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Impact of an Immune Modulator Fingolimod on Acute Ischemic Stroke

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Impact of an Immune Modulator Fingolimod on Acute Ischemic Stroke Impact of an immune modulator fingolimod on acute ischemic stroke Ying Fua,b, Ningnannan Zhangc, Li Rena, Yaping Yana, Na Suna, Yu-Jing Lia, Wei Hanc, Rong Xuea, Qiang Liua,b, Junwei Haoa, Chunshui Yuc, and Fu-Dong Shia,b,d,1 Departments of aNeurology and cRadiology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300070, China; bDepartment of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013; and dDepartment of Immunology, Tianjin Medical University, Tianjin, 300070, China Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved November 5, 2014 (received for review August 21, 2014) Peripheral lymphocytes entering brain ischemic regions orches- brain (7, 8). Cell types most frequently known to enter the brain + + trate inflammatory responses, catalyze tissue death, and worsen during AIS belong to the CD4 T-cell, CD8 T-cell, neutrophil, clinical outcomes of acute ischemic stroke (AIS) in preclinical and macrophage, and natural killer (NK) cell subpopulations. studies. However, it is not known whether modulating brain Such cells, as infiltrate within the peri-infarcted areas of brain inflammation can impact the outcome of patients with AIS. In this tissues from AIS patients (9, 10), become intimately involved in open-label, evaluator-blinded, parallel-group clinical pilot trial, we all stages of the ischemic cascade (7, 8). Studies in experimental recruited 22 patients matched for clinical and MRI characteristics, stroke have indicated that all these cells contribute to the death with anterior cerebral circulation occlusion and onset of stroke of ischemic neurons by promoting focal inflammatory reactions, that had exceeded 4.5 h, who then received standard manage- direct killing, triggering of antigen-specific immune responses, or ment alone (controls) or standard management plus fingolimod alterations in neuronal excitability (6, 10–12). (FTY720, Gilenya, Novartis), 0.5 mg per day orally for 3 consecutive The amplification of initial brain injury by inflammatory and days. Compared with the 11 control patients, the 11 fingolimod immune reactions continues well beyond the initial 4.5 h of recipients had lower circulating lymphocyte counts, milder neuro- stroke onset (therapeutic window for tPA), and that prolonged logical deficits, and better recovery of neurological functions. This response provides a window of opportunity for blocking the difference was most profound in the first week when reduction of secondary events that expand infarction caused by cells of the National Institutes of Health Stroke Scale was 4 vs. −1, respec- immune system. Because the extended detrimental impact on tively (P = 0.0001). Neurological rehabilitation was faster in the stroke-affected sites is likely a coordinated event mediated by fingolimod-treated group. Enlargement of lesion size was more multiple cellular and soluble elements of the immune system, the restrained between baseline and day 7 than in controls (9 vs. question arises as to whether these events offer a unique target 27 mL, P = 0.0494). Furthermore, rT1%, an indicator of microvas- for altering the related outcome. Indeed, among a number of cular permeability, was lower in the fingolimod-treated group at strategies tested to modulate the immune system in this context 7 d (20.5 vs. 11.0; P = 0.005). No drug-related serious events oc- (12–14), fingolimod emerges as a very promising candidate, pre- curred. We conclude that in patients with acute and anterior cere- sumably because of its action on many lymphocyte subsets bear- bral circulation occlusion stroke, oral fingolimod within 72 h of ing the sphinogosine-1-phosphate receptor (S1PR). Fingolimod disease onset was safe, limited secondary tissue injury from base- acts as a S1PR modulator that inhibits the egress of lympho- line to 7 d, decreased microvascular permeability, attenuated neu- cytes from lymph nodes and limits their recirculation (15, 16). rological deficits, and promoted recovery. By reducing the trafficking of T cells, B cells, NK cells, and other S1PR-bearing cells into the central nervous system (CNS) acute ischemic stroke | immune modulation | fingolimod Significance he devastating, often crippling aftermath of stroke makes it Tsecond only to cardiac ischemia as a cause of death world- In patients with acute ischemic stroke (AIS), the abrupt and wide. Therapy for acute ischemic stroke (AIS) centers first on massive influx of lymphocytes from the periphery to the is- rapid revascularization of arterial territories, with additional chemic region orchestrates focal inflammatory responses, cat- focus on the management of blood pressure and cerebral edema. alyzes tissue death, and worsens clinical outcomes. In this early Revascularization