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The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay ( P  = 0.0198) and less time required for symptoms remission ( P  = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 ( P  = 0.0099) and day 21 ( P  = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2 + hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors — CX3CR1 and L-selectin — were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.

Purpose A subset of patients with common variable immunodeficiency (CVID) develops granulomatous and lymphocytic interstitial lung disease (GLILD), a restrictive lung disease associated with early mortality. The optimal therapy for GLILD is unknown. This study was undertaken to see if rituximab and azathioprine (combination chemotherapy) would improve pulmonary function and/or radiographic abnormalities in patients with CVID and GLILD. Methods A retrospective chart review of patients with CVID and GLILD who were treated with combination chemotherapy was performed. Complete pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) scans of the chest were done prior to therapy and >6 months later. HRCT scans of the chest were blinded, randomized, and scored independently (in pairs) by two radiologists. The differences between pre- and post-treatment HRCT scores and PFT parameters were analyzed. Results Seven patients with CVID and GLILD met inclusion criteria. Post-treatment increases were noted in both FEV1 ( p  = 0.034) and FVC ( p  = 0.043). HRCT scans of the chest demonstrated improvement in total score ( p  = 0.018), pulmonary consolidations ( p  = 0.041), ground-glass opacities ( p  = 0.020) nodular opacities ( p  = 0.024), and both the presence and extent of bronchial wall thickening ( p  = 0.014, 0.026 respectively). No significant chemotherapy-related complications occurred. Conclusions Combination chemotherapy improved pulmonary function and decreased radiographic abnormalities in patients with CVID and GLILD.

•Underweight children had decreased antibody response after pneumococcal vaccination.•Specific B-cell subsets were associated with pneumococcal antibody decay.•B-cells, metabolic hormones and nutritional status correlated with vaccine response. We explored the role of metabolic hormones and the B-cell repertoire in the association between nutritional status and vaccine responses. In this prospective cohort study, nested within a larger randomized open-label trial, 211 South African children received two doses of measles vaccine and two or three doses of pneumococcal conjugate vaccine (PCV). Metabolic markers (leptin, ghrelin and adiponectin) and distribution of B-cell subsets (n = 106) were assessed at 18 months of age. Children with a weight-for-height z-score (WHZ) ≤ −1 standard deviation (SD) at booster vaccination had a decreased mean serotype-specific PCV IgG response compared with those with WHZ > −1 and <+1 SD or WHZ ≥ +1 SD at 9 months post-booster (18 months of age). (Naive) pre-germinal center B-cells were associated with pneumococcal antibody decay between one to nine months post-booster. Predictive performance of elastic net models for the combined effect of B-cell subsets, metabolic hormones and nutritional status (in addition to age, sex, and randomization group) on measles and PCV vaccine response had an average area under the receiver operating curve of 0.9 and 0.7, respectively. The combined effect of B-cell subsets, metabolic hormones and nutritional status correlated well with the vaccination response for measles and most PCV serotypes. ClinicalTrials.gov registration of parent studies: NCT02943902 and NCT03330171.

Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). Low environmental exposure to UV radiation is implicated in risk of developing MS, and therefore, narrowband UVB phototherapy might delay progression to MS in people with CIS. Twenty individuals with CIS were recruited, and half were randomised to receive 24 sessions of narrowband UVB phototherapy over a period of 8 weeks. Here, the effects of narrowband UVB phototherapy on the frequencies of circulating immune cells and immunoglobulin levels after phototherapy are reported. Peripheral blood samples for all participants were collected at baseline, and 1, 2, 3, 6 and 12 months after enrolment. An extensive panel of leukocyte populations, including subsets of T cells, B cells, monocytes, dendritic cells, and natural killer cells were examined in phototherapy-treated and control participants, and immunoglobulin levels measured in serum. There were significant short-term increases in the frequency of naïve B cells, intermediate monocytes, and fraction III FoxP3+ T regulatory cells, and decreases in switched memory B cells and classical monocytes in phototherapy-treated individuals. Since B cells are increasingly targeted by MS therapies, the effects of narrowband UVB phototherapy in people with MS should be investigated further.

