Immunological treatment of multiple sclerosis

Immunosuppressive treatment of multiple sclerosis (MS) is based on the autoimmune hypothesis for which the main evidence is the close histological similarity between the human disease and chronic relapsing EAE. Although controlled trials indicate that ACTH is effective in accelerating recovery from relapses, long term ACTH or oral steroids are ineffective. Two controlled trials have suggested a beneficial effect of azathioprine, but neither was conducted "blind" and neither was sufficiently convincing to cause the widespread adoption of azathioprine by neurologists. One controlled trial, also not blind, reported a beneficial effect of an intensive course of cyclophosphamide, but this hazardous treatment will not be widely adopted unless other trials confirm this result. The converse hypothesis that MS is due to a deficient immune response to a virus has led to trials of immunostimulation. Interferon and levamisole have proven ineffective so far, but transfer factor slowed disease progression in one well conducted trial.     

Immunological monitoring of azathioprine treatment in multiple sclerosis patients

Despite the longstanding clinical use of azathioprine as an immunosuppressive agent in multiple sclerosis, little is known about the action of this drug on a number of parameters of putative pathogenic relevance in the disease. Eleven patients with multiple sclerosis, treated with azathioprine 2.5–3 mg/kg per day, and six untreated patients were studied with serial blood sampling for 1 year. The following immunological parameters were investigated: peripheral blood lymphocyte subsets, natural killer activity, serum IgG, IgM, ICAM-1 and tumour necrosis factor alpha (TNF-α). The most relevant changes included a decrease in CD3^–CD56⁺ cells, an increase in CD4⁺CD45RA⁺ cells and a decrease in TNF-α levels only in treated patients, while no changes occurred in untreated patients over a 1-year period. The decrease in TNF-α levels and the increase in “suppressor-inducer” lymphocytes could reduce chronic inflammation in multiple sclerosis, and paralleled an overall favourable clinical response to azathioprine treatment in our patients. Received: 9 July 1996 Received in revised form: 21 October 1996 Accepted: 22 November 1996     

Immunological update on multiple sclerosis

The present review of the recent literature focuses on antigen-specific immune reactions in multiple sclerosis. New techniques have allowed precise quantitative analysis of the antigen-receptor repertoire of infiltrating T cells in the multiple sclerosis brain. Novel candidate autoantigens, including B-cell autoantigens, have been identified. 'Humanized' animal models allow the functional characterization of human immune molecules in vivo. Finally, several therapeutic trials have recently assessed the clinical benefit of selective immunotherapies.     

Immunological markers in multiple sclerosis

Multiple sclerosis (MS) is characterized by the presence in the central nervous system (CNS) of perivascular inflammatory infiltrates containing, among others, autoreactive T cells and activated macrophages. These observations indicate that MS is a T cell-mediated CNS-confined chronic inflammatory demyelinating disease in which the ultimate effector cell is the activated macrophage. The inflammatory process, leading to patchy demyelination and axonal loss, is mainly sustained by pro-inflammatory cytokines that, along with chemokines, adhesion molecules and metalloproteases, modulate at different levels the pathogenic process underlying MS. Due to their central role in MS pathogenesis, “inflammatory” molecules might represent suitable peripheral markers of disease (disease-trail) and/or disease activity (state-trait). However, reliable disease-trait or state-trait immunological markers for MS have not yet been identified. The intrinsic characteristics of these molecules (i. e. autocrine/paracrine activity, short half-life, redundancy) may in part explain their inconsistency as disease markers. Additionally, the unreliability of methodologies and the lack of careful patient stratification can also, at least in part, account for the unsatisfactory results so far obtained.     

Immunological differentiation between neuroborreliosis and multiple sclerosis

Summary Neuroborreliosis, a tick-borne spirochaetosis of the central nervous system, is diagnosed by the presence of intrathecally synthesized Borrelia burgdorferispecific antibodies. Multiple sclerosis and neuroborreliosis can show similarities in clinical symptoms as well as lymphocytic cell reactions and oligoclonal bands in the isoelectric focusing of cerebrospinal fluid. To differentiate between multiple sclerosis and neuroborreliosis we tested intrathecally synthesized IgM and virus antibodies. The IgM indices were higher for most of the neuroborreliosis patients studied than for those with multiple sclerosis, and cell counts were also significantly higher in the acute stage of the disease. In 84% of multiple sclerosis patients we were able to demonstrate intrathecal antibody production against measles, rubella or mumps virus. Neuroborreliosis patients had no intrathecal virus antibody synthesis. The specification of oligoclonal bands resulting from isoelectric focusing of cerebrospinal fluid with an ELISA for B. burgdorferi can further substantiate the diagnosis of neuroborreliosis or help to rule it out in multiple sclerosis patients with positive borreliaspecific serology.     

