Randomized study of antibodies to IFN-g and TNF-a in secondary progressive multiple sclerosis

Abstract

Studies of cytokines in multiple sclerosis (MS) have shown that immune mechanisms connected with disturbance of the synthesis of cytokines probably play critical roles in the initiation and prolongation of MS. In a double-blind, placebo-controlled trial, 45 patients with active secondary progressive MS were randomized to three groups of 15 patients, each receiving a short course of antibodies to IFN-gamma, to tumor necrosis factor (TNF)-alpha, or a placebo. After 12 months with analysis of disability (Expanded Disability Status Scale scores), accompanied by interval determinations of lymphocyte subpopulations, cytokine production levels, MRI, and evoked potentials, it was found that only patients who received antibodies to IFN-gamma showed statistically significant improvement compared to the placebo group--a significant increase in the number of patients without confirmed disability progression. This was supported by MRI data (a decrease in the number of active lesions) and systemic changes in cytokine status (a decrease in IL-1beta, TNF-alpha, and IFN-gamma concentrations in supernatants of actvated blood cells of these MS patients and an increase in TGF-beta production). Neutralization of IFN-gamma could be a new approach to treating secondary progressive MS. Long-term administration of humanized monoclonal antibodies to IFN-gamma and simultaneous use of antibodies to IFN-gamma together with IFN-beta products are planned.

A Pathogenic Role for CD8+ T Cells in a Spontaneous Model of Demyelinating Disease

“…ϩ T cell-mediated brain inflammation parallels findings in MS where administration of IFN-␥ resulted in disease exacerbation (60) and anti-IFN-␥ Ab therapy reduced disability in secondary progressive MS (61).…”

Interactions Between Hemopoietically Derived TNF and Central Nervous System-Resident Glial Chemokines Underlie Initiation of Autoimmune Inflammation in the Brain

“…Targeting of specific TNF-inducible chemokines or preferably their receptors, perhaps in concert with anti-TNF-based therapies, may represent a valid therapeutic approach for treatment of CNS inflammatory disease, multiple sclerosis especially. In this context, alternatives to TNF-directed therapies for the treatment of CNS inflammation are desirable in view of clinical studies showing that TNF blockade is either ineffective (50) in the treatment of multiple sclerosis or even detrimental (51,52). Access of biologicals to TNF produced by infiltrating cells within the CNS could explain lack of efficacy.…”

Suppressor of Cytokine Signaling 1 Expression Protects Oligodendrocytes from the Deleterious Effects of Interferon-γ

“…IFN-␥ is critical to the immunoregulation of autoimmune demyelinating disorders of the CNS (Panitch et al, 1987;Glabinski et al, 1999;Tran et al, 2000;Skurkovich et al, 2001;Steinman, 2001). In addition, IFN-␥ provides an intricate link between inflammation and oligodendrocyte injury.…”

“…IFN-␥ is found in demyelinated lesions, and its levels in CSF correlate with disease severity (Vartanian et al, 1995;Calabresi et al, 1998;Becher et al, 1999;Moldovan et al, 2003). Administration of IFN-␥ to multiple sclerosis patients exacerbated the disease, and neutralizing antibodies to IFN-␥ have been shown to delay disease progression (Panitch et al, 1987;Skurkovich et al, 2001). Diminishing the local effect of IFN-␥, perhaps through the targeted expression of SOCS1 by oligodendrocytes, could prove to be therapeutically beneficial.…”