Abstract Background Protection induced by acellular pertussis (aP) vaccines is partial and short-lived, especially in teenagers, calling for novel immunization strategies. Methods We conducted an investigator-driven proof-of-concept randomized controlled trial in aP-primed adolescents in Geneva to assess the immunogenicity and reactogenicity of a novel recombinant aP (r-aP) vaccine including recombinant pertussis toxin (PT) and filamentous hemagglutinin (FHA) coadministered with tetanus-diphtheria toxoids (Td), compared to a licensed tetanus-diphtheria-aP vaccine containing chemically detoxified PT (cd/Tdap). The primary immunological endpoints were day 28/365 geometric mean concentrations (GMCs) of total and neutralizing anti-PT antibodies. Memory B cells were assessed. Results Sixty-two aP-primed adolescents were randomized and vaccinated with r-aP + Td or cd/Tdap. Reactogenicity, adverse events, and baseline GMCs were similar between the groups. Day 28 PT-neutralizing GMCs were low after cd/Tdap (73.91 [95% confidence interval {CI}, 49.88–109.52] IU/mL) and approximately 2-fold higher after r-aP + Td (127.68 [95% CI, 96.73–168.53] IU/mL; P = .0162). Anti-PT GMCs were also low after cd/Tdap (52.43 [95% CI, 36.41–75.50] IU/mL) and 2-fold higher after r-aP + Td (113.74 [95% CI, 88.31–146.50] IU/mL; P = .0006). Day 28 anti-FHA GMCs were similar in both groups. Day 365 anti-PT (but not PT-neutralizing) GMCs remained higher in r-aP + Td vaccinees. PT-specific memory B cells increased significantly after r-aP + Td but not cd/Tdap boosting. Conclusions Boosting aP-primed adolescents with r-aP induced higher anti-PT and PT-neutralizing responses than cd/Tdap and increased PT-specific memory B cells. Despite this superior immunogenicity, r-aP may have to be given repeatedly, earlier, and/or with novel adjuvants to exert an optimal influence in aP-primed subjects. Clinical Trials Registration NCT02946190. We compared recombinant vs chemically detoxified pertussis toxin (PT)–containing vaccines in adolescents primed with 5 doses of acellular pertussis vaccines. Recombinant PT was safe and significantly more immunogenic, and reactivated more memory B cells than the comparator licensed vaccine.

•The immunogenicity of a novel live attenuated pertussis vaccine, BPZE1, was evaluated.•After intranasal vaccination of BPZE1 B-cell responses were tested in a phase I clinical trial.•Seven of 36 subjects were colonized and mounted strong B-cell responses. Despite high vaccination coverage, pertussis is still a global concern in infant morbidity and mortality, and improved pertussis vaccines are needed. A live attenuated Bordetella pertussis strain, named BPZE1, was designed as an intranasal vaccine candidate and has recently been tested in man in a phase I clinical trial. Here, we report the evaluation of the B-cell responses after vaccination with BPZE1. Forty-eight healthy males with no previous pertussis-vaccination were randomized into one of three dose-escalating groups or into a placebo group. Plasma blast- and memory B-cell responses were evaluated by ELISpot against three different pertussis antigens: pertussis toxin, filamentous haemagglutinin and pertactin. Seven out of the 36 subjects who had received the vaccine were colonized by BPZE1, and significant increases in the memory B-cell response were detected against all three tested antigens in the culture-positive subjects between days 0 and 28 post-vaccination. The culture-positive subjects also mounted a significant increase in the filamentous haemagglutinin-specific plasma blast response between days 7 and 14 post-vaccination. No response could be detected in the culture-negatives or in the placebo group post-vaccination. These data show that BPZE1 is immunogenic in humans and is therefore a promising candidate for a novel pertussis vaccine. This trial is registered at ClinicalTrials.gov (NCT01188512).

The Bacillus Calmette–Guérin vaccine (BCG) has been associated with beneficial non-specific effects (NSEs) on infant health. Within a randomized trial on the effect of neonatal BCG on overall health, we investigated the possible immunological impact of neonatal BCG vaccination on lymphocyte subsets, determined by flow cytometry. In 118 infants blood samples were obtained 4 (±2) days post randomization to BCG vaccination or no intervention, and at 3 and 13 months of age. No effects of BCG were found at 4 days. However, BCG increased proportions of effector memory cells at 3 months (Geometric mean ratio (GMR) 1.62, 95% confidence interval (CI) (1.20–2.21), p = 0.002 for CD4 + T cells and GMR 1.69, 95% CI (1.06–2.70), p = 0.03 for CD8 + T cells), and reduced proportions of late differentiated CD4 + T cells (GMR = 0.62, 95% CI (0.38–1.00), p = 0.05) and apoptotic CD4 + T cells at 13 months (GMR = 0.55, 95% CI (0.32–0.92), p = 0.03). In conclusion, limited overall impact of neonatal BCG vaccination on lymphocyte subsets was found in healthy Danish infants within the first 13 months of life. This is in line with the limited clinical effects of BCG observed in our setting.

