Immune Interventions In Neurological Disease

(Part 1)Immune Interventions in Acute Cerebral Stroke(Clinical trial NCT02002390)Aims Inflammatory and immune responses in the brain can shape the clinical presentation and outcome of stroke. In the context of the extremely sparse of medical managements for acute stroke, the failure of other brain-protective measures, our increasing ability in modulating the immune system and the success of disease modifying therapies in multiple sclerosis, immune interventions are currently explored as new therapeutic revenue for acute stroke. Immune activation in stroke are triggered by microglia and cell death products within the brain, the inflammatory cascade and associated damage take place from minutes to hours after onset of ischemia or hemorrhage. Importantly, the bi-phasic neural-immune interactions characterized by transition from immune destruction to immune suppression during the course of stroke dictate the time frame and duration for immune intervention.Thus, immune interventions aiming at attenuation of brain inflammation, vascular permeability and tissue edema must have fast action and cession to reduce acute immune destruction and avoid subsequent immune suppression. Preliminary results suggest that rationalized utilization of disease modifying drugs for multiple sclerosis,i.e. fingolimod, might accomplish these goals in both ischemic and hemorrhagic stroke. With further elucidation of the specific immune mechanisms in stroke, two prepective pilot trials about fingolimod intervene in intracerebral hemorrhage or in acute ischemia stroke were done.Subjects and Methods Fingolimod for the treatment of ICH:In this 2-arm, evaluator-blinded study, we included 23 patients with primary supratentorial ICH with hematomal volume of 5 to 30 m L. Clinical and neuroimaging feature–matched patients were treated with standard care with or without oral fingolimod. The study was conducted in Tianjin Medical University General Hospital,Tianjin.All patients received standard management alone(control participants)orcombined with fingolimod(FTY720, Gilenya), 0.5mg, orally for 3 consecutive days.Treatment was initiated within 1 hour after the baseline computed tomographic scan and no later than 72 hours after the onset of symptoms.Neurologic status and hematomal and PHE volumes(Ev) and relative PHE, defined as Ev divided by hematomal volume, were monitored by clinical assessment and magnetic resonance imaging, respectively, for 3 months.Impact of an immune modulator fingolimod on acute ischemic stroke:In this open-label, evaluator-blinded, parallel-group clinical pilot trial, we recruited22 patients matched for clinical and MRI characteristics, with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h, who then received standard management alone(controls) or standard management plus fingolimod(FTY720, Gilenya, Novartis), 0.5 mg per day orally for 3 consecutive days.Neurologic statuses, enlargement of lesion volume and microvascular permeability were monitored by clinical assessment and magnetic resonance imaging,respectively, for 3 months.ResultsFingolimod for the treatment of Intracerebral Hemorrhage(ICH):Patients treated with fingolimod exhibited a reduction of neurologic impairment compared with control individuals, regained a Glasgow Coma Scale score of 15 by day7(100% vs 50%, P =.01), and had a National Institutes of Health Stroke Scale score reduction of 7.5 vs 0.5(P <.001). Neurologic functions improved in these patients in the firstweek coincident with a reduction of circulating lymphocyte counts. At 3 months,a greater proportion of patients receiving fingolimod achieved full recovery of neurologic functions(modified Barthel Index score range, 95-100; 63%vs 0%; P =.001; modified Rankin Scale score range, 0-1; 63%vs 0%; P =.001), and fewer reported ICH-related lung infections. Perihematomal edema volume and r PHEwere significantly smaller in fingolimod-treated patients than in control individuals(Ev at day 7, 47 m L vs108 m L, P =.04; Ev at day 14, 55 m L vs 124 m L, P =.07; r PHE at day 7, 2.5 vs 6.4, P<.001; r PHE at day 14, 2.6 vs 7.7, P =.003, respectively).We recorded no differences between groups in the occurrence of adverse events.Impact of an immune modulator fingolimod on acute ischemic stroke:Compared with the 11 control patients, the 11 fingolimod recipients had lower circulating lymphocyte counts, milder neurological deficits, and better recovery of neurological functions. This difference was most profound in the first week when reduction of National Institutes of Health Stroke Scale was 4 vs.-1, respectively(P =0.0001). Neurological rehabilitation was faster in the fingolimod-treated group.Enlargement of lesion size was more restrained between baseline and day 7 than in controls(9 vs 27 m L, P = 0.0494). Furthermore, r T1%, an indicator of microvascular permeability, was lower in the fingolimod-treated group at 7 d(20.5 vs. 11.0; P =0.005). No drug-related serious events occurred.ConclusionPreliminary results in these trials suggest that the rational use of a disease modifying drug, fingolimod, for multiple sclerosis might accomplish the goals in which both ischemic and hemorrhagic stroke; and immune interventions attenuated brain inflammation, vascular permeability and tissue edema which transpire rapidly to reduce acute immune destruction and avoid subsequent immune suppression. The efficacy of fingolimod in preventing secondary brain injury in patients with ICH or AIS warrants further investigation in late-phase trials.(Part 2)Autologous mesenchymal stem cell therapy for neuromyelitis optica spectrum disorder(Clinical trial NCT02249676)Ojective: There are currently no effective therapies to halt the autoantibody-mediated astrocyte damage and secondary demyelination that lead to frequent relapses and rapid progressive disability inneuromyelitis optica spectrum disorder(NMOSD). We evaluated the safety and efficacy of autologous bone marrow-derived mesenchymal stem cells(MSC) as a potential treatment for NMOSD.Methods:Patients with neuromyelitis optica, or AQP4 antibody positive recurrent optic neuritis and recurrent longitudinally extensive transverse myelitiswere recruited into a single arm, open-label trial. All patients received a single intravenous infusion of 1.0 ×108 MSC. The primary endpoints of the study were efficacy to reduce inflammatory activity as reflected by annualized relapse rates, and inflammatory lesionsobserved by MRI.A secondary outcome was recovery of disease, by assessing the Expanded Disability Status Scale(EDSS), visual acuity, retinal nerve fiber layer thickness, optic nerve area diameter, brain volume and upper cervical cord area. At the baseline and at 1, 3, 6, 9, and 12 months after MSC infusion, clinical,immunological, and imaging assessments were performed and an adverse event questionnaire was performed. This trial is registered with Clinical Trials.gov, number NCT02249676.Results:At 12 months after a single MSC infusion, 12 patients were relapse-free and three had milder relapses, the mean annualizedrelapse rate was reduced(1.1 vs 0.3, p= 0.002), and the T2 or gadolinium-enhancing T1 lesions decreased in the optic nerve(0.2 vs 0, P = 0.031; 0.13 vs 0, P = 0.043) and spinal cord(10 vs 7 segments, p<0.001; 0.6 vs 0.1, p = 0.015, respectively). Disability in these patients was significantly reduced(EDSS, 4.3 vs 4.9, p= 0.021;Visual acuity,0.4 vs 0.5, p = 0.007).The patients had an increase in retinal nerve fiber layer thickness(73 vs 81 μm, p <0.001), optic nerve diameters(2.3 vs 2.6 mm, p < 0.001) and upper cervical cord area( 69 vs 73 mm2, p <0.001). We did not identify any serious MSC-related adverse events during the 12-month follow-up period.Conclusion:MSC infusion is safe and this treatment dramatically reduces the relapse frequency, halts disease progression and mitigates neurological disability parameters in patients with NMOSD. In parallel with these clinical benefits, neural structures in the optic nerve and spinal cord recover. The beneficial effects of MSC on NMOSD are associated with modulation of inflammation in the periphery and central nervous system, and promotion of neurostructural and functional recovery.