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Neurotrophin secretion from PBMC cultures from 15 patients before and 12 months after alemtuzumab treatment. Cultures were either unstimulated (unstim) or stimulated with the myelin antigen, MBP or polyclonally stimulated with anti-CD3/anti-CD28 antibodies (CD3/28). Supernatants were harvested after 72 h and assayed for: (A) brain-derived neurotrophic factor, (B) CNTF, (C) platelet-derived neurotrophic factor, (D) FGF, and (E) insulin-like growth factor-1. Error bars represent 95% confidence intervals. (*P50.05, **P50.01, ***P50.001).
Source publication
Treatment of early relapsing-remitting multiple sclerosis with the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath [registered trade mark]) significantly reduced the risk of relapse and accumulation of disability compared with interferon β-1a in a phase 2 trial [Coles et al., (Alemtuzumab vs. interferon β-1a in early multipl...
Contexts in source publication
Context 1
... months after alemtuzumab, PBMCs derived from this cohort secreted increased BDNF, CNTF, PDGF and FGF but reduced IGF-1, compared with baseline (Fig. 3). BDNF, CNTF and PDGF production followed a similar pattern, with maximal increases in secretion (3-to 6-fold) after alemtuzumab in response to MBP, and less marked increases in unstimulated or polyclonally stimulated cultures (Figs 3A-C). FGF secretion was increased after alemtuzumab, but equally for all culture conditions (Fig. 3D). ...
Context 2
... months after alemtuzumab, PBMCs derived from this cohort secreted increased BDNF, CNTF, PDGF and FGF but reduced IGF-1, compared with baseline (Fig. 3). BDNF, CNTF and PDGF production followed a similar pattern, with maximal increases in secretion (3-to 6-fold) after alemtuzumab in response to MBP, and less marked increases in unstimulated or polyclonally stimulated cultures (Figs 3A-C). FGF secretion was increased after alemtuzumab, but equally for all culture conditions (Fig. 3D). ...
Context 3
... with baseline (Fig. 3). BDNF, CNTF and PDGF production followed a similar pattern, with maximal increases in secretion (3-to 6-fold) after alemtuzumab in response to MBP, and less marked increases in unstimulated or polyclonally stimulated cultures (Figs 3A-C). FGF secretion was increased after alemtuzumab, but equally for all culture conditions (Fig. 3D). In contrast, IGF-1 secretion decreased 3-fold after alemtuzumab (Fig. 3E), with no additional response to MBP or polyclonal stimulation. NGF, NT-3, NT-4/5 and GDNF could not be detected in patient or healthy control derived ...
Context 4
... pattern, with maximal increases in secretion (3-to 6-fold) after alemtuzumab in response to MBP, and less marked increases in unstimulated or polyclonally stimulated cultures (Figs 3A-C). FGF secretion was increased after alemtuzumab, but equally for all culture conditions (Fig. 3D). In contrast, IGF-1 secretion decreased 3-fold after alemtuzumab (Fig. 3E), with no additional response to MBP or polyclonal stimulation. NGF, NT-3, NT-4/5 and GDNF could not be detected in patient or healthy control derived ...
Context 5
... or following MBP or polyclonal stimulation, for gene expression analysis by real-time RT-PCR. Under all conditions, CNTF was expressed by only T cells, whereas BDNF was expressed by all cell types. After alemtuzumab, the only significant change was an increase in T-cell expression of BDNF; there was also a trend towards increased T-cell CNTF mRNA (Fig. 3B and Supplementary Data). PDGF and FGF mRNA expression were observed in all cell types with no clear change after alemtuzumab (data not ...
Citations
... While the direct actions of alemtuzumab occur in the periphery, it is not well understood how this has effects on the brain, including cognition. It is plausible that these effects occur by reducing the destructive neuroinflammatory actions of MS (Ruck et al., 2015), promoting repair through the release of cytokines and other factors (Jones et al., 2010), a combination of these pathways, or another mechanism that remains to be elucidated. Further, alemtuzumab increases the percentage of functionally active regulatory T-cells, which in turn promotes myelin regeneration in the CNS (Havari et al., 2014;Dombrowski et al., 2017). ...
