. An individual with an anti-SARS-CoV-2 spike IgG titer below 50 BAU/mL might be considered a poor or non-responder between 14 and 90 days after the last vaccine dose. Booster vaccination or additional protective measures should be recommended to poor or non-responders as soon as possible to reduce disease severity and mortality.

The magnitude and timing of recalled immunity after breakthrough infection is shaped by SARS-CoV-2 variants.

Vaccination against SARS-CoV-2 protects from infection and improves clinical outcomes in breakthrough infections, likely reflecting residual vaccine-elicited immunity and recall of immunological memory. Here, we define the early kinetics of spike-specific humoral and cellular immunity after vaccination of seropositive individuals and after Delta or Omicron breakthrough infection in vaccinated individuals. Early longitudinal sampling revealed the timing and magnitude of recall, with the phenotypic activation of B cells preceding an increase in neutralizing antibody titers. While vaccination of seropositive individuals resulted in robust recall of humoral and T cell immunity, recall of vaccine-elicited responses was delayed and variable in magnitude during breakthrough infections and depended on the infecting variant of concern. While the delayed kinetics of immune recall provides a potential mechanism for the lack of early control of viral replication, the recall of antibodies coincided with viral clearance and likely underpins the protective effects of vaccination against severe COVID-19.

B-cell activating factor and IL-21 levels predict treatment response in autoimmune hepatitis.

Background & Aims: Increased serum IgG and autoantibodies suggest involvement of B cells in autoimmune hepatitis (AIH). The aim of this study was to assess levels of B cell activating factor of the tumour necrosis family (BAFF), IL-21, and circulating B cell populations in AIH and correlate these to treatment response. Methods: BAFF and IL-21 levels were determined in 66 patients with AIH before treatment and 10 healthy controls. Flow cytometry was performed on circulating B cells of 10 patients with AIH and 12 healthy controls. Results: Based on BAFF and IL-21 levels, untreated patients with AIH were divided into 3 groups: 27 (41%) patients with normal BAFF and IL-21 (normal BAFF), 27 (41%) patients with elevated BAFF but normal IL-21 (high BAFF), and 12 (18%) patients with elevated IL-21 (high IL-21). The high BAFF group presented with higher bilirubin compared with the normal BAFF and high IL-21 groups (159 vs. 26 vs. 89 µmol/L; p = 0.001; Mann-Whitney U test). After 12 months of treatment, 54% of the high BAFF group reached remission compared with 34% of the normal BAFF group and 0% of the high IL-21 group (p = 0.006, Chi-square test). During follow-up, 3 patients (25%) with high IL-21 developed primary sclerosing cholangitis (PSC) variant syndrome. Autoimmune-associated B cells were increased in patients with AIH compared with healthy controls (4.4 vs. 1.4%; p = 0.003, Mann-Whitney U test). BAFF levels were correlated positively with naïve B cells (p = 0.01) and negatively with class-switched B cells (p = 0.003) and nonclass-switched B cells (p = 0.005, Spearman correlation). Discussion: Using BAFF and IL-21, we identified different immunological phenotypes of AIH with a different presentation, treatment response, and outcome. Patients with high IL-21 had the poorest treatment response and a risk of developing PSC variant syndrome. BAFF level was related to shifts in circulating B-cell populations. Lay summary: In patients with untreated autoimmune hepatitis (AIH), circulating B-cell activating factor of the tumour necrosis family (BAFF), IL-21, and B-cell populations were determined. Three subgroups were identified: with (1) normal BAFF and IL-21, (2) elevated BAFF and normal IL-21, and (3) elevated IL-21. Remission after 1-year treatment occurred in 54, 34, and 0% in Groups 1, 2, and 3, respectively. Group 2 had higher bilirubin, indicating more liver dysfunction. In 25% of patients with high IL-21, AIH-PSC variant syndrome developed, but none in the other groups. Autoimmune-associated B cells were elevated and BAFF levels correlated with certain B cells.

