Allogeneic B cell immunomodulatory therapy in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease. Immune system dysregulation plays an essential role in ALS onset and progression. Our preclinical studies have shown that the administration of exogenous allogeneic B cells improves outcomes in murine models of skin and brain injury through a process termed pligodraxis, in which B cells adopt an immunoregulatory and neuroprotective phenotype in an injured environment. Here, we investigated the effects of B-cell therapy in the SOD1G93A mouse preclinical model of ALS and in a person living with ALS. Purified splenic mature naïve B cells from haploidentical donor mice were administered intravenously in SOD1G93A mice for a total of 10 weekly doses. For the clinical study in a person with advanced ALS, IgA gammopathy of unclear significance, and B lymphopenia, CD19+ B cells were positively selected from a healthy haploidentical donor and infused intravenously twice, at a 60-day interval. Repeated intravenous B-cell administration was safe and significantly delayed disease onset, extended survival, reduced cellular apoptosis, and decreased astrogliosis in SOD1G93A mice. Repeated B-cell infusion in a person with ALS was safe and did not appear to generate a clinically evident inflammatory response. An improvement of 5 points on the ALSFRS-R scale was observed after the first infusion. Levels of inflammatory markers showed persistent reduction post-infusion. This represents a first demonstration of the efficacy of haploidentical B-cell infusion in the SOD1G93A mouse and the safety and feasibility of using purified haploidentical B lymphocytes as a cell-based therapeutic strategy for a person with ALS.

Inflammation and immunomodulation in central nervous system injury - B cells as a novel therapeutic opportunity.

Acute injury to the central nervous system (CNS) remains a complex and challenging clinical need. CNS injury initiates a dynamic neuroinflammatory response, mediated by both resident and infiltrating immune cells. Following the primary injury, dysregulated inflammatory cascades have been implicated in sustaining a pro-inflammatory microenvironment, driving secondary neurodegeneration and the development of lasting neurological dysfunction. Due to the multifaceted nature of CNS injury, clinically effective therapies for conditions such as traumatic brain injury (TBI), spinal cord injury (SCI), and stroke have proven challenging to develop. No therapeutics that adequately address the chronic inflammatory component of secondary CNS injury are currently available. Recently, B lymphocytes have gained increasing appreciation for their role in maintaining immune homeostasis and regulating inflammatory responses in the context of tissue injury. Here we review the neuroinflammatory response to CNS injury with particular focus on the underexplored role of B cells and summarize recent results on the use of purified B lymphocytes as a novel immunomodulatory therapeutic for tissue injury, particularly in the CNS.

B cell treatment promotes a neuroprotective microenvironment after traumatic brain injury through reciprocal immunomodulation with infiltrating peripheral myeloid cells.

Traumatic brain injury (TBI) remains a major cause of death and severe disability worldwide. We found previously that treatment with exogenous naïve B cells was associated with structural and functional neuroprotection after TBI. Here, we used a mouse model of unilateral controlled cortical contusion TBI to investigate cellular mechanisms of immunomodulation associated with intraparenchymal delivery of mature naïve B lymphocytes at the time of injury. Exogenous B cells showed a complex time-dependent response in the injury microenvironment, including significantly increased expression of IL-10, IL-35, and TGFß, but also IL-2, IL-6, and TNFα. After 10 days in situ, B cell subsets expressing IL-10 or TGFß dominated. Immune infiltration into the injury predominantly comprised myeloid cells, and B cell treatment did not alter overall numbers of infiltrating cells. In the presence of B cells, significantly more infiltrating myeloid cells produced IL-10, TGFß, and IL-35, and fewer produced TNFα, interferon-γ and IL-6 as compared to controls, up to 2 months post-TBI. B cell treatment significantly increased the proportion of CD206+ infiltrating monocytes/macrophages and reduced the relative proportion of activated microglia starting at 4 days and up to 2 months post-injury. Ablation of peripheral monocytes with clodronate liposomes showed that infiltrating peripheral monocytes/macrophages are required for inducing the regulatory phenotype in exogenous B cells. Reciprocally, B cells specifically reduced the expression of inflammatory cytokines in infiltrating Ly6C+ monocytes/macrophages. These data support the hypothesis that peripheral myeloid cells, particularly infiltrating monocyte/macrophages, are key mediators of the neuroprotective immunomodulatory effects observed after B cell treatment.