Background:
Alemtuzumab is effective in reducing relapse rate and disability, but limited data exist on its effect on cognitive function in relapsing multiple sclerosis (RMS). The present study assessed neurocognitive function and safety associated with alemtuzumab treatment in RMS.
Methods:
This longitudinal, single-arm, prospective study included people with RMS (aged 25-55 years) who were treated with alemtuzumab in clinical practice in the United States of America and Canada. The first participant was enrolled in December 2016. The primary endpoint was the change from baseline to post-baseline (month [M] 12/24) in MS-COGnitive (MS-COG) composite score. Secondary endpoints included Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), Selective Reminding Test (SRT), Controlled Oral Word Association Test (COWAT), and Automated Neuropsychological Assessment Metrics (ANAM) scores. Depression and fatigue were assessed using Hamilton Rating Scale-Depression (HAM-D) and Fatigue Severity Scale (FSS)/Modified Fatigue Impact Scale (MFIS), respectively. Magnetic resonance imaging (MRI) parameters were assessed when available. Safety was assessed throughout the study. Descriptive statistics were used for the pre-specified statistical analyses. Since the study was terminated early (November 2019) because of operational and resource difficulties, post hoc analyses for statistical inference were performed among participants who had a baseline value and at least one complete post-baseline assessment for cognitive parameters, fatigue, or depression.
Results:
Of the 112 participants enrolled, 39 were considered as the primary analysis population at M12. At M12, a mean change of 0.25 (95% confidence interval [CI]: 0.04, 0.45; p = 0.0049; effect size [ES]: 0.39) was observed in the MS-COG composite score. Improvements were observed in processing speed (based on PASAT and SDMT; p < 0.0001; ES: 0.62), as well as in individual PASAT, SDMT and COWAT scores. An improvement was also noted in HAM-D (p = 0.0054; ES: -0.44), but not in fatigue scores. Among MRI parameters, decreases in burden of disease volume (BDV; ES: -0.12), new gadolinium-enhancing lesions (ES: -0.41) and newly active lesions (ES: -0.07) were observed at M12. About 92% of participants showed stable or improved cognitive status at M12. There were no new safety signals reported in the study. The most common adverse events (≥10% of participants) were headache, fatigue, nausea, insomnia, urinary tract infection, pain in extremity, chest discomfort, anxiety, dizziness, arthralgia, flushing, and rash. Hypothyroidism (3.7%) was the most frequent adverse event of special interest.
Conclusion:
The findings from this study suggest that alemtuzumab has a positive impact on cognitive function with significant improvements in processing speed and depression in people with RMS over a period of 12 months. The safety profile of alemtuzumab was consistent with previous studies.
... Despite haziness surrounding the underlying cause of the inflammation seen in MS, the evidence of T cell involvement is strong. It has been shown that activated T cells can induce experimental autoimmune encephalomyelitis in healthy mice [97,177,209] and that global reduction of most lymphocytes via alemtuzumab can improve MS pathology [161,249]. Th1 cells have been implicated as important detrimental players in MS due to their ability to stimulate M1 macrophages through the secretion of TNF-α and IFN-γ, which are important mediators of inflammation and cellular damage [192]. Most of the earlier research in MS focused on the role of T cells, however, recently researchers have also acknowledged a cooperation between B cells and T cells in MS pathogenesis [155]. ...
The adaptive immune system and associated inflammation are vital in surveillance and host protection against internal and external threats, but can secondarily damage host tissues. The central nervous system is immune-privileged and largely protected from the circulating inflammatory pathways. However, T cell involvement and the disruption of the blood–brain barriers have been linked to several neurodegenerative diseases including Parkinson's disease, Alzheimer’s disease, and multiple sclerosis. Under normal physiological conditions, regulatory T cells (Treg cells) dampen the inflammatory response of effector T cells. In the pathological states of many neurodegenerative disorders, the ability of Treg cells to mitigate inflammation is reduced, and a pro-inflammatory environment persists. This perspective review provides current knowledge on the roles of T cell subsets (e.g., effector T cells, Treg cells) in neurodegenerative and ocular diseases, including uveitis, diabetic retinopathy, age-related macular degeneration, and glaucoma. Many neurodegenerative and ocular diseases have been linked to immune dysregulation, but the cellular events and molecular mechanisms involved in such processes remain largely unknown. Moreover, the role of T cells in ocular pathologies remains poorly defined and limited literature is available in this area of research. Adoptive transfer of Treg cells appears to be a vital immunological approach to control ocular pathologies. Similarities in T cell dysfunction seen among non-ocular neurodegenerative diseases suggest that this area of research has a great potential to develop better therapeutic agents for ocular diseases and warrants further studies. Overall, this perspective review article provides significant information on the roles of T cells in numerous ocular and non-ocular neurodegenerative diseases.