Robust and Functional Immune Memory Up to 9 Months After SARS-CoV-2 Infection: A Southeast Asian Longitudinal Cohort.

The duration of humoral and cellular immune memory following SARS-CoV-2 infection in populations in least developed countries remains understudied but is key to overcome the current SARS-CoV-2 pandemic. Sixty-four Cambodian individuals with laboratory-confirmed infection with asymptomatic or mild/moderate clinical presentation were evaluated for Spike (S)-binding and neutralizing antibodies and antibody effector functions during acute phase of infection and at 6-9 months follow-up. Antigen-specific B cells, CD4+ and CD8+ T cells were characterized, and T cells were interrogated for functionality at late convalescence. Anti-S antibody titers decreased over time, but effector functions mediated by S-specific antibodies remained stable. S- and nucleocapsid (N)-specific B cells could be detected in late convalescence in the activated memory B cell compartment and are mostly IgG+. CD4+ and CD8+ T cell immune memory was maintained to S and membrane (M) protein. Asymptomatic infection resulted in decreased antibody-dependent cellular cytotoxicity (ADCC) and frequency of SARS-CoV-2-specific CD4+ T cells at late convalescence. Whereas anti-S antibodies correlated with S-specific B cells, there was no correlation between T cell response and humoral immune memory. Hence, all aspects of a protective immune response are maintained up to nine months after SARS-CoV-2 infection and in the absence of re-infection.

The immunopathogenesis of idiopathic nephrotic syndrome: a narrative review of the literature.

Idiopathic nephrotic syndrome (INS) is a common glomerular disease in childhood, and the immunological involvement in the pathogenesis of non-genetic INS, although not fully elucidated, is evident. This narrative review aims to offer a concise and in-depth view of the current knowledge on the immunological mechanisms of the development of INS as well as the role of the immunological components of the disease in the responsiveness to treatment. T cell immunity appears to play a major role in the INS immunopathogenesis and has been the first to be linked to the disease. Various T cell immunophenotypes are implicated in INS, including T-helper-1, T-helper-2, T-helper-17, and T regulatory cells, and various cytokines have been proposed as surrogate biomarkers of the disease; however, no distinct T helper or cytokine profile has been conclusively linked to the disease. More recently, the recognition of the role of B cell mediated immunity and the various B cell subsets that are dysregulated in patients with INS have led to new hypotheses on the underlying immunological causes of INS. Finally, the disambiguation of the exact mechanisms of the INS development in the future may be the key to the development of more targeted personalized approaches in managing INS. CONCLUSIONS: INS demonstrates particularly interesting immunopathogenetic pathways, in which multiple interactions between T cell and B cell immunity and the podocyte are involved. The disambiguation of these pathways will provide promising novel therapeutic targets in INS. WHAT IS KNOWN: • INS is the most common glomerular disease in the paediatric population, and its onset and relapses have been linked to various immunological triggers. • Multiple immunological mechanisms have been implicated in the pathogenesis of INS; however, no single distinct immunological profile has been recognized. WHAT IS NEW: • Th17 cells and Treg cells play an important role in the immune dysregulation in INS. • Transitional B cell levels as well as the transitional/memory B cell ratio have been correlated to nephrotic relapses and have been proposed as biomarkers of INS relapses in SSNS patients.

Comprehensive gene cluster analysis of head and neck squamous cell carcinoma TCGA RNA-seq data defines B cell immunity-related genes as a robust survival predictor.

BACKGROUND: The authors aimed to define novel gene expression signatures that are associated with patients' survival with head and neck squamous cell carcinoma (HNSCC). METHODS: TCGA RNA-seq data were used for gene expression clusters extraction from 499 tumor samples by the "EPIG" method. Tumor samples were then partitioned into lower and higher than median level groups for survival relevant analysis by Kaplan-Meier estimator. RESULTS: We found that two gene clusters (_1, _2) are favorably, while two (_3, _4) are unfavorably, associated with patients' survival with HNSCC. Notably, most genes on the top lists of cluster_2 are associated with B cells. A gene expression signature with combined genes from cluster_2 and _4 was further determined to be associated with HNSCC survival rate. CONCLUSION: Our work strongly supported a favorable role of B cells in patients' survival with HNSCC and identified a novel coexpressed gene signature as prognostic biomarker for patients' survival with HNSCC estimation.

