Raymond Troiano

EFFECT OF TOTAL LYMPHOID IRRADIATION IN CHRONIC PROGRESSIVE MULTIPLE SCLEROSIS

Total lymphoid irradiation (TLI; 1980 cGy) or sham irradiation was given to 40 patients with chronic progressive multiple sclerosis (MS) in a prospective, randomised, double-blind study. During mean follow-up of 21 months, MS patients treated with TLI had less functional decline than sham-irradiated MS patients (p less than 0.01). A significant relation was noted between absolute blood lymphocyte counts in the first year after TLI and subsequent course, patients with higher lymphocyte counts generally having a worse prognosis (p less than 0.01). TLI was well tolerated and associated with only mild short-term, and to date, long-term side-effects.

Serum soluble interleukin-2 receptor levels in chronic progressive, stable and steroid-treated multiple sclerosis

ABSTRACT Serum levels of the soluble interleukin‐2 receptor (sIL‐2R), an indicator of T cell activation, were significantly elevated in chronic progressive MS (CPMS) patients, clinically stable MS patients and in patients with other neurological diseases (OND) as compared to healthy controls. Levels of sIL‐2R in steroid treated CPMS patients were markedly lower than in untreated CPMS patients and were comparable to healthy controls. Thus, systemic T cell activation occurs in MS during clinically stable and progressive disease stages and in other neurological disorders. The ability of oral corticosteroids to depress serum sIL‐2R levels in vivo may be one mechanism by which they exert their therapeutic effect.

Modified total lymphoid irradiation and low dose corticosteroids in progressive multiple sclerosis

In a double-blind prospective randomized trial, we assessed the efficacy and safety of modified total lymphoid irradiation (TLI) plus low dose prednisone (TLI-LDP) as compared to sham TLI plus identical prednisone therapy (sham TLI-LDP) in 46 patients with progressive forms of multiple sclerosis (MS). No significant difference existed between groups at study entry in patient age, sex, duration of MS, or disability status. However, following treatment, significantly fewer TLI patients showed a sustained one point decline in the Expanded Disability Status Scale, the primary study endpoint, as compared to the sham TLI group using the Kaplan-Meier Product-limit survival analysis, (P<0.005). Risk for relapse requiring treatment with intravenous methylprednisolone was reduced by 54% in the TLI-treated group (P<0.05). Significantly fewer TLI-LDP patients had gadolinium enhancing plus new T2-weighted lesions (P=0.018) when compared to the sham group post-treatment. There was also a substantial and significant decrease in blood lymphocytes in the TLI-LDP group when compared to either pretreatment values or to sham TLI-LDP through at least 12 months post-therapy. Side effects secondary to TLI were generally mild and well-tolerated. These results further support the hypothesis that TLI and systemic immunosuppression have a beneficial effect in progressive forms of MS.

Decreased suppressor-inducer T lymphocytes in multiple sclerosis and other neurological diseases

Decreased numbers of CD4+CD45R+ suppressor-inducer T cells have been reported in patients with a variety of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis but not in patients with other neurological diseases. We now report our findings using murine monoclonal antibodies and two-color flow cytometric analysis on CD4+CD45R+ T cells in 22 patients with chronic progressive multiple sclerosis, 23 patients with other neurological diseases and 42 normal, healthy controls. Suppressor-inducer T cells were significantly reduced (p less than 0.001) in both patients with multiple sclerosis and other neurological diseases as compared to controls. Both patient populations had elevated helper T cell subset ratios. Thus, our data suggests that decreases in suppressor-inducer T cells may represent a common immunological defect among autoimmune and presumably non-autoimmune neurological disorders.

Combination total lymphoid irradiation and low‐dose corticosteroid therapy for progressive multiple sclerosis

Total lymphoid irradiation (TLI) has been reported to delay deterioration in patients with progressive multiple sclerosis and other autoimmune disorders. Methods— In an open trial, the effect of TLI combined with a one year course of low dose prednisone was compared to the effect of sham TLI and TLI only in a prior double‐blind study of patients with progressive multiple sclerosis. Results— Twenty‐seven patients receiving TLI combined with corticosteroids had significantly greater lymphocytopenia in the year post‐therapy than those receiving TLI only or sham TLI and Kaplan Meier product‐limit survival analysis showed significantly less progression in the TLI plus steroid group over 4 years of follow‐up. No difference in lymphocytopenia or progression was found with TLI plus corticosteroid therapy when the spleen was removed from the field of irradiation. Conclusion— These results lend further support to the hypothesis that TLI may be effective in progressive MS, and indicates that adding low‐dose prednisone may enhance this effect. The study also suggests that TLI may be equally effective whether or not the spleen is irradiated.