... The phenotype analysis of T cells in the circulating blood of AD patients have shown that CD25 + CCR6 + Th17 cells are significantly increased, and these phenotypes of Th17 cells have been reported to promote neuronal damage in MS and PD [85] . In addition, investigators have reported an obvious infiltration of Th17 cells in the hippocampus of an AD rodent model, and also reported that IL-17 and IL-22 secreted by Th17 cells aggravate the loss of neurons in the CA1 area of the hippocampus and the activation of glial cells [86] . Moreover, it is known that Fas ligand (FasL) is highly expressed in the hippocampal Th17 cells of AD model animals, and that neurons with similar high Fas expression may undergo apoptosis through the Fas-FasL pathway [86] . ...
... In addition, investigators have reported an obvious infiltration of Th17 cells in the hippocampus of an AD rodent model, and also reported that IL-17 and IL-22 secreted by Th17 cells aggravate the loss of neurons in the CA1 area of the hippocampus and the activation of glial cells [86] . Moreover, it is known that Fas ligand (FasL) is highly expressed in the hippocampal Th17 cells of AD model animals, and that neurons with similar high Fas expression may undergo apoptosis through the Fas-FasL pathway [86] . In summary, Aβ, an important pathological indicator of AD, can induce T cells to differentiate into different types of cells, such as Th1, Th2, and Th17, and different types of Th cells can participate in the regulation of AD-like pathological processes through different mechanisms. ...
Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive defects. The role of the central immune dominated by microglia in the progression of AD has been extensively investigated. However, little is known about the peripheral immune system in AD pathogenesis. Recently, with the discovery of the meningeal lymphatic vessels and glymphatic system, the roles of acquired immunity in the maintenance of central homeostasis and neurodegenerative diseases have attracted increasing attention. T cells not only regulate the function of neurons, astrocytes, microglia, oligodendrocytes and brain microvascular endothelial cells, but also participate in clearance of β-amyloid (Aβ) plaques. Apart from producing antibodies to bind Aβ peptides, B cells affect Aβ-related cascades via a variety of antibody-independent mechanisms. This review systemically summarizes the recent progress in understanding pathophysiological roles of T cells and B cells in AD.
... The antibiotic minocycline reduces the severity of sickness in an experimental autoimmune encephalomyelitis model by inhibiting microglial activation. [91][92][93][94][95][96][97] In conclusion, since microglia play an important role in the normal physiology of the brain (brain development, maintenance of homeostasis) as well as in neuroinflammation and neurodegeneration, their detection is very important, especially in disease states. Multi-compartment DWI methods such as NODDI and PET imaging can be used for imaging microglial activation. ...
Microglia are important in the development, homeostasis, and disorders of the central nervous system. Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as autism, severe depression, and schizophrenia, have all been related to microglia-derived neuroinflammation. Imaging techniques such as magnetic resonance imaging and positron emission tomography can detect neuroinflammation. The purpose of this review was to examine the role of microglia in neurodegenerative disorders, with a focus on imaging.
... The T lymphocytes reconstructed in MS patients after treatment of alemtuzumab secret more brain-derived neurotrophic factor (BDNF) (22). BDNF produced from astrocytes and peripheral immune cells have been reported to protect neurons and attenuate EAE symptoms (23,24). ...
