Effect of adherence to the first-generation injectable immunomodulatory drugs on disability accumulation in multiple sclerosis: a longitudinal cohort study.

OBJECTIVE: To examine the association between optimal adherence to the first-generation injectable immunomodulatory drugs (IMDs) for multiple sclerosis (MS) and subsequent disability accumulation. METHODS: We accessed prospectively collected linked clinical and administrative health data from British Columbia, Canada. Subjects with MS treated with a first-generation injectable IMD at an MS clinic (1996-2004) were followed until their last clinic visit before 2009. Adherence was estimated using the proportion of days covered (PDC). The primary outcome was disability accumulation, defined as an increase in the Expanded Disability Status Scale (EDSS) score as recorded during each year of follow-up. Generalised estimating equation models, adjusted for baseline sex, age, EDSS and time between scores, were used to measure associations between optimal adherence (≥80% PDC) during the first year of treatment and subsequent disability accumulation. The relationship between early IMD adherence and the secondary outcome, time to sustained EDSS 6, was examined using Cox proportional hazards regression. RESULTS: Among 801 subjects, 598 (74.7%) had optimal adherence over the first year of IMD treatment and 487 (39.0%) demonstrated one or more instances of disability accumulation. Early optimal adherence was not associated with disability accumulation (adjusted OR 0.94; 95% CI 0.78 to 1.15), nor with time to sustained EDSS 6 (adjusted HR 0.91; 95% CI 0.57 to 1.44). CONCLUSION: Almost three-quarters of subjects with MS had optimal early adherence to their first-line injectable IMD. There was no evidence that this was associated with disability accumulation in the following years.

A NK complex-linked locus restricts the spread of herpes simplex virus type 1 in the brains of C57BL/6 mice.

The most frequent cause of sporadic viral encephalitis in western countries is Herpes simplex virus (HSV). Despite treatment, mortality rates reach 20-30% while survivors often suffer from significant morbidity. In mice, resistance to lethal Herpes simplex encephalitis (HSE) is multifactorial and influenced by mouse and virus strain as well as route of infection. The ability to restrict viral spread in the brain is one factor contributing to resistance. After infection of the oral mucosa with HSV type 1 (HSV-1), virus spreads throughout the brains of susceptible strains but is restricted in resistant C57BL/6 mice. To further investigate restriction of viral spread in the brain, mendelian analysis was combined with studies of congenic, intra-natural killer complex (intra-NKC) recombinant and antibody-depleted mice. Results from mendelian analysis support the restriction of viral spread as a dominant trait and consistent with a single gene effect. In congenic mice, the locus maps to the NKC on chromosome 6 and is provisionally termed Herpes Resistance Locus 2 (Hrl2). In intra-NKC recombinants, the locus is further mapped to the segment Cd69 through D6Wum34; a different location from previously identified loci (Hrl and Rhs1) also associated with HSV-1 infection. Studies with antibody-depleted mice indicate the effect of this locus is mediated by NK1.1(+) expressing cells. This model increases our knowledge of lethal HSE, which may lead to new treatment options.

The effect of mouse strain on herpes simplex virus type 1 (HSV-1) infection of the central nervous system (CNS).

BACKGROUND: Mice infected with HSV-1 can develop lethal encephalitis or virus induced CNS demyelination. Multiple factors affect outcome including route of infection, virus and mouse strain. When infected with a sub-lethal dose of HSV-1 strain 2 via the oral mucosa, susceptible SJL/J, A/J, and PL/J mice develop demyelinating lesions throughout the brain. In contrast, lesions are restricted to the brainstem (BST) in moderately resistant BALB/c mice and are absent in resistant BL/6 mice. The reasons for the strain differences are unknown. METHODS: In this study, we combine histology, immunohistochemistry, and in-situ hybridization to investigate the relationship between virus and the development of lesions during the early stage (< 24 days PI) of demyelination in different strains of mice. RESULTS: Initially, viral DNA and antigen positive cells appear sequentially in non-contiguous areas throughout the brains of BALB/c, SJL/J, A/J, and PL/J mice but are restricted to an area of the BST of BL/6 mice. In SJL/J, A/J, and PL/J mice, this is followed by the development of 'focal' areas of virus infected neuronal and non-neuronal cells throughout the brain. The 'focal' areas follow a hierarchical order and co-localize with developing demyelinating lesions. When antigen is cleared, viral DNA positive cells can remain in areas of demyelination; consistent with a latent infection. In contrast, 'focal' areas are restricted to the BST of BALB/c mice and do not occur in BL/6 mice. CONCLUSIONS: The results of this study indicate that susceptible mouse strains, infected with HSV-1 via the oral mucosa, develop CNS demyelination during the first 24 days PI in several stages. These include: the initial spread of virus and infection of cells in non-contiguous areas throughout the brain, the development of 'focal' areas of virus infected neuronal and non-neuronal cells, the co-localization of 'focal' areas with developing demyelinating lesions, and latent infection in a number of the lesions. In contrast, the limited demyelination that develops in BALB/c and the lack of demyelination in BL/6 mice correlates with the limited or lack of 'focal' areas of virus infected neuronal and non-neuronal cells in these two strains.