Insulin Resistance Adversely Affect IVF Outcomes in Lean Women Without PCOS.

Objective: To investigate the effects of insulin resistance (IR) on IVF outcomes and a potential underlying mechanism in lean women without PCOS. Design: A prospective cohort study at the University Clinic. Setting: IVF center at the University setting. Patients: A total of 155 lean women (body mass index <25) without PCOS undergoing IVF cycle. Intervention: Patients were allocated to IR and non-IR groups based on HOMA-M120. Main Outcome Measures: IVF outcomes, including egg quality, the percentage of mature oocytes, fertilization rate, blastocyst formation rate, advanced embryo rate, and cumulative live birth rate were investigated. Auto-immune parameters, peripheral blood immunophenotypes, thyroid hormone, homocysteine, and 25-OH-vitamin D3 (25-OH-VD3) levels were analyzed. Results: The percentage of mature oocytes and blastocyst formation rate were significantly lower in the IR group as compared with those of the non-IR group (p<0.05, respectively). The proportion of peripheral blood CD19+ B cells was significantly higher in the IR group than those of the non-IR group (p<0.05). Homocysteine, 25-OH-VD3, and auto-immune parameters were the same between the two groups. Conclusion: In lean infertile women without PCOS, IR is associated with the decreased percentage of mature eggs and poor embryo quality in which B cell immunity may play a role.

Generation and Characterization of Universal Live-Attenuated Influenza Vaccine Candidates Containing Multiple M2e Epitopes.

Influenza viruses constantly evolve, reducing the overall protective effect of routine vaccination campaigns. Many different strategies are being explored to design universal influenza vaccines capable of protecting against evolutionary diverged viruses. The ectodomain of influenza A M2e protein (M2e) is among the most promising targets for universal vaccine design. Here, we generated two recombinant live attenuated influenza vaccines (LAIVs) expressing additional four M2e tandem repeats (4M2e) from the N-terminus of the viral hemagglutinin (HA) protein, in an attempt to enhance the M2e-mediated cross-protection. The recombinant H1N1+4M2e and H3N2+4M2e viruses retained growth characteristics attributable to traditional LAIV viruses and induced robust influenza-specific antibody responses in BALB/c mice, although M2e-specific antibodies were raised only after two-dose vaccination with LAIV+4M2e viruses. Mice immunized with either LAIV or LAIV+4M2e viruses were fully protected against a panel of heterologous influenza challenge viruses suggesting that antibody and cell-mediated immunity contributed to the protection. The protective role of the M2e-specific antibody was seen in passive serum transfer experiments, where enhancement in the survival rates between classical LAIV and chimeric H3N2+4M2e LAIV was demonstrated for H3N2 and H5N1 heterologous challenge viruses. Overall, the results of our study suggest that M2e-specific antibodies induced by recombinant LAIV+4M2e in addition to cellular immunity by LAIV play an important role in conferring protection against heterologous viruses.

HIF1α-Dependent Metabolic Signals Control the Differentiation of Follicular Helper T Cells.