Background. A 23-valent unconjugated pneumococcal polysaccharide vaccine (23vP), routinely administered at the age of 65, has limited effectiveness, and revaccination induces attenuated antibody responses. It is not known whether pneumococcal polysaccharide-protein conjugated vaccines (PCV), although highly effective in infants, offer any immunological advantages over 23vP in adults. Methods. We immunized adults with schedules combining both PCV and 23vP and investigated B-cell responses to establish whether PCV7 (a 7-valent PCV) induced T-dependent responses in adults, to assess the role of memory B cells in 23vP-induced antibody hyporesponsiveness, and to identify the B-cell subtypes involved. Results. A single dose of PCV7 induced significant increases in serotype-specific memory B-cell populations in peripheral blood indicating a T-dependent response. Conversely, immunization with 23vP resulted in a decrease in memory B-cell frequency. Furthermore, memory B-cell responses to subsequent immunization with PCV7, when given after 23vP, were attenuated. Notably, B1b cells, a subset important in protecting mice against pneumococci, were also depleted following immunization with 23vP in humans. Conclusions. This study indicates that PCV7 may have an immunological advantage over 23vP in adults and that 23vP-induced depletion of memory and B1b-cell subsets may provide a basis for antibody hyporesponsiveness and the limited effectiveness of 23vP. Clinical Trials Registration. ISRCTN: 78768849.

Multiple sclerosis results from T-cell-dependent inflammatory demyelination of the central nervous system. Our objective was long-term suppression of inflammation with short-term monoclonal antibody treatment. We depleted 95% of circulating lymphocytes in 27 patients with multiple sclerosis by means of a 5-day pulse of the humanised anti-CD52 monoclonal antibody, Campath-1H. Clinical and haematological consequences of T-cell depletion, and in-vitro responses of patients' peripheral-blood mononuclear cells were analysed serially for 18 months after treatment. Radiological and clinical markers of disease activity were significantly decreased for at least 18 months after treatment. However, a third of patients developed antibodies against the thyrotropin receptor and carbimazole-responsive autoimmune hyperthyroidism. The depleted peripheral lymphocyte pool was reconstituted with cells that had decreased mitogen-induced proliferation and interferon gamma secretion in vitro. Campath-1H causes the immune response to change from the Th1 phenotype, suppressing multiple sclerosis disease activity, but permitting the generation of antibody-mediated thyroid autoimmunity.

The ultimate goal of pegylated interferon-alfa-2a (Peg-IFN-α) therapy in chronic hepatitis B (CHB) infection is HBsAg seroconversion. Even though B cells are major mediators of a positive clinical outcome, their modulation during Peg-IFN-α therapy has not yet been described. We investigated here the effects of Peg-IFN-α on eight circulating B-cell subsets thanks to an original multi-gating approach based on CD19, CD27, IgD, CD10, and CD38 markers in patients with CHB treated with nucleos(t)ide analog alone or in combination with Peg-IFN-α. These dynamic changes were analyzed during the 48-weeks of Peg-IFN-α therapy and up to 2 years after the cessation of treatment. The CD19+CD27-IgD+CD10+CD38high transitional B cells and the CD19+CD27+IgD-CD10-CD38high plasmablasts continuously increased, whereas the CD19+CD27-IgD+CD10-CD38low naive, CD19+CD27+IgD+ natural memory, and CD19+CD27+IgD-CD10-CD38low post-germinal center B cells decreased during the course of Peg-IFNα treatment. Such modulations correlated with a sustained increase in sCD30 levels and the decrease in plasma HBsAg. However, no seroconversion occurred and all parameters returned to baseline after the stop of the treatment. Peg-IFN-α therapy mediates a remodeling of B-cell compartmentalization, without clinical relevance. Our study provides new insights into the immunomodulatory effects of Peg-IFN-α on circulating B-cells, and questioned the benefit of the add-on Peg-IFN-α treatment in CHB.