Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis.

BACKGROUND: The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis. METHODS: In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability. RESULTS: A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P<0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P<0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P<0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group. CONCLUSIONS: Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).

Patients transitioning from non-pegylated to pegylated interferon beta-1a have a low risk of new flu-like symptoms: ALLOW phase 3b trial results.

BACKGROUND: Flu-like symptoms are common adverse events associated with interferon beta relapsing multiple sclerosis therapies. OBJECTIVES: To evaluate the incidence and severity of flu-like symptoms after transitioning from non-pegylated interferons to peginterferon beta-1a and assess flu-like symptom mitigation using naproxen. METHODS: ALLOW was a phase 3b open-label study in relapsing multiple sclerosis patients. Patients had received non-pegylated interferon for 4 or more months immediately before beginning a 4-week screening period. At baseline, patients switched to peginterferon beta-1a and were randomly assigned (1:1) to continue their current flu-like symptoms management regimen or start twice-daily naproxen 500 mg for 8 weeks. Patients then switched to their preferred regimen and were followed for 48 weeks in total. RESULTS: Of 201 patients, 89.6% did not experience new/worsening flu-like symptoms during their first 8 weeks on peginterferon beta-1a. Flu-like symptom severity remained low in current-regimen and naproxen patients, with no significant between-group differences. Median flu-like symptom duration per injection was 3.2 hours longer with peginterferon beta-1a versus prior interferon, but the 4-week cumulative duration was reduced 49-78%. No new safety signals were identified. CONCLUSION: Most patients who switched from non-pegylated interferon to peginterferon beta-1a did not experience new/worsening flu-like symptoms. Flu-like symptom duration per injection increased, but the cumulative duration significantly decreased. These data may inform flu-like symptom management guidance.

Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow.

OBJECTIVE: The present study was undertaken to determine the efficacy of coadministration of fingolimod with alteplase in acute ischemic stroke patients in a delayed time window. METHODS: This was a prospective, randomized, open-label, blinded endpoint clinical trial, enrolling patients with internal carotid artery or middle cerebral artery proximal occlusion within 4.5 to 6 hours from symptom onset. Patients were randomly assigned to receive alteplase alone or alteplase with fingolimod. All patients underwent pretreatment and 24-hour noncontrast computed tomography (CT)/perfusion CT/CT angiography. The coprimary endpoints were the decrease of National Institutes of Health Stroke Scale scores over 24 hours and the favorable shift of modified Rankin Scale score (mRS) distribution at day 90. Exploratory outcomes included vessel recanalization, anterograde reperfusion, and retrograde reperfusion of collateral flow. RESULTS: Each treatment group included 23 patients. Compared with alteplase alone, patients receiving fingolimod plus alteplase exhibited better early clinical improvement at 24 hours and a favorable shift of mRS distribution at day 90. In addition, patients who received fingolimod and alteplase exhibited a greater reduction in the perfusion lesion accompanied by suppressed infarct growth by 24 hours. Fingolimod in conjunction with alteplase significantly improved anterograde reperfusion of downstream territory and prevented the failure of retrograde reperfusion from collateral circulation. INTERPRETATION: Fingolimod may enhance the efficacy of alteplase administration in the 4.5- to 6-hour time window in patients with a proximal cerebral arterial occlusion and salvageable penumbral tissue by promoting both anterograde reperfusion and retrograde collateral flow. These findings are instructive for the design of future trials of recanalization therapies in extended time windows. Ann Neurol 2018;84:725-736.

Treatment satisfaction significantly improves in patients with multiple sclerosis switching from interferon beta therapy to peginterferon beta-1a every 2 weeks.