Immunological basis for the therapy of multiple sclerosis

Much progress is currently being made in different areas of clinical and experimental multiple sclerosis (MS) research, including epidemiology and genetics, immunological mechanisms, possible role of infectious agents, imaging, clinical trials and development of new therapeutic agents. This article reviews some principles of MS pathogenesis and immunotherapy.     

Update in multiple sclerosis treatment.

The treatment of múltiple sclerosis (MS) has experienced an important change in the last decade, once it has been demonstrated that several drugs could modify the evolution if this disease. In the recent years, several papers have offered some new knowledge and therapeutic possibilities. In this article we review the current pharmacological treatment for MS, for the acute bouts, for preventing evolution and for its symptoms.

For the acute bouts, steroids continue to be the usual therapy, even though they are used in variable protocols. Plasma exchange can be an alternative for those patients who do not respond to steroids.

Beta-interferons or glatiramer are considered as the drugs of choice for the prevention of evolution of active forms of remitting-recurrent MS, with azatioprine being the second option. For non-responders with aggressive clinical course mitoxantrone or drug associations can be used. In those cases with a first demyelinating episode with MRI highly suggestive of MS BETA-interferon 1a can be indicated. In those cases with severe clinical course mitoxantrone can be an alternative.

There is no efficacious and safe preventive treatment for those patients with primary progressive forms for MS. Finally, symptomatic treatment is very important for the majority of MS patients. Even though this treatment can improve the quality of life of our MS patients, it is frequently forgotten by the clinicians. We review the current possibilities for the usual MS symptoms.

Neurología 2004;19(Supl 2):8-21

     

Immunological complications in multiple sclerosis patients receiving interferon

In a prospective, placebo-controlled study designed to test the efficacy of human alpha interferon (1FN) in the treatment of multiple sclerosis, we monitored several immunological functions. Interferon was shown to have many effects on the immune system, including activation of natural killer cells in vivo and elevation of serum immunoglobulin and cerebrospinal fluid IgG ratios. Furthermore, all patients who received IFN developed antibody titers to a protein contaminant (molecular weight, 27 kilodaltons) in the IFN preparation. This antibody was associated with an elevation in serum concentrations of Clq- and Raji-binding immune complexes in 6 of 12 patients. Some of these 12 patients developed symptoms suggestive of immune complex disease. IFN had pronounced effects on the immune system of these patients.     

Immunological abnormalities in the tears of multiple sclerosis patients

IgG and IgM concentrations in tears of multiple sclerosis patients (n = 38) are increased compared to normal controls (n = 23). The occurrence of oligoclonal tear IgG bands (7.9%)--as determined by immunoblotting--did not differ between groups. Our findings suggest an altered reactivity of the secretory immune system in MS patients, but did not differ from findings in patients with eye affections or wearing hard contact lenses.     

Immunological heterogeneity of multiple sclerosis in Sardinia and Sweden

Subjects from Sardinia, Italy, are relatively homogeneous compared to Swedes. Although ethnically distant, both populations have similarly high multiple sclerosis (MS) incidence rates. Pro- and anti-inflammatory cytokines and their receptors, signalling molecules and other immune response-associated factors might influence MS pathogenesis, though definite proof is missing. The study of populations with similar MS incidence but different genetic and environmental background could make possible the definition of factors that relate to such background differences. We selected untreated female MS patients from Sassari, Sardinia, and Stockholm, Sweden, and corresponding sex- and age-matched healthy controls (HC), to study blood mononuclear cells (MNC) for mRNA expression of 20 immune response-related genes considered relevant in MS, employing real-time PCR. Higher expression of IL-12p40 mRNA was confined to MS from both Sassari and Stockholm, compared to corresponding HC. MS patients from Sassari, but not Stockholm, expressed higher TNF-alpha compared to corresponding HC. MS patients from Stockholm, but not Sassari, expressed higher IL-6. Indoleamine 2,3 dioxygenase (IDO), a molecule necessary in tolerance induction, was lower in MS from Stockholm compared to corresponding HC. This was not observed in Sassari. No differences were detected for other members of the IL-12 family, other Th1 and Th2 cytokines, and the signalling molecules Stat 4 and 6. The results corroborate a pro-inflammatory state in MS as reflected by high expression of IL-12, TNF-alpha and IL-6, although the extent of expression of TNF-alpha, IL-6 and IDO differs between strictly matched MS patients from different high-incidence areas. This might result from genetic and/or environmental differences. They may account for some of the discrepancies regarding immune response-related molecules previously reported in MS. In conclusion, a pro-inflammatory state exists in MS patients from Sassari as well as Stockholm. The changes of pro-inflammatory and other immune response-related variables differ however between the two MS populations. This may be attributed to the genetic and/or environmental background.     

