A double-blind, placebo-controlled trial of extracorporeal photopheresis in chronic progressive multiple sclerosis.

Extracorporeal photopheresis is a safe therapy for cutaneous T-cell lymphoma and may have efficacy in certain autoimmune disorders. We performed a randomized, double-blinded, placebo-controlled trial of monthly photopheresis therapy in 16 patients with clinically definite multiple sclerosis (MS). All patients had progressed during the preceding year with entry Expanded Disability Status Scale (EDSS) scores between 3.0 and 7.0. Patients received photopheresis or sham therapy for 1 year and were followed for an additional 6 to 12 months. Patients were clinically evaluated by three disability scales: (1) EDSS; (2) Ambulation index and (3) Scripp's quantitative neurologic assessment. No serious side effects occurred in either group. There were no differences between the photopheresis and sham therapy groups by the disability measures. Additionally, there were no differences in progression of MRI plaque burden or evoked potential latencies. In this limited study, photopheresis was found to be safe but did not significantly alter the course of chronic progressive MS.

Specific treatment of multiple sclerosis.

Attempts to provide specific treatment for individuals with multiple sclerosis (MS) are mostly within the realm of immunotherapy. The word "specific" is somewhat misleading, since it implies sufficient understanding of the pathogenesis of MS to relate a specific action by a therapeutic agent to a desired effect. Therapies can be categorized as antiinflammatory (e.g., glucocorticoids, immunosuppressants), or immunomodulatory (e.g., interferons, monoclonal antibodies). However, many agents have multiple actions that confound simple categorization. The current favorites include glucocorticoids for the treatment of acute attacks and interferon-beta (IFN-beta) to reduce the number and severity of attacks.

Revised estimate of the prevalence of multiple sclerosis in the United States.

Using three adjustments, we have revised a 1976 prevalence count for multiple sclerosis in the United States. The adjustments were made to data from a US national survey; they used 1990 population projections from the US Bureau of the Census, and results of investigations conducted in Weld and Larimer Countries, Colorado, and Olmsted County, Minnesota. It is estimated that approximately 250,000 to 350,000 persons in the United States in 1990 had physician-diagnosed multiple sclerosis.

Galactosyl ceramide or a derivative is an essential component of the neural receptor for human immunodeficiency virus type 1 envelope glycoprotein gp120.

This report demonstrates that galactosyl ceramide (GalCer) or a molecule derived from it may serve as an alternative receptor for human immunodeficiency virus in the nervous system. Recombinant gp120, an envelope glycoprotein of human immunodeficiency virus type 1, specifically binds to GalCer and its derivatives. This specificity was studied by inhibiting binding of radioiodinated gp120 to GalCer with antibodies to GalCer, antibodies to gp120, and an excess of unlabeled gp120. Binding activity was also removed by absorbing gp120 with liposomes containing GalCer. In addition, studies using natural and semisynthetic lipids indicate that the linkage between galactose and ceramide is essential for binding. The significance of an alternative receptor for human immunodeficiency virus in the nervous system is discussed.

Inhibition of entry of HIV-1 in neural cell lines by antibodies against galactosyl ceramide.

Although the CD4 molecule is the principal cellular receptor for the human immunodeficiency virus (HIV), several CD4-negative cell lines are susceptible to infection with one or more HIV strains. These findings indicate that there are alternate modes of viral entry, perhaps involving one or more receptor molecules. Antibodies against galactosyl ceramide (galactocerebroside, or GalC) inhibited viral internalization and infection in two CD4-negative cell lines derived from the nervous system: U373-MG and SK-N-MC. Furthermore, recombinant HIV surface glycoprotein gp120 bound to GalC but not to other glycolipids. These results suggest a role for GalC or a highly related molecule in HIV entry into neural cells.

Expression of neural cell adhesion molecule in dysmyelinating mutants.