OBJECTIVES: Posthoc analysis of treatment satisfaction in patients switching to subcutaneous (SC) peginterferon beta-1a in the ALLOW study. PATIENTS AND METHODS: Patients with relapsing multiple sclerosis treated with intramuscular interferon (IFN) beta-1a or SC IFN beta-1a or beta-1b remained on their current therapy for a 4-week run-in period, followed by a switch to SC peginterferon beta-1a 125 mcg every 2 weeks for 48 weeks. Treatment satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM), which covers effectiveness, side effects, convenience, and global satisfaction. Patients completed the TSQM at baseline (prior to starting the 4-week run-in period) and 4, 12, 24, 36, and 48 weeks after switching, and scores were analyzed for the overall population and compared to baseline. Patients reported the severity of flu-like symptoms (FLS) at baseline and with each peginterferon beta-1a injection; clinicians evaluated the occurrence of injection-site reactions (ISRs) after the first dose of peginterferon beta-1a and every 12 weeks thereafter. TSQM scores were stratified by the presence of FLS or ISRs during the study period and by prior IFN therapy use. RESULTS: For the overall population (n=194), convenience and global satisfaction scores significantly improved from baseline at all time points, and side effect satisfaction scores significantly improved up to week 36. Convenience scores significantly improved regardless of FLS, ISRs, or prior IFN therapy. Patients without FLS during the study period showed significant improvements in global satisfaction, but not side effect satisfaction, versus those with FLS. Patients switching from SC IFN therapies achieved greater improvements in treatment satisfaction than patients who switched from intramuscular IFN beta-1a. CONCLUSIONS: Switching relapsing multiple sclerosis patients to SC peginterferon beta-1a from other IFN therapies significantly improved treatment satisfaction and convenience.

Subcutaneous peginterferon ß-1a injection-site reaction experience and mitigation: Delphi analysis of the ALLOW study.

AIM: The objective of this Delphi analysis was to obtain consensus on injection-site reaction (ISR) experience and mitigation strategies for patients with relapsing-remitting multiple sclerosis switching from nonpegylated interferons (IFNs) to peginterferon ß-1a in the ALLOW Phase IIIb trial using a three-step approach. METHODS: Study investigators and coordinators from investigative sites enrolling four or more patients in ALLOW participated in three rounds of questionnaires and interviews. RESULTS: Respondents (n = 37) agreed that the most common ISR, erythema, was not disruptive to daily activities. Patient education, as a conversation with a clinician about ISR potential, was recommended. CONCLUSION: The consensus of Delphi respondents on ISR experience and ISR management after switching from nonpegylated IFNs to peginterferon ß-1a can help inform treatment decisions and manage patient expectations.

Dimethyl Fumarate and Monomethyl Fumarate Promote Post-Ischemic Recovery in Mice.

Oxidative stress plays an important role in cerebral ischemia-reperfusion injury. Dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) are antioxidant agents that can activate the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and induce the expression of antioxidant proteins. Here, we evaluated the impact of DMF and MMF on ischemia-induced brain injury and whether the Nrf2 pathway mediates the effects provided by DMF and MMF in cerebral ischemia-reperfusion injury. Using a mouse model of transient focal brain ischemia, we show that DMF and MMF significantly reduce neurological deficits, infarct volume, brain edema, and cell death. Further, DMF and MMF suppress glial activation following brain ischemia. Importantly, the protection of DMF and MMF was mostly evident during the subacute stage and was abolished in Nrf2-/- mice, indicating that the Nrf2 pathway is required for the beneficial effects of DMF and MMF. Together, our data indicate that DMF and MMF have therapeutic potential in cerebral ischemia-reperfusion injury and their protective role is likely mediated by the Nrf2 pathway.

Management Strategies for Flu-Like Symptoms and Injection-Site Reactions Associated with Peginterferon Beta-1a: Obtaining Recommendations Using the Delphi Technique.

