Search

Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system. Autoantibodies are though to participate in the pathogenesis. Previous reports on the role of immunoglobulin (Ig) variable gene segments in MS are contradictory. Here, by using a highly polymorphic variable number tandem repeat (VNTR) marker located in the centre of the IgH chain locus, we demonstrate a lack of linkage and association with MS in 34 multiplex families and 113 sporadic MS patients in Sweden. Stratification for the presence or absence of the MS-associated HLA-Dw2 haplotype did not influence the negative outcome. We conclude that the IgH chain genes are unlikely to play a role in genetic susceptibility to MS in the Swedish population.

Biological pharmaceuticals are increasingly used in modern medicine and give remarkable improvements for many different patient groups. Unfortunately, for several of these compounds, undesirable immune reactions are induced against the drug. The resulting anti-drug antibodies modify the pharmacokinetic and pharmacodynamic properties of the drug and, by blocking the drug-target interaction, reduce the effects of the treatment. Anti-drug antibodies may also increase the risk of hypersensitivity reactions by the formation of immune complexes. Furthermore, by cross-reacting with the endogenous homolog of the drug, the anti-drug antibodies might impair important physiological functions even after treatment cessation. As a consequence, anti-drug antibodies need to be taken in account when estimating the benefit-burden ratio of a treatment for an individual patient, but also when calculating the value of therapeutics on a socio-economic level. In this review we give an overview over the current understanding of the immunogenicity against drugs, exemplified for patients with hemophilia A, multiple sclerosis, rheumatoid arthritis and Crohn’s disease. We discuss known and potential risk factors for anti-drug antibody formation and finally outline suggested strategies for prediction and prevention.

Objective: Investigate if certain human leukocyte antigen (HLA) class I and II allele groups are associated with the susceptibility to develop neutralizing antibodies (NAbs) in a Swedish cohort of patients with multiple sclerosis (MS) treated with interferon-beta (IFN-beta) and whether or not an association with clinically relevant NAb-titers exists. Background A proportion of MS patients receiving IFN-beta therapy develop NAbs that interfere with treatment efficacy. However, NAbs only occur in a subset of patients, which indicates that factors like the carrying of different HLA allele groups could be involved in determining the risk for developing NAbs. Design/Methods: 1066 patients with NAb-status, from the Swedish NAb-registry, and HLA genotype data were included. Patients were regarded as NAb-positive when having at least one positive sample. Negativity was defined as never having a positive titer, with either one negative sample taken 24±3 months after the start of IFN-beta treatment or two negative samples taken between 6 to 21 and 27 to 36 months after treatment start. 419 patients matched these criteria of which 230 were NAb-positive and 189 NAb-negative. Cut-off for clinical relevant titers was a NAb-titer higher than 150 TRU/ml. The frequency distribution for each allele was analyzed by chi-square and odds ratio was assessed with 95% confidence interval, p Results: No significant association could be found between allele group frequency distribution and the development of NAbs, neither with nor without correcting for treatment. However, HLA-DRB1*15 was associated with clinically relevant titers (OR 1.45, p-value 0.036). Conclusions: NAb development being associated with specific allele groups, as described in earlier studies, could not be replicated but our results indicate that the development of clinically relevant titers is associated with HLA-DRB1*15. Knowing this could help when choosing newer substitute medications for IFN-beta. Disclosure: Dr. Fink has received research support from Biogen Idec. Dr. Lundkvist has received research support from Biogen Idec. Ms. Link has received research support from Karolinska Institutet. Dr. Kockum has nothing to disclose. Dr. Hermanrud has nothing to disclose. Dr. Brynedal has received research support from the Swedish Research Council. Dr. Hillert has received personal compensation for activities with Biogen Idec, Merck-Serono, Novartis and Teva Neuroscience as participant on advisory boards, consulting and/or speaking engagements.Dr. Hillert has received research support from Sanofi-Aventis Pharmaceuticals, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec and Merck-Serono. Dr. Fogdell has received research support from Biogen Idec, Merck Serono, and Sanofi-Aventis Pharmaceuticals, Inc.