The possible role of neural cell adhesion molecule (NCAM) in myelination was studied in the dysmyelinating mouse mutants jimpy and shiverer, by characterizing the expression of the different molecular forms of brain NCAM as a function of age. In jimpy, the expression of NCAM-120 (120,000-Da NCAM) was low and in shiverer both NCAM-120 and NCAM-180 (180,000-Da NCAM) were reduced when compared to controls. In both jimpy and shiverer there was no significant change in the phospholipase C-sensitive NCAM-120. These data further support the possibility that NCAM may be involved in myelination.

Induction of MHC class I antigens on glial cells is dependent on persistent mouse hepatitis virus infection.

H-2 class I antigens, but not class II antigens, were detected on the surface of glial cells persistently infected with mouse hepatitis virus strain A59 (MHV-A59) as late as 90 days post-infection. Uninfected glial cells remained negative for H-2 class I and class II surface antigens. We have previously shown that conditioned media from infected glial cell cultures (supernatants) contain a factor unrelated to infectious virus and capable of inducing H-2 class I antigens on uninfected glial cells. The synthesis of this factor appears to be dependent on production of infectious virus since the H-2 inducing activity could not be detected 3 days following the addition of neutralizing antibodies to the cultures. This suggests that H-2 inducing activity contains an unstable component, the synthesis of which is dependent on continual virus production. Persistent MHV infection and H-2 class I antigen expression may play a role in MHV-induced demyelination.

Lymphokines facilitate maturation of oligodendrocytes in vitro.

As oligodendrocytes develop in vitro, A2B5+ progenitor cells acquire the oligodendrocyte-specific marker, galactocerebroside (GalC), to become A2B5+ GalC+ cells. They then gradually lose reactivity to A2B5, to become A2B5- GalC+ mature oligodendrocytes. By examining this developmental surface antigen expression with and without lymphokine stimuli we found that crude lymphokines, but not interleukin-2 or gamma-interferon, facilitate this maturation process. Thus, lymphokines may have a role in differentiation of oligodendrocytes. The same lymphokine stimuli, however, did not enhance the proliferation of oligodendrocytes.

Multiple sclerosis: serial study of gadolinium-enhanced MR imaging.

Thirteen patients with definite multiple sclerosis (MS), studied 16-24 months previously with magnetic resonance (MR) imaging with and without enhancement by intravenously administered gadolinium diethylenetriaminepentaacetic acid (DTPA) dimeglumine, were reexamined with a similar protocol. Assessment of enhancement and clinical activity in both studies revealed that enhancement was observed in 13 of 14 cases in which clinical activity had changed within 4 weeks of the study and thus appeared more sensitive than clinical examination in determining active disease. The 3-minute postinjection, short repetition time image (TR) was the most efficient for depicting enhancement. Enhancing lesions (active plaques) arose from previously hyper- or isointense regions on long TR images. Previously active lesions reverted to areas of iso- or hyperintensity on long TR images. Serial comparison of long TR images in this population reveals a decrease in high-intensity lesions on long TR images in some cases and an increase in others. The findings of high-intensity regions on long TR images and previously enhancing lesions both becoming isointense suggests that transient inflammatory changes with concomitant edema without demyelination and/or with significant remyelination may occur in some MS lesions. MS lesions are dynamic; both active and inactive lesions may show dramatic change on longitudinal MR imaging studies.

Azathioprine in multiple sclerosis: the cons.

Azathioprine has the longest continuing history of clinical use in the treatment of multiple sclerosis (MS) of any immunosuppressive therapy besides corticosteroids. To date, 19 clinical trials of azathioprine in MS have been reported, and another eight are under way. A review of the reported trials indicates little evidence for a therapeutic effect in MS. This and the lack of evidence for a specific immune alteration in the pathogenesis of MS are relative contraindications for the use of high risk immunosuppressive therapies in this disease. A further caveat is raised by a recent report suggesting that azathioprine may have contributed to an increased incidence of carcinomas in MS patients treated with this drug. In view of these considerations, perhaps the best position to take at the present time is to encourage investigators already engaged in controlled clinical trials of azathioprine to complete their work, so that this data can be considered before new studies of azathioprine in MS are undertaken.

NCAM-180, the largest component of the neural cell adhesion molecule, is reduced in dysmyelinating quaking mutant mouse brain.