BACKGROUND: Flu-like symptoms (FLSs) and injection-site reactions (ISRs) have been reported with interferon beta treatments for multiple sclerosis (MS). We sought to obtain consensus on the characteristics/management of FLSs/ISRs in patients with relapsing-remitting MS based on experiences from the randomized, placebo-controlled ADVANCE study of peginterferon beta-1a. METHODS: ADVANCE investigators with a predefined number of enrolled patients were eligible to participate in a consensus-generating exercise using a modified Delphi method. An independent steering committee oversaw the development of two sequential Delphi questionnaires. An average rating (AR) of 2.7 or more was defined as consensus a priori. RESULTS: Thirty and 29 investigators (ie, responders) completed questionnaires 1 and 2, respectively, representing 374 patients from ADVANCE. Responders reported that the incidence/duration of FLSs/ISRs in their typical patient generally declined after 3 months of treatment. Responders reached consensus that FLSs typically last up to 24 hours (AR = 3.17) and have mild/moderate effects on activities of daily living (AR = 3.34). Patients should initiate acetaminophen/nonsteroidal anti-inflammatory drug treatment on a scheduled basis (AR = 3.31) and change the timing of injection (AR = 3.28) to manage FLSs. Injection-site rotation/cooling and drug administration at room temperature (all AR ≥ 3.10) were recommended for managing ISRs. Patient education on FLSs/ISRs was advocated before treatment initiation. CONCLUSIONS: Delphi responders agreed on the management strategies for FLSs/ISRs and agreed that patient education is critical to set treatment expectations and promote adherence.

Natalizumab-treated patients at high risk for PML persistently excrete JC polyomavirus.

Sixty-three natalizumab-treated patients with relapsing multiple sclerosis were screened for JC polyomavirus (JCV) viruria. Urinary-positive patients were longitudinally sampled for up to 24 weeks. Using methods that distinguish encapsidated virus from naked viral DNA, 17.5 % of patients were found to excrete virus, consistent with the prevalence of urinary excretion in the general population. Unexpectedly, urinary excretion was predominantly seen (>73 %) in patients with high JC antibody index (≥2.0). Active JCV infection, therefore, tends to occur in natalizumab patients that carry a high risk factor for the development of disease, directly linking JC infection to the risk factors for PML development.

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Preclinical studies and a proof-of-concept clinical study have shown that sphingosine-1-phosphate receptor (S1PR) modulator, fingolimod, improves the clinical outcome of intracerebral hemorrhage (ICH). However, the specific subtype of the S1PRs through which immune modulation provides protection in ICH remains unclear. In addition, fingolimod-induced adverse effects could limit its use in patients with stroke because of interactions with other S1PR subtypes, particularly with S1PR3. RP101075 is a selective S1PR1 agonist with superior cardiovascular safety profile. In this study, we investigated the impact of RP101075 treatment in a mouse model of ICH. METHODS: ICH was induced by injection of autologous blood in 294 male C57BL/6J and Rag2(-/-) mice. ICH mice randomly received vehicle, RP101075, or RP101075 plus S1PR1 antagonist W146 by daily oral gavage for three consecutive days, starting from 30 minutes after surgery. Neurodeficits, brain edema, brain infiltration of immune cells, blood-brain barrier integrity, and cell death were assessed after ICH. RESULTS: RP101075 significantly attenuated neurological deficits and reduced brain edema in ICH mice. W146 blocked the effects of RP101075 on neurodeficits and brain edema. RP101075 reduced the counts of brain-infiltrating lymphocytes, neutrophils, and microglia, as well as cytokine expression after ICH. Enhanced blood-brain barrier integrity and alleviated neuronal death were also seen in ICH mice after RP101075 treatment. CONCLUSIONS: S1PR1 modulation via RP101075 provides protection in experimental ICH. Together with the advantageous pharmacological features of RP101075, these results warrant further investigations of its mechanisms of action and translational values in ICH patients.

Challenges in randomized controlled trials and emerging multiple sclerosis therapeutics.