Atypical presentations and course of JC virus infection.

There is increasing evidence that the spectrum of human polyomavirus 2 (JCV) CNS disease includes novel syndromes other than progressive multifocal leukoencephalopathy (PML), the appreciation of which is increasingly important in the context of MS therapies and immunodeficiency states. Our objective is to describe unusual presentations of JCV infection to heighten clinician awareness. We describe three case reports of various PML presentations. Firstly a 56-year-old HIV positive male with decades of viral suppression and normal immune function presented with 1 month of non-specific headache that spontaneously resolved despite an MRI showing a new area of PML and CSF being JC DNA + . He had had two similar episodes in 2013 and 2014 with MRI scans consistent with PML, CSF, JCV, and PCR positivity once and brain biopsy-positive twice. Another 61-year-old male presented with subacute binocular vision loss and was found to have newly diagnosed HIV and JCV DNA detected in CSF. MRI brain only demonstrated symmetrical chiasmo-hypothalamic enhancement. There has been some improvement with combination antiretroviral therapy and corticosteroids for immune reconstitution inflammatory syndrome (IRIS). Thirdly, a 65-year-old male presented with subacute progressive confusion and behavioural disturbance, one year post-bilateral lung transplantation. MRI brain demonstrated no evidence of PML but CSF on three occasions demonstrated a progressively increasing JCV DNA load. Despite reduction in his immunosuppression, the patient developed profound encephalopathy without localising features leading to death two months later. These cases emphasise the atypical presentations of JCV: chronic relapsing, unusual symmetrical visual pathway disease, and non-localising encephalopathy without MRI evidence of PML.

Successful Osimertinib Rechallenge After Relapse Following Adjuvant Osimertinib: A Case Report.

Adjuvant osimertinib represents a recent paradigm shift in the management of resected EGFR-mutated lung cancer. The optimal subsequent treatment of patients who relapse after completion of 3 years of adjuvant osimertinib is unknown. Here, we report two cases of complete response to osimertinib rechallenge after relapse from previous adjuvant osimertinib use, and a serial molecular panel exhibiting a lack of acquired resistance mechanisms. Future prospective studies are warranted to confirm the optimal treatment of patients who relapse after previous adjuvant osimertinib.

Estimating the annual attack rate of seasonal influenza among unvaccinated individuals: A systematic review and meta-analysis.

INTRODUCTION: Seasonal influenza affects millions of people globally each year, causing significant morbidity and mortality. However, there remains substantial uncertainty about the attack rate (incidence) of influenza, particularly in unvaccinated individuals. METHODS: We undertook a systematic review of vaccine randomised controlled trials (RCTs) that reported on laboratory-confirmed seasonal influenza in the placebo arm. We calculated the influenza attack rate from included studies as the number of laboratory-confirmed positive seasonal influenza cases in the placebo arm divided by the total number of subjects in this arm. A random effects meta-analysis was conducted to estimate the influenza attack rate among unvaccinated individuals (both symptomatic only as well as symptomatic and asymptomatic combined). RESULTS: We included 32 RCTs that had a total of 13,329 participants. The pooled estimates for symptomatic influenza were 12.7% (95%CI 8.5%, 18.6%) for children (<18 years), 4.4% (95%CI 3.0%, 6.3%) for adults, and 7.2% (95%CI 4.3%, 12.0%) for older people (65 years and above). The pooled estimates for symptomatic and asymptomatic influenza combined for all influenza were 22.5% (95%CI 9.0%, 46.0%) for children and 10.7% (95%CI 4.5%, 23.2%) for adults. Only one study was identified for symptomatic and asymptomatic combined in older people which had a rate of 8.8% (95%CI 7.0%, 10.8%). There was substantial heterogeneity between studies. CONCLUSION: Overall, we found that approximately 1 in 5 unvaccinated children and 1 in 10 unvaccinated adults were estimated to be infected by seasonal influenza annually, with rates of symptomatic influenza roughly half of these estimates. Our findings help to establish the background risk of seasonal influenza infection in unvaccinated individuals.