Redundancy in the immune system restricts the spread of HSV-1 in the central nervous system (CNS) of C57BL/6 mice.

Resistance to lethal encephalitis in mice infected with HSV-1 via the oral mucosa is mouse strain dependent. In susceptible BALB/c, HSV-1 spreads throughout the CNS but in resistant BL/6 mice, virus is restricted to the brainstem. To examine the contribution of cellular immunity in restricting viral spread, we used a combination of antibody depleted and KO mice. Individually, NK/NKT, iNKT, CD4(+), CD8(+), and gammadelta T-cells do not restrict HSV-1 spread. In contrast, virus spreads throughout the CNS of BL/6 CL I KO mice and BL/6 mice treated with either anti-asialoGM1 Ab or both anti-CD8 and anti-NK1.1 mAbs. The results highlight the importance of redundancy in the immune system in restricting viral spread in the CNS, argue for a role of NK/NKT and CD8(+) T-cells in mediating the restriction, and provide a hierarchical order of the individual elements in controlling virus in BL/6 mice infected with HSV-1 via the oral mucosa.

Clinical relapses of multiple sclerosis are associated with 'novel' valleys in natural killer cell functional activity.

Natural killer (NK) cells are implicated in the pathogenesis of multiple sclerosis (MS). Nine relapsing-remitting MS (RRMS) patients along with age, sex, and NK responder status matched controls were studied serially. Although the average NK cell functional activity (FA) was not significantly different between both groups, four clinical relapses in RRMS patients were associated with the development of 'novel' valleys in FA. These valleys are of greater depth and duration than cyclical valleys observed in both RRMS and controls, precede the onset of clinical attacks, and are observed in RRMS but not controls. In both RRMS and controls, cyclical peaks and valleys in FA are determined by the number of CD33+, CD3-CD56+, and to a lesser extent CD3+CD56+ cells capable of binding targets and inducing cell-mediated cytotoxicity (CMC). In contrast, 'novel' valleys in FA result from a reduction in the ability of CD3-CD56+ bound to targets to induce CMC. The results suggest that RRMS patients are at greater risk for clinical relapses during 'novel' valleys in FA. Furthermore, these valleys are the result of cells with a NK cell phenotype being unable to deliver a 'lethal' hit to targets.

Oligodendrocytes from human donors differ in resistance to herpes simplex virus 1 (HSV-1).

Primary cultures of human oligodendrocytes (HOLs) were established from six different donors. Differences in resistance to infection with herpes simplex virus 1 (HSV-1) were determined between the primary cultures of HOL in tissue culture infective dose 50 (TCID(50)), indirect immunofluoresence (IF), and serial electron microscopy (EM) studies. Virus production at different multiplicities of infection (MOIs) indicated that differences in HSV-1 replication were statistically significant and MOI-dependent. Overall, virus yield from the HOL cultures infected at an MOI of 1 increased up to 6 days postinfection (PI); no additional enhancement occurred at 7 days PI. However, differences in the replication capacity of the six HOL cultures observed at 5 days PI persisted at 6 and 7 days PI. When taken together, the results of these investigations indicate that, similar to experimental animals, resistance to HSV-1 differs between primary cultures of HOL and is donor-dependent. The results also raise the possibility that similar to experimental animals, resistance to HSV-1, mediated at the level of HOL, may be genetically determined. Furthermore, permissive infections of primary cultures of HOL were established with HSV-1 over a wide range of MOIs, similar to results obtained with viral infection of primary murine oligodendrocytes, but neither latent nor abortive infections of HOL were induced in vitro, even at very low MOIs. Resistance to HSV-1, mediated by glial cells, is a nonimmune mechanism that may influence the development of acute CNS infection in man as well as individual susceptibility to this virus.