The remarkable global development of disease-modifying therapies (DMTs) specific for multiple sclerosis (MS) has significantly reduced the frequency of relapse, slowed the progression of disability, and improved the quality of life in patients with MS. With increasing numbers of approved DMTs, neurologists in North America and Europe are able to present multiple treatment options to their patients to achieve a better therapeutic outcome, and in many cases, no evidence of disease activity. MS patients have improved accessibility to various DMTs at no or minimal out-of-pocket cost. The ethical guidelines defined by the Edinburgh revision of the Declaration of Helsinki strongly discourage the use of placebo control groups in modern MS clinical trials. The use of an active comparator control group increases the number of participants in each group that is essential to achieve statistical significance, thus further increasing the difficulty of completing randomized controlled trials (RCTs) for the development of new MS therapies. There is evidence of a high prevalence of MS and a large number of patients in Asia. The belief of the existence of Asian types of MS that are distinct from Western types, and regulatory policies are among the reasons why DMTs are limited in most Asian countries. Lack of access to approved DMTs provides a good opportunity for clinical trials that are designed for the development of new MS therapies. Recently, data from RCTs have demonstrated excellent recruitment of participants and the completion of multi-nation and single-nation MS trials within this region. Recent studies using the McDonald MS diagnostic criteria carefully excluded patients with neuromyelitis optica (NMO) and NMO spectrum disorder, and demonstrated that patients with MS in Asia have clinical characteristics and treatment responses similar to those in Western countries.

Combination of the Immune Modulator Fingolimod With Alteplase in Acute Ischemic Stroke: A Pilot Trial.

BACKGROUND: Inflammatory and immune responses triggered by brain ischemia worsen clinical outcomes of stroke and contribute to hemorrhagic transformation, massive edema, and reperfusion injury associated with intravenous alteplase. We assessed whether a combination of the immune-modulator fingolimod and alteplase is safe and effective in attenuating reperfusion injury in patients with acute ischemic stroke treated within the first 4.5 hours of symptom onset. METHODS AND RESULTS: In this multicenter trial, we randomly assigned 25 eligible patients with hemispheric ischemic stroke stemming from anterior or middle cerebral arterial occlusion to receive alteplase alone and 22 patients to receive alteplase plus oral fingolimod 0.5 mg daily for 3 consecutive days within 4.5 hours of the onset of ischemic stroke. Compared with patients who received alteplase alone, patients who received the combination of fingolimod with alteplase exhibited lower circulating lymphocytes, smaller lesion volumes (10.1 versus 34.3 mL; P=0.04), less hemorrhage (1.2 versus 4.4 mL; P=0.01), and attenuated neurological deficits in National Institute of Health Stroke Scales (4 versus 2; P=0.02) at day 1. Furthermore, restrained lesion growth from day 1 to 7 (-2.3 versus 12.1 mL; P<0.01) with a better recovery at day 90 (modified Rankin Scale score 0-1, 73% versus 32%; P<0.01) was evident in patients given fingolimod and alteplase. No serious adverse events were recorded in all patients. CONCLUSIONS: In this pilot study, combination therapy of fingolimod and alteplase was well tolerated, attenuated reperfusion injury, and improved clinical outcomes in patients with acute ischemic stroke. These findings need to be tested in further clinical trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02002390.

Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study.

