Treatment of multiple sclerosis with gamma interferon

Abstract

Article abstract-We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 pg), intermediate (30 pg) dence that a viral infection, an immunoregulatory defect, or both, may be implicated in disease In a double-blind, placebo-controlled crossover trial of natural alpha IFN given systemically,* the number of acute exacerbations in patients with relapsing-remitting MS was reduced, but the study was complicated by the crossover design and a marked placebo effect. Natural beta IFN administered intrathecally to 10 patients5 appeared to prevent exacerbations; however, the study lacked a placebo-treated control group. Recently, a multicenter double-blind controlled trial of intrathecal beta IFN6 confirmed the favorable results of the earlier study. The first clinical trial of recombinant IFN in MS, in which 2 million units of alpha, IFN were given subcutaneously three times per week for 1 year, was recently ~ompleted.~ There was no therapeutic effect, possibly because the dose was too low. Other studies, using higher systemic doses of recombinant IFN, are in progress.Gamma or immune IFN has many of the antiviral and immunoregulatory properties of other interferonss; in addition, it can activate macrophages and induce class I1 histocompatibility antigens on monocytes,9 endothelial cells,1° and astrocytes." These are properties that could stimulate an autoimmune process. On the other hand, recent reports of deficient gamma IFN production in MS patients12J3 suggested the possibility of a therapeutic trial. We therefore performed a pilot study of recombinant gamma IFN to determine toxicity and dose, and to judge whether a larger, long-term clinical trial would be feasible. The results have been partially reported elsewhere as a preliminary comm~nication.'~ Methods. Patients and treatment protocol. Eighteen patients with clinically definite relapsing-remitting MS participated. There were 3 men and 15 women ranging in age from 19 to 42 years. All patients had had at least two exacerbations in the preceding 2 years, and were in remission at the time of entry. The study was approved by the University of Maryland Human Volunteers Research Committee. Recombinant gamma IFN (Immuneron, Biogen Research, Cambridge, MA) was given in doses of 1, 30, or 1,000 pg, corresponding approximately to 1.5 X lo4, 4.5 X lo5, and 1.5 X lo7 IU of IFN, respectively. Patients were selected at random to receive the low, intermediate, or high doses twice a week for 4 weeks. One half of each dose was administered as an intravenous bolus; the remainder was given as an intravenous infusion over 2 hours. At the beginning and end of the trial, patients were scored according to the

Roles of M1 and M2 Macrophages in Herpes Simplex Virus 1 Infectivity

“…The concept that treatment with IFN-␥ to push the macrophage responses toward an M1 response may act to exacerbate HSV-1 latency rather than playing a protective role in mice is consistent with reports of the deleterious effects of the M1 macrophage population on IFN-␥ treatment of atherosclerosis in mice (94). In addition, it has been reported that treatment of multiple sclerosis patients with recombinant IFN-␥ exacerbated the disease (95). Similarly, we have shown that the central nervous system (CNS) demyelination observed in HSV IL-2-infected mice was exacerbated on coinfection with recombinant HSV IFN-␥ (96).…”

Predicting the Impact of CD8+T Cell Polyfunctionality on HIV Disease Progression

“…As lytic as well as nonlytic responses, if acting locally, can drive CTL escape (73,75), more polyfunctional responses might also mediate increased selective pressure. Determination of which combination of functions would minimize the emergence of escape would be an interesting topic for future study but is beyond the scope of the present analysis.…”

The Inducibly Expressed GTPase Localizes to the Endoplasmic Reticulum, Independently of GTP Binding

“…In addition, IFN␥ is thought to be involved in many pathological responses; in multiple sclerosis for instance, its production exacerbates disease symptoms (8) and increases the relapse rate (9).…”