Multiple sclerosis (MS) is a chronic autoimmune disease driven by T and B lymphocytes. The remyelination failure and neurodegeneration results in permanent clinical disability in MS patients. A desirable therapy should not only modulate the immune system, but also promote neuroprotection and remyelination. To investigate the neuroprotective effect of CD52 antibody in MS, both C57BL/6J and SJL mice with experimental autoimmune encephalomyelitis (EAE) were treated with CD52 antibody at the peak of disease. Treatment with CD52 antibody depleted T but not B lymphocytes in the blood, reduced the infiltration of T lymphocytes and microglia/macrophages in the spinal cord. Anti-CD52 therapy attenuated EAE scores during the recovery phase. It protected neurons immediately after treatment (within 4 days) as shown by reducing the accumulation of amyloid precursor proteins. It potentially promoted remyelination as it increased the number of olig2/CC-1-positive mature oligodendrocytes and prevented myelin loss in the following days (e.g., 14 days post treatment). In further experiments, EAE mice with a conditional knockout of BDNF in neurons were administered with CD52 antibodies. Neuronal deficiency of BDNF attenuated the effect of anti-CD52 treatment on reducing EAE scores and inflammatory infiltration but did not affect anti-CD52 treatment-induced improvement of myelin coverage in the spinal cord. In summary, anti-CD52 therapy depletes CD4-positive T lymphocytes, prevents myelin loss and protects neurons in EAE mice. Neuronal BDNF regulates neuroprotective and anti-inflammatory effect of CD52 antibody in EAE mice.
... Additional studies are required to confirm a direct interaction among monocytes, T cells and B cells in which increased functional capacity requires or is dependent upon BDNF. Interestingly, lymphocytes from alemtuzumab treated patients also produce higher levels of BDNF and CNTF in response to myelin basic protein stimulation in vitro (58). ...
Alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis. It selectively targets the CD52 antigen to induce profound lymphocyte depletion, followed by recovery of T and B cells with regulatory phenotypes. We previously showed that regulatory T cell function is restored with cellular repletion, but little is known about the functional capacity of regulatory B-cells and peripheral blood monocytes during the repletion phase. In this study (ClinicalTrials.gov ID# NCT03647722) we simultaneously analyzed the change in composition and function of both regulatory lymphocyte populations and distinct monocyte subsets in cross-sectional cohorts of MS patients prior to or 6, 12, 18, 24 or 36 months after their first course of alemtuzumab treatment. We found that the absolute number and percentage of cells with a regulatory B cell phenotype were significantly higher after treatment and were positivity correlated with regulatory T cells. In addition, B cells from treated patients secreted higher levels of IL-10 and BDNF, and inhibited the proliferation of autologous CD4⁺CD25⁻ T cell targets. Though there was little change in monocytes populations overall, following the second annual course of treatment, CD14⁺ monocytes had a significantly increased anti-inflammatory bias in cytokine secretion patterns. These results confirmed that the immune system in alemtuzumab-treated patients is altered in favor of a regulatory milieu that involves expansion and increased functionality of multiple regulatory populations including B cells, T cells and monocytes. Here, we showed for the first time that functionally competent regulatory B cells re-appear with similar kinetics to that of regulatory T-cells, whereas the change in anti-inflammatory bias of monocytes does not occur until after the second treatment course. These findings justify future studies of all regulatory cell types following alemtuzumab treatment to reveal further insights into mechanisms of drug action, and to identify key immunological predictors of durable clinical efficacy in alemtuzumab-treated patients.
... 32,33 Increased secretion of neurotrophic factors, such as BDNF and ciliary neurotrophic factor, by regenerating immune cells may exert a neuroprotective effect and provide some explanation for disability improvement in patients treated with alemtuzumab. 34 Alemtuzumab decreases the level of NfL concentrations in plasma obtained from relapsing-remitting MS (RRMS) patients. As NfL is a markers of neuroaxonal damage, reflecting disease progress, this may also indicate the neuroprotective outcome of alemtuzumab. ...