IMPORTANCE: Pronounced inflammatory reactions occurring shortly after intracerebral hemorrhage (ICH) contribute to the formation and progression of perihematomal edema (PHE) and secondary brain injury. We hypothesized that modulation of brain inflammation reduces edema, thus improving clinical outcomes in patients with ICH. OBJECTIVE: To investigate whether oral administration of fingolimod, a Food and Drug Administration-approved sphingosine 1-phosphate receptor modulator for multiple sclerosis, is safe and effective in alleviating PHE and neurologic deficits in patients with ICH. DESIGN, SETTING, AND PARTICIPANTS: In this 2-arm, evaluator-blinded study, we included 23 patients with primary supratentorial ICH with hematomal volume of 5 to 30 mL. 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, China. INTERVENTIONS: All patients received standard management alone (control participants) or combined with fingolimod (FTY720, Gilenya), 0.5 mg, 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. MAIN OUTCOMES AND MEASURES: 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. RESULTS: Patients treated with fingolimod exhibited a reduction of neurologic impairment compared with control individuals, regained a Glasgow Coma Scale score of 15 by day 7 (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 first week 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 rPHE were significantly smaller in fingolimod-treated patients than in control individuals (Ev at day 7, 47 mL vs 108 mL, P = .04; Ev at day 14, 55 mL vs 124 mL, P = .07; rPHE at day 7, 2.5 vs 6.4, P < .001; rPHE at day 14, 2.6 vs 7.7, P = .003, respectively). We recorded no differences between groups in the occurrence of adverse events. CONCLUSIONS AND RELEVANCE: In patients with small- to moderate-sized deep primary supratentorial ICH, administration of oral fingolimod within 72 hours of disease onset was safe, reduced PHE, attenuated neurologic deficits, and promoted recovery. The efficacy of fingolimod in preventing secondary brain injury in patients with ICH warrants further investigation in late-phase trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT02002390.

Advances in the immune pathogenesis and treatment of multiple sclerosis.

Multiple sclerosis (MS) is a disorder of the central nervous system (CNS). It is characterized by episodic and progressive neurological dysfunction resulting from inflammatory and autoimmune reactions, myelin loss, conduction block, oligodendrocyte pathology, gliosis, and axonal loss in CNS. Recent years have witnessed advances in better understanding the immune pathogenesis of MS, prompted by animal models, human pathological observations and MRI studies. There have been significant changes in the therapeutic regimens in MS, with an emphasis on preventative treatment of an ongoing disease process. Agents in use and in the research pipeline have mechanisms that act on various anti-inflammatory and immunomodulatory properties, including blocking leukocyte migration into CNS and targeting chemoattraction. In addition, recent studies on the neurodegenerative components of MS have directed therapeutic trials to neuroprotection and neurorestoration. In this paper, we summarize the current understanding of the mechanisms of approved pharmacological agents and review the putative mechanisms and status of some important agents in clinical phase two or three trials in MS.

Neurodegeneration and neuroprotective agents in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune/ inflammatory disease of the central nervous system (CNS). MS affects more than two million people worldwide and has been recognized as the leading cause of neurological disability in young adults. MS has long been considered as a CNS disease of demyelination and inflammation. Axonal degeneration has however been increasingly accepted as a key pathogenetic element. Certain noninvasive tests such as optic coherence tomography (OCT), magnetization transfer imaging (MTI), and proton magnetic resonance spectroscopy (MRS) might be superior in early detection of axonal loss and neurodegeneration as compared to conventional neuroimaging studies. New therapeutic strategies targeting the neurodegenerative process in MS provide hope to the MS community. A number of phase II or III clinical trials that are designed to target such specific pathogenetic mechanisms include sodium channel blockers, matrix metalloproteinases (MMP) inhibitors, c-AMP selective phosphodiesterase inhibitors, NMDA receptor antagonists, amongst others. In the current review, we will discuss the current understanding of the mechanisms of neurodegeneration in MS, agents with neuroprotective properties, patents currently available and, their possible application in the treatment of MS.

Update on PML: lessons from the HIV uninfected and new insights in pathogenesis and treatment.

Significant advances in our understanding of progressive multifocal leukoencephalopathy (PML) and its causative agent, JC virus, have been made since PML was first described 50 years ago. However, immune reconstitution remains the only proven, effective therapy in this devastating central nervous system disorder. Early diagnosis and adjustments of immune suppressants and modulator agents are critical in managing PML in HIV-negative patients. This review summarizes recent advances in our understanding of PML in HIV-uninfected patients in oncology, rheumatology, organ transplantation, and idiopathic immune deficiency and in association with novel therapeutics. Brain MRI data from our case series of brain biopsy-proven HIV-negative PML patients indicate the presence of an inflammatory/immune reaction in brain tissues, which was confirmed by immunocytologic analysis. Future studies to better understand PML pathogenesis in HIV-negative individuals may help uncover new potential therapeutic targets and improve PML outcomes.