Immunological markers of disease activity in the course of 2-CDA treatment of multiple sclerosis

52 clinically definite multiple sclerosis (MS) patients were treated with subcutaneous injection of 5 mg 2-CDA in 5 consecutive days. The injection courses were repeated 6 times in one month interval. The MRI pattern and immunological markers were studied in serum and CSF before and after 6 months of treatment. The obtained results suggest that treatment with 2-CDA has not any significant effect on humoral immunological events in multiple sclerosis, what is in contrast to some normalization of cellular immunopathological processes.     

Class II HLA antigens in multiple sclerosis.

HLA typing in Wellington revealed a stronger association of multiple sclerosis with DR2 than with DQw1. The association with DQw1 appeared to be due to linkage disequilibrium of this antigen with DR2. These results, when considered in conjunction with other studies, are most easily explained by the hypothesis that susceptibility to multiple sclerosis is influenced by multiple risk factors, with DR2 being an important risk factor in Caucasoid populations.     

Methisoprinol in the treatment of multiple sclerosis.

Twenty-five patients affected by remittent form of multiple sclerosis (MS) were treated with methisoprinol for a period of 2 years. The clinical parameters, recorded during a 2-year observation period preceding onset of therapy, were compared with the analogous measures recorded during treatment. Treatment was associated with significant favourable changes. In fact, there were observed: a reduction in mean annual relapse rate for 22 of 25 patients; an improvement in the clinical status as demonstrated by the reduction of the Kurtzke Disability Status Scale values obtained in 14 of 25 patients; a reduction in the mean period of standard corticosteroid therapy.     

Immunological and gadolinium-DTPA MRI evaluation of relapsing remitting multiple sclerosis

The levels of lymphocytes, blood lymphocytes subsets (CD3+, CD4+, CD8+, DR+, CD25+, CD4+, CD45RA+, CD4+, CD29+ cells) and sIL-2r of 10 patients affected by relapsing-remitting multiple sclerosis were serially studied. The identification of the activity of the disease was made by gadolinium-DTPA (Gd-DTPA) MRI. The immunological determinations and the MRI of the brain and spinal cord were performed every 14th day for a period of three months. No significant difference of the immunological values were found between the presence and the absence of Gd-DTPA enhancing areas, except lymphocytes (p < 0.05). These immunological parameters, evaluated in the peripheral blood, are not a marker of disease activity in relapsing-remitting MS patients.     

Immunological and cytological studies of autoimmune demyelination and multiple sclerosis

The early history of experimental allergic encephalomyelitis is reviewed from the point of view of the characterization and recognition of myelin basic protein and the active agent in acid-fast bacilli, namely muramyl dipeptide. Protocols effective in inducing demyelination are pinpointed. Special attention is paid to the protocol which depends on pretreating guinea pigs with muramyl dipeptide and foreign protein followed by a second injection of foreign protein and then the animals are injected with myelin basic protein and Freund's complete adjuvant. Variations in the timing and amounts of muramyl dipeptide are described as are their effects on the demyelination. The myelin breakdown has been studied with a monoclonal antibody reactive to P2. Similar pretreatment enhances the demyelination in Semliki Forest virus infection in mice. The changes in the blood brain barrier are found at 7 days after the myelin basic protein is injected and show grossly increased uptake by the cerebral vascular endothelium of IgG and perivascular uptake of IgG. The changes in the cerebrospinal fluid (CSF) proteins are described (IgG and albumin). Studies of P2 protein in the CSF by means of a new ELISA technique have been performed on human CSF in multiple sclerosis.