CD52 is a small surface glycoprotein composed of 12 amino acids. CD52 is found mostly on the surface of mature immune cells, such as lymphocytes, monocytes, eosinophils, and dendritic cells, as well as the male genital tract: within the epididymis and on the surface of mature sperm. Low CD52 expression is also found in neutrophils. CD52 function is not fully understood, although experiments with anti-CD52 antibodies have shown that CD52 is essential for lymphocyte transendothelial migration and may contribute to costimulation of CD4+ T cells and T-cell activation and proliferation. Although knowledge about exact CD52 function is still poor, CD52 presence on the surface of a broad spectrum of immune cells makes it a therapeutic target, especially in immunomediated diseases, such as multiple sclerosis. In multiple sclerosis, alemtuzumab is registered for adult patients with the relapsing-remitting form of the disease defined by clinical and imaging features. Despite the high efficacy of the drug, the main issue is its safety. The main adverse effects of alemtuzumab are associated with drug infusion due to cytokine release and cytotoxic effects of antibodies associated with lymphocyte depletion, which leads to immunosuppression, and secondary autoimmunity that may be the effect of excessive B-cell repopulation and cancer. This review presents current knowledge on the drug's mechanism of action, efficacy and safety data from clinical trials, and real-world observations, including available though scarce data on using alemtuzumab in the COVID era.
... Alternatively, these findings could also suggest that patients with advanced focal inflammatory disease may be better responders to a highly effective treatment, such as alemtuzumab. To this end, previous studies have suggested that long-term disability improvements with alemtuzumab may not be solely due to its anti-inflammatory effect, but may be also attributable to a neuroprotective effect via neurotrophin secretion from immune cells regenerating after alemtuzumab treatment [35]. ...
Introduction:
In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing-remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW.
Methods:
CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed.
Results:
Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a -0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a -0.10-point mean EDSS score change; 98% had stable or improved EDSS scores.
Conclusion:
CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9.
... The durability of efficacy has been demonstrated over 5 years of follow-up without continuous treatment 129,130 . The efficacy of alemtuzumab has largely been attributed to the long-lasting drug-induced T cell lymphopenia and the homeostatic changes it induces 131,132 . ...
Increasing evidence indicates the involvement of B cells in the pathogenesis of multiple sclerosis (MS), but their precise roles are unclear. In this Review, we provide an overview of the development and physiological functions of B cells and the main mechanisms through which B cells are thought to contribute to CNS autoimmunity. In MS, abnormalities of B cell function include pro-inflammatory cytokine production, defective B cell regulatory function and the formation of tertiary lymphoid-like structures in the CNS, which are the likely source of abnormal immunoglobulin production detectable in the cerebrospinal fluid. We also consider the hypothesis that Epstein-Barr virus (EBV) is involved in the B cell overactivation that leads to inflammatory injury to the CNS in MS. We also review the immunological effects - with a focus on the effects on B cell subsets - of several successful therapeutic approaches in MS, including agents that selectively deplete B cells (rituximab, ocrelizumab and ofatumumab), agents that less specifically deplete lymphocytes (alemtuzumab and cladribine) and autologous haematopoietic stem cell transplantation, in which the immune system is unselectively ablated and reconstituted. We consider the insights that these effects on B cell populations provide and their potential to further our understanding and targeting of B cells in MS.
... It is possible that this drug exerts other effects beside T-cells suppression, such as neuroprotection and repair. 96 Rarely, narcolepsy can develop together with multiple sclerosis (MS), either secondarily to hypothalamic demyelinating lesions or as a concomitant disorder. 97 In a small series of NT1 cases with concomitant MS, two patients reported EDS improvement upon treatment with IVIG and long-term steroid therapy, respectively. ...
Narcolepsy type 1 (NT1) is a lifelong sleep disorder, primarily characterized clinically by excessive daytime sleepiness and cataplexy and pathologically by the loss of hypocretinergic neurons in the lateral hypothalamus. Despite being a rare disorder, the NT1-related burden for patients and society is relevant due to the early onset and chronic nature of this condition. Although the etiology of narcolepsy is still unknown, mounting evidence supports a central role of autoimmunity. To date, no cure is available for this disorder and current treatment is symptomatic. Based on the hypothesis of the autoimmune etiology of this disease, immunotherapy could possibly represent a valid therapeutic option. However, contrasting and limited results have been provided so far. This review discusses the evidence supporting the use of immunotherapy in narcolepsy, the outcomes obtained so far, current issues and future directions.