To explore the role of the neural cell adhesion molecule (NCAM) in myelination and remyelination, we studied the developmental expression of various molecular forms of NCAM in dysmyelinating quaking mouse brain as compared with normal mouse brain. Normal mouse brain expressed the several molecular forms differentially during development. Quaking showed a marked reduction in the expression of NCAM-180, which represents the largest component of NCAM, in comparison with normal brain. This suggests that the defective myelin compaction in the quaking mutation may be the result of a deficiency of NCAM-180.

Developmental expression of neural cell adhesion molecules of oligodendrocytes in vivo and in culture.

Previously, we have shown that oligodendrocyte adhesion molecules are related to the 120,000-Mr neural cell adhesion molecule (NCAM-120). In this report, we present further evidence that the oligodendrocyte adhesion molecule is NCAM-120. Studies on the expression of NCAM-120 and other molecular forms of NCAM in vivo in rat brain, in vitro in primary mixed cultures, and in cultures enriched for oligodendrocytes are described. Western blot analysis of rat brain using anti-NCAM showed that NCAM-120 first appears at postnatal day 7 and increases in quantity thereafter, coincident with the development of oligodendrocytes in vivo and comparable to the expression of myelin basic protein. Purified oligodendrocytes from 4-week-old rat brains expressed only NCAM-120. Quantitation of various forms of NCAMs in rat brain showed marked age-related differences in the expression of three molecular forms of NCAM. Immunofluorescence analysis showed that oligodendrocytes, at all ages tested, expressed NCAM, but in older oligodendrocytes, the intensity of staining was less. Western blot analysis of oligodendrocyte-enriched cultures showed that from day 1 after isolation (12 days of age) through day 7 after isolation (18 days of age) only NCAM-120 is seen. A possible role for NCAM in myelination and remyelination is discussed.

Tumor necrosis factor induces expression of MHC class I antigens on mouse astrocytes.

The effect of tumor necrosis factor (TNF) on expression of major histocompatibility complex (MHC) antigens was examined in mouse glial cells in vitro. TNF induced MHC class I, but not class II, antigen expression on the surface of astrocytes but not on oligodendrocytes. Glial cells do not normally express detectable amounts of MHC antigens. Thus TNF may play a role in the immunopathogenesis of neurologic diseases that involve MHC class I-restricted reactions.

Induction of glial cell MHC antigen expression in neurotropic coronavirus infections. Characterization of the H-2-inducing soluble factor elaborated by infected brain cells.

Neurotropic coronavirus (mouse hepatitis virus strain A59) infection induces major histocompatibility complex class I (H-2) surface antigens on oligodendrocytes and astrocytes, cells that do not normally express detectable MHC antigens on their surface. The induction on MHC antigen expression potentially allows immunocytes to interact with infected glial cells and may play a critical role in the development of virus-induced, immune-mediated demyelination in the central nervous system, a possible model of human multiple sclerosis. In this study, we characterized the soluble factor involved in MHC antigen induction, quantitated induction of MHC antigens, and analyzed the central nervous system cell type involved in the production of the factor. The H-2-inducing factor, most likely produced by astrocytes, was found to be nondialyzable, heat- and trypsin-sensitive, but resistant to treatment at pH 2.0. The m.w. of the factor was estimated as 50 to 100 kDa. Studies on fractionation by ultrafiltration and sucrose density gradient along with antibody-blocking experiments indicate that the factor is not interferon or virus particles.

Neuroblastoma cell-oligodendrocyte interaction is mediated by neural cell adhesion molecules.

The role of neural cell adhesion molecule (NCAM) in the interaction between neurons and oligodendrocytes was studied using N2A neuroblastoma cells, which express only the 180,000 Mr NCAM and rat oligodendrocytes which express only 120,000 Mr NCAM. Oligodendrocytes bound to neuroblastoma cells, and the binding was inhibited by anti-NCAM, suggesting that NCAM is involved in oligodendrocyte-neuron interaction. The possible role of NCAM in myelination and remyelination is discussed.