is currently achieved by the intravenous ad- phase clinical study, we reduced lymphocyte migration to the ministration of tissue plasminogen activator (tPA) and intra- brain during the first 72 h of AIS via oral administration of vascular therapy. However, the benefit of tPA is highly time- three doses of fingolimod. This administration led to a signifi- dependent, considering that pooled analysis has documented loss cant reduction of secondary lesion enlargement, microvascular of benefit beyond 4.5 h from onset of symptoms (1, 2). This permeability, and better clinical outcomes during the acute narrow time window renders only about 2–5% of stroke patients phase and 3-mo follow-up visit. This study will provoke new eligible for tPA (3). Data from five randomized controlled trials investigations on the efficacy of modulation of brain in- that have been published in the past year show that endovascular flammation in AIS. therapy has provided no benefit over tPA injected intravenously Author contributions: Y.F. and F.-D.S. designed research; Y.F., N.Z., L.R., N.S., Y.-J.L., W.H., (4). Therefore, a significant hiatus exists during which no means MEDICAL SCIENCES R.X., J.H., and F.-D.S. performed research; N.Z. and C.Y. contributed new reagents/analytic of effective medical management is available for patients with tools; Y.F., N.Z., Y.Y., Q.L., C.Y., and F.-D.S. analyzed data; and Y.F., Q.L., and F.-D.S. wrote AIS. Moreover, despite numerous clinical trials conducted to the paper. salvage cells from death, no significant breakthrough has been The authors declare no conflict of interest. made to improve the outcome of stroke patients (5, 6). This article is a PNAS Direct Submission. Injured and dying cells during brain hypoxia, after cessation of Freely available online through the PNAS open access option. blood and oxygen supply activates the innate and adaptive im- 1To whom correspondence should be addressed. Email: [email protected]. – mune systems, compromise the blood brain barrier (BBB) and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. lead to a massive migration of peripheral leukocytes into the 1073/pnas.1416166111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1416166111 PNAS | December 23, 2014 | vol. 111 | no. 51 | 18315–18320 Downloaded by guest on September 28, 2021 (14, 17), thereby reducing relapses as well as brain volume loss, Table 1. Baseline characteristics and timing of treatment fingolimod became the first oral therapy approved by the Food Control Fingolimod and Drug Administration for the relapsing form of multiple scle- Variable (n = 11) (n = 11) P value rosis (MS) (18). This compound’s ability to enhance the BBB’s integrity (19) and its direct effects on the CNS (17) are also Age (y) 54.7 ± 11.0 62.3 ± 8.0 0.07 expected to alleviate infarctions and promote cell regeneration. Female, n (%) 2 (18) 3 (27) 1.00 Indeed, demonstration of the beneficial effect of fingolimod on Previous stroke 2 (18) 2 (18) 1.00 multiple experimental models of stroke by independent groups Risk factors and other establishes a foundation for clinical translation (12-14, 20-26). diseases, n (%) The goal of this study is to provide preliminary results as to the Heart disease 1 (9) 3 (27) 0.59 safety, feasibility, and efficacy of fingolimod for patients with AIS. Hypertension 9 (82) 6 (55) 0.36 Hyperlipidemia 4 (36) 3 (27) 1.00 Results Smoking 5 (45) 4 (36) 1.00 Baseline Characteristics. A total of 22 patients with AIS enrolled Renal failure 0 (0) 1 (9) 1.00 directly into this trial (Fig. 1). There was no mortality, no loss Diabetes mellitus 2 (18) 2 (18) 1.00 during follow-up, and no drop-outs during the study. The mean Etiology*, n (%) time from disease onset to fingolimod treatment was 20 ± 15 h. Subtype 1: atheromatosis 8 (73) 8 (73) 1.00 Four patients received fingolimod treatment between 7 and 12 h Subtype 2: embolus 0 (0) 0 (0) 1.00 after enrollment, five patients between 13 and 24 h, one at 32 h, Subtype 3: lacunar infarct 3 (27) 3 (27) 1.00 Subtype 4: other causes 0 (0) 0 (0) 1.00 and one at 62 h. The average mean time to admission of the Subtype 5: undetermined 0 (0) 0 (0) 1.00 control group was 29 ± 21 h. The 11 fingolimod-treated patients † Location , n (%) had a mean age of 62.3 ± 8.0 y and a male:female ratio of 8:3. Total anterior circulation 1 (9) 1 (9) 1.00 The control group of 11 patients had a mean age of 54.7 ± 11 and Partial anterior circulation 7 (64) 7 (64) 1.00 a male:female ratio of 9:2. Demographic, clinical, and radiolog- Lacunar syndrome 3 (27) 3 (27) 1.00 ical characteristics are shown in the Table 1. At baseline, brain NIHSS on admission 9.0 ± 2.6 11.0 ± 5.6 0.30 lesion volume and location on MRI from 22 patients were paired ± ± P = Infarct volume on admission (mL) 60 86 61 89 0.97 to match each other with our best effort ( 0.4553, paired Time to enrollment (h) 29 ± 21 20 ± 15 0.27 t test).
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