Immunological complications in multiple sclerosis patients receiving interferon.

In a prospective, placebo-controlled study designed to test the efficacy of human alpha interferon (IFN) 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 C1q- 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.

Endoneurial injection of antisera to myelin antigens.

When antisera to purified myelin antigens were injected into rat sciatic nerves, some produced significant demyelination, whereas others merely induced an inflammatory infiltrate. Extensive demyelination was produced by antisera to galactocerebroside and the peripheral nerve glycoprotein P0. Demyelination resulting from injections of antisera to ganglioside GM1, P2, myelin basic protein, sulfatide, and glucocerebroside did not exceed that produced by normal rabbit serum. Addition of guinea pig complement had no effect. It is of interest that the greatest demyelination followed injection of antisera to two molecules, galactocerebroside and P0, the main antigenic determinants of which present at the Schwann cell surface.

A neurologic rating scale (NRS) for use in multiple sclerosis.

A neurologic rating scale (NRS) has been developed for clinical assessment of MS patients. The scale has been tested on 250 MS patients. Assignment of the NRS score is based on assessment of each component of the neurologic examination and accurately reflects overall neurologic function. Clinical exacerbations are evident as significant deviations from baseline scores. There was close interexaminer correlation, with the range of variability no greater than 2.6%. The NRS is a simple, reliable, and sensitive scale that can be used with other objective measurements of neurologic function, such as neurophysiologic studies, in the clinical assessment of MS patients.

Systemic alpha-interferon therapy of multiple sclerosis.

A randomized, double-blind, placebo-controlled crossover study tested the efficacy of natural alpha interferon in altering exacerbating-remitting MS. Twenty-four patients with frequent exacerbations were treated for 6-month periods, beginning with either 5 X 10(6) IU of interferon daily or placebo. A 6-month washout period followed each treatment. Exacerbation rates were reduced during interferon and placebo phases compared with pre-study rates; a greater reduction occurred on interferon, particularly following placebo, possibly reflecting a learning phenomenon. Fifteen patients with a strictly exacerbating-remitting course had fewer and milder exacerbations on interferon compared with those on placebo, whereas 9 patients with a progressive component continued to have active disease. These results suggest that interferon might reduce exacerbations in certain patients and indicate guidelines for future trials of interferon in MS.

Disease activity markers in multiple sclerosis. Another look at suppressor cells defined by monoclonal antibodies OKT4, OKT5, and OKT8.

Here we report our experience in profiling peripheral blood T-cell subsets with the monoclonal antibodies OKT4, OKT5 , and OKT8. Lymphocyte surface phenotype was measured by automated cytofluorometry. In a population survey, we were unable to detect differences between patients with multiple sclerosis (MS) and control subjects when we compared ratios of lymphocytes of helper cell phenotype (OKT4) to those with suppressor cell phenotype ( OKT5 and OKT8). No differences could be established between patients with stable disease, chronic progressive disease, or those with active disease. In a study of 10 patients followed through an exacerbation, we were also unable to define perturbations in these lymphocyte ratios that correlated with disease activity. Detailed analysis of the fluorescence histogram, which examines the entire spectrum of cell surface fluorescence intensity in a population of lymphocytes, was also not useful in predicting disease activity in these patients. The discrepancies between these data and other reports in the literature are discussed. We propose that these reagents are inadequate indices of disease activity, and that until other monoclonal reagents are developed and studied, the suppressor cell compartment is best assessed by assays of function.

Antigen-specific demyelination and significance of the bystander effect in peripheral nerves.

In an experiment designed to evaluate bystander demyelination in peripheral nerve, immune reactions to tuberculin and albumin failed to induce demyelination, except in animals previously sensitized to a myelin component. The peripheral nerves of tuberculin-sensitized rats and guinea pigs and rabbits were examined at intervals from 8 to 144 hours after intraneural challenge with purified protein derivative (PPD). The results were compared with the immune reaction produced by endoneurial injection of bovine serum albumin (BSA) in rats sensitized to BSA in Freund's complete antigen (FCA). Tuberculin-sensitized rats responded to endoneurial PPD injection by developing perivascular lymphocytic infiltrates which were most severe 5 days after injection. Albumin-sensitized rats responded within hours of BSA injection, showing severe endoneurial edema due to vasculitis with extravasation of polymorphonuclear leukocytes, red cells, and fibrin. The reaction tapered off within 2 days. No significant demyelination occurred in either group. However, demyelination was elicited when the hapten galactocerebroside (GC) was included in the sensitizing inoculum. Schwann-cell necrosis was visible 2 days after endoneurial challenge injection, and demyelination became extensive 5 days after injection. The findings were compared with those after direct injection of anti-GC-antibody, which produced demyelination by lysis of Schwann cells. In rabbits the occurrence of demyelination correlated with the presence of circulating antibodies to GC.

Early changes in experimental allergic neuritis.

Edema and increased endoneurial fluid pressure (EFP) accompany the inflammatory process in experimental allergic neuritis. EFP was measured at regular intervals 6 to 21 days after intradermal inoculation of Lewis rats with an emulsion of peripheral nerve in complete Freund's adjuvant. Control rats received similar injections of an emulsion containing all other ingredients, except peripheral nerve. Altered vascular permeability was illustrated by leakage of horseradish peroxidase into rat sciatic nerve endoneurial space as early as 10 days after inoculation. A difference in EFP between controls and test animals became apparent after 11 days, and highest values were obtained 12 to 16 days postinoculation. Nerves were excised for histologic examination after EFP measurement. Severe endoneurial edema was present after 12 days and was associated with appreciable inflammatory cell infiltration. Inflammatory cells were clustered around small vessels and also were numerous in the subperineurial space which was expanded by edema. Degranulation of mast cells was also noted in association with edema and inflammation. Immunoperoxidase staining revealed immunoglobulin in the subperineurial and perivascular spaces 10 to 12 days postinoculation, but not in sections 6 to 9 days (postinoculation). These findings suggest suggest that altered vascular permeability is the earliest morphologic change in experimental allergic neuritis, followed by accumulation of antibody-containing edema fluid, penetration of the endoneurium by inflammatory cells, and increased EFP.