Measles Vaccination Does Not Prevent Multiple Sclerosis

Twenty-seven young patients with multiple sclerosis (MS) were studied to determine if they had received prior measles vaccination. Fourteen patients whose immunization records were available had received measles vaccine in childhood. Eight other patients gave a history of receiving measles vaccine. These results suggest that infection by measles virus is probably not the sole cause of MS and that, unlike subacute sclerosing panencephalitis and postmeasles encephalitis, MS may not be preventable by measles vaccination given at an appropriate age.

T cell subsets and disease progression after total lymphoid irradiation in chronic progressive multiple sclerosis.

T lymphocyte subset percentages were determined in 16 total lymphoid irradiation (TLI) treated and 18 sham treated control patients with chronic progressive multiple sclerosis. During the first year after treatment, the ratio of T helper/inducer to T suppressor/cytotoxic cells (Th/Ts ratio) was significantly higher in sham treated multiple sclerosis patients who worsened clinically compared with TLI treated and sham treated multiple sclerosis patients who remained clinically stable. TLI caused a fall in the percentage of T helper cells in treated patients, while the percentage of T suppressor cells remained stable during the first year after treatment. In contrast, the percentage of T suppressor cells fell in sham treated multiple sclerosis patients who worsened clinically.

MHC-restricted autoantigen-reactive T cell clones in multiple sclerosis

Multiple sclerosis is a demyelinating disease of the central nervous system with genetic, viral and autoimmune characteristics. Myelin basic protein (MBP) is a suspected target autoantigen since it induces experimental autoimmune encepha‐lomyelitis, an animal model closely resembling multiple sclerosis. The disease is mediated by Class II restricted, MBP‐reactive T cells possessing the T helper/inducer phenotype. In the present study, we have isolated MBP‐reactive T cell clones from the peripheral blood of a chronic progressive multiple sclerosis patient. The clones displayed blastogenic memory responses when rechallenged with the autoantigen and irradiated autologous lymphocytes. MBP recognition by the autoantigen‐reactive T lymphocytes was restricted by major histocompatibility complex Class II antigens. Both CD4+8−‐ and CD4–8+ MBP‐reactive T cell clones were obtained.

Total Lymphoid Irradiation in Multiple Sclerosis

Immunosuppressive drugs have been increasingly used in both uncontrolled and controlled studies in an attempt to modify the relentless deterioration in neurologic function which commonly occurs in patients with chronic/progressive multiple sclerosis (CPMS) (The Multiple Sclerosis Study Group 1990; Rudge et al. 1989; Hauser et al. 1983; British and Dutch Multiple Sclerosis Azathioprine Trial Group 1988; Ellison et al. 1988). Unfortunately, no unequivocal long-term clinical benefits have been documented with immunosuppressive drugs in carefully controlled trials of CPMS. Further, many immunosuppressive drugs must be given at frequent intervals or even daily to sustain remissions in autoimmune disorders, which obviously increases their potential for toxic side effects including infection and neoplasia.

Advances in the Pharmacological and Neurological Treatment of Patients with Multiple Sclerosis

Multiple sclerosis (MS) is an acquired inflammatory demyelinating disease of the central nervous system (CNS) believed to be of autoimmune pathogenesis. Progressive MS is a common cause of disability in young adults in the United States. Although several immunomodulating therapies have been tested in clinical and animal studies, there is no known treatment that prevents further progression and disability. Current research efforts are being focused on the development of novel, safe immunospecific treatments. Until such therapies become available, a major component of patient management should be to relieve symptoms, prevent complications, and maximize function in activities of daily living. A team approach involving health care professionals of various specialties is ideal for the management of patients with progressive MS.