Follicular helper T (TFH) cells are critical for germinal center (GC) formation and are responsible for effective B cell-mediated immunity; metabolic signaling is an important regulatory mechanism for the differentiation of TFH cells. However, the precise roles of hypoxia inducible factor (HIF) 1α-dependent glycolysis and oxidative phosphorylation (OXPHOS) metabolic signaling remain unclear in TFH cell differentiation. Herein, we investigated the effects of glycolysis and OXPHOS on TFH cell differentiation and GC responses using a pharmacological approach in mice under a steady immune status or an activated immune status, which can be caused by foreign antigen stimulation and viral infection. GC and TFH cell responses are related to signals from glycolytic metabolism in mice of different ages. Foreign, specific antigen-induced GC, and TFH cell responses and metabolic signals are essential upon PR8 infection. Glycolysis and succinate-mediated OXPHOS are required for the GC response and TFH cell differentiation. Furthermore, HIF1α is responsible for glycolysis- and OXPHOS-induced alterations in the GC response and TFH cell differentiation under steady or activated conditions in vivo. Blocking glycolysis and upregulating OXPHOS signaling significantly recovered TFH cell differentiation upon PR8 infection and ameliorated inflammatory damage in mice. Thus, our data provide a comprehensive experimental basis for fully understanding the precise roles of HIF1α-mediated glycolysis and OXPHOS metabolic signaling in regulating the GC response and TFH cell differentiation during stable physiological conditions or an antiviral immune response.

Vaccine-Induced Carbohydrate-Specific Memory B Cells Reactivate During Rodent Malaria Infection.

A long-standing challenge in malaria is the limited understanding of B cell immunity, previously hampered by lack of tools to phenotype rare antigen-specific cells. Our aim was to develop a method for identifying carbohydrate-specific B cells within lymphocyte populations and to determine whether a candidate vaccine generated functional memory B cells (MBCs) that reactivated upon challenge with Plasmodium (pRBCs). To this end, a new flow cytometric probe was validated and used to determine the kinetics of B cell activation against the candidate vaccine glycosylphosphatidylinositol conjugated to Keyhole Limpet Haemocyanin (GPI-KLH). Additionally, immunized C57BL/6 mice were rested (10 weeks) and challenged with pRBCs or GPI-KLH to assess memory B cell recall against foreign antigen. We found that GPI-specific B cells were detectable in GPI-KLH vaccinated mice, but not in Plasmodium-infected mice. Additionally, in previously vaccinated mice GPI-specific IgG1 MBCs were reactivated against both pRBCs and synthetic GPI-KLH, which resulted in increased serum levels of anti-GPI IgG in both challenge approaches. Collectively our findings contribute to the understanding of B cell immunity in malaria and have important clinical implications for inclusion of carbohydrate conjugates in malaria vaccines.

The PI3Kδ selective inhibitor AS2541019 suppresses donor-specific antibody production in rat cardiac and non-human primate renal allotransplant models.

Long-term graft survival after organ transplantation is difficult to achieve because of the development of chronic rejection. One cause of chronic rejection arises from antibody-mediated rejection (AMR), which is dependent on the production of donor-specific antibodies (DSA). Current immunosuppression in organ transplantation is effective in preventing acute T cell-mediated rejection, but the risk of DSA production and graft loss due to AMR remains unchanged. Phosphatidylinositol-3-kinase p110δ (PI3Kδ), a member of the family of PI3K lipid kinases, is a key mediator of B cell activation, proliferation and antibody production. AS2541019 is a novel PI3Kδ selective inhibitor that prevents antibody production by inhibiting B cell immunity. The purpose of this study was to evaluate the inhibitory effect of AS2541019 on DSA production in preclinical rodent and non-human primate allotransplant models. Concomitant administration of AS2541019 with tacrolimus and mycophenolate mofetil (MMF) inhibited de novo DSA production in an ACI-to-Lewis rat cardiac allotransplant model. To predict the efficacy of AS2541019 in clinical practice, we evaluated its effects in cynomolgus monkeys. AS2541019 inhibited B cell proliferation and major histocompatibility complex (MHC) class II expression on B cells in cynomolgus monkeys. Oral administration of AS2541019 inhibited MHC class II expression on peripheral B cells and anti-tetanus toxoid antibody production. In cynomolgus monkey renal allotransplant model, concomitant administration of AS2541019 with tacrolimus and MMF significantly inhibited de novo DSA production. Together, our findings indicate that the PI3Kδ selective inhibitor AS2541019 is a potential candidate for preventing AMR development by inhibiting DSA production.