CCL2 recruitment of IL-6-producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17-dependent B cell-mediated autoimmunity.

The development and function of Th17 cells are influenced in part by the cytokines TGF-beta, IL-23 and IL-6, but the mechanisms that govern recruitment and activity of Th17 cells during initiation of autoimmunity remain poorly defined. We show here that the development of autoreactive Th17 cells in secondary lymphoid organs in experimental autoimmune myasthenia gravis--an animal model of human myasthenia gravis--is modulated by IL-6-producing CD11b(+) cells via the CC chemokine ligand 2 (CCL2). Notably, acetylcholine receptor (AChR)-reactive Th17 cells provide help for the B cells to produce anti-AChR antibodies, which are responsible for the impairment of the neuromuscular transmission that contributes to the clinical manifestations of autoimmunity, as indicated by a lack of disease induction in IL-17-deficient mice. Thus, Th17 cells can promote humoral autoimmunity via a novel mechanism that involves CCL2.

Inflammatory progressive multifocal leukoencephalopathy in human immunodeficiency virus-negative patients.

OBJECTIVE: Inflammatory progressive multifocal leukoencephalopathy (iPML) with enhancing magnetic resonance imaging (MRI) lesions and leukocyte infiltration occurs in human immunodeficiency virus (HIV)-infected individuals after highly active antiretroviral therapy (HAART) treatment. MRI diagnostic criteria for PML suggest that iPML does not occur in HIV-negative individuals. METHODS: We studied pathologically proved PML (12 by biopsy, 9 with MRI, 32 at autopsy). RESULTS: HIV-negative (2/5) and -positive (2/4) PML patients had enhancing MRI lesions, correlated with CD3(+) lymphocyte infiltration. Inflammatory infiltrates occurred in the majority of HIV-negative (7/8) and HIV-positive/HAART (17/20) cases (p > 0.2), but in only 2 of 16 HIV-positive/non-HAART cases (p < 0.001). INTERPRETATION: iPML showed radiographic and pathological similarity in HIV-positive/HAART and HIV-negative patients. HIV-negative iPML necessitates further consideration of MRI criteria for PML.

The neuronal chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system.

Leukocyte trafficking to the central nervous system (CNS), regulated in part by chemokines, determines severity of the demyelinating diseases multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). To examine chemokine receptor CX3CR1 in EAE, we studied CX3CR1(GFP/GFP) mice, in which CX3CR1 targeting by insertion of Green Fluorescent Protein (GFP) allowed tracking of CX3CR1+ cells in CX3CR1(+/GFP) animals and cells destined to express CX3CR1 in CX3CR1(GFP/GFP) knockouts. NK cells were markedly reduced in the inflamed CNS of CX3CR1-deficient mice with EAE, whereas recruitment of T cells, NKT cells and monocyte/macrophages to the CNS during EAE did not require CX3CR1. Impaired recruitment of NK cells in CX3CR1(GFP/GFP) mice was associated with increased EAE-related mortality, nonremitting spastic paraplegia and hemorrhagic inflammatory lesions. The absence of CD1d did not affect the severity of EAE in CX3CR1(GFP/GFP) mice, arguing against a role for NKT cells. Accumulation of NK cells in livers of wild-type (WT) and CX3CR1(GFP/GFP) mice with cytomegalovirus hepatitis was equivalent, indicating that CX3CL1 mediated chemoattraction of NK cells was relatively specific for the CNS. These results are the first to define a chemokine that governs NK cell migration to the CNS, and the findings suggest novel therapeutic manipulation of CX3CR1+ NK cells.