Objective: To assess anti-JCV antibody titer changes in patients with Multiple Sclerosis (MS) prior to and after initiation of treatment with natalizumab. Background Progressive multifocal leukoencephalopathy (PML) is a known side effect associated with natalizumab. Recently, an analytically validated anti-JCV antibody assay has been introduced into clinical practice to stratify patients with MS for higher or lower risk of PML. Design/Methods: The anti-JCV antibody assay (Gorelik et al., Ann. Neurol. 2010) was applied to serum samples of Swedish MS patients during treatment with interferon beta (n=415), prior to (n=840), and during treatment with natalizumab (n=840). Positive samples were diluted in 1:3 dilution steps to determine titer levels. A randomly selected proportion (n=211) of the same patients were also tested for 1:3 dilution titers of antibodies toward a nuclear human-cytomegalovirus (CMV) antigen (Schmitz et al., J. Clin. Microbiol. 1977). In addition, 716 of the patients were studied for antibodies toward the recombinant varicella-zoster (VZV) glycoprotein E antigen (Thomsson, J. Virol. Methods 2011). Results: The majority of patients did not change in anti-JCV antibody titers during treatment with natalizumab. However, in anti-JCV antibody positive patients, the relative number of patients having a decrease in anti-JCV antibody titers was higher in natalizumab treated patients compared with interferon beta treated patients, suggesting an effect of natalizumab treatment on the humoral immune response to JCV. While this was not seen for titers toward CMV, anti-VZV-IgG antibodies also declined in a majority of the natalizumab treated patients. Whereas only 5% of all anti-JCV antibody positive patients during natalizumab treatment showed an increase in anti-JCV antibody titers, a Swedish PML case demonstrated rising titers prior to diagnosis - albeit only by one titer level compared with baseline. Conclusions: An increase in anti-JCV antibody titers during natalizumab therapy warrants further study in the context of PML risk stratification. Supported by: CW is supported by an ECTRIMS fellowship stipend. We acknowledge the help of A. Mattsson, E. Karlberg, M. Lundqvist, C. Hermanrud, H. Westerlind, R. Ramanujam, A. Ahlberg, R. Jungedal, J. Link, I. Lima Bomfim, B. Davoudi, V. Bedarova, L. Mascarell Maricic, A. Carlsson, M. Johansson and K. Fink to realize this project. Disclosure: Dr. Warnke has nothing to disclose. Dr. Subramanyam has received personal compensation for activities with Biogen Idec as an employee. Dr. Subramanyam holds stock and/or stock options in Biogen Idec. Dr. Bergstrom has nothing to disclose. Dr. Goelz has received personal compensation for activities with Biogen Idec and Elan Pharmaceuticals as an employee. Dr. Goelz holds stock and/or stock options in Biogen Idec., which sponsored research in which Dr. Goelz was involved as an investigator. Dr. Goelz holds stock and/or stock options in Biogen Idec. Dr. Goelz has received research support from Biogen Idec. Dr. Plavina has received personal compensation for activities with Biogen Idec as an employee.Dr. Plavina holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Plavina was involved as an investigator. Dr. Kockum has nothing to disclose. Dr. Rahbar has nothing to disclose. Dr. Olsson has nothing to disclose. Dr. Hillert has received personal compensation for activities with Biogen Idec, Merck-Serono, Novartis and Teva Neuroscience as participant on advisory boards, consulting and/or speaking engagements.Dr. Hillert has received research support from Sanofi-Aventis Pharmaceuticals, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec and Merck-Serono. Dr. Fogdell has received research support from Biogen Idec, Merck Serono, and Sanofi-Aventis Pharmaceuticals, Inc.

The ultrastructural replication cycle of human herpesvirus 6A and 6B, both T-lymphotropic viruses, with tropism for the central nervous system,wascomparedbyelectronmicroscopyin the same cells, that is, in the T-lymphoblastoid cell line SupT-1 and in human astrocytes. Both HHV-6A and HHV-6B replicated efficiently in SupT-1 and formed viral particles. The tegument is the least characterized structure of the herpesviral particle and both variants were able to form intranuclear membrane compartments called tegusomes in SupT-1 where tegumentation occurred. Also, tegumentation occurred in HHV6A infected cells in the nucleoplasm without the presence of a tegusome. This suggests that there is more than one possible route of tegumentation.Differencesinthereplicationcyclesbetween