Plasmapheresis combined with interferon: an effective therapy for multiple sclerosis.

The rationale for the use of interferon (IFN) in the treatment of multiple sclerosis (MS) is based on its recognized antiviral and immunomodulating actions. The pathogenesis of MS is believed to be due to an immunologic response in a genetically predisposed individual, localized within the central nervous system white matter, and triggered by exposure to an environmental agent such as a virus. Based on our personal experience we find that the efficacy of IFN therapy is hampered in MS patients by the presence of an interferon inhibitor factor (IIF) in the patients' sera which we have isolated and characterized. When plasmapheresis (PP) was done on 24 MS patients with intermittent 3-day administration of IFN-alpha and human leukocyte IFN, marked increase of IFN in 18 patients and modest increase in three patients correlated with clinical improvement. Three clinical nonresponders showed no increase in IFN levels following therapy. The ability to remove IIF and lymphokine inhibitor factor (LIF) by PP may explain the successful treatment of our patients. We describe the evaluation of helper T cells, suppressor T cells, HLADR antigen, natural killer cells, and monocyte/macrophage cell populations by flow cytometry before and after PP. A significant increase in these immune-competent cells correlated with marked improvement in Kurtzke disability status scale in 13 patients, while eight stabilized. Patients showing progression of the disease either showed decrease or no change in these parameters after therapy. Encouraging results from this pilot study suggest that PP combined with immunomodulatory regimens of IFN may be an effective therapy for MS.

Interferon inhibitor factor predicting success of plasmapheresis in patients with multiple sclerosis.

Interferons (IFN) are biological molecules with antiviral, antiproliferative, and immunomodulatory actions. Plasmapheresis (PP) combined with IFN therapy in 24 multiple sclerosis (MS) patients was associated with a rapid increase in detectable IFN levels. We describe the presence of a detectable factor in the serum of MS patients which decreases the efficacy of IFN therapy in these patients. We call this factor "interferon inhibitor factor" (IIF). Standard IFN assay indicates inhibition of WISH cell protection by IFN owing to the presence of IIF in patient's serum. Similar results were also obtained with human fibroblast and human leukocyte IFNs. The best results were obtained with an IFN mixture; results with 1:20 diluted patient's sera showed elevation of 120% greater than 1:10 dilution. With 1:40 dilution, an elevation of 1,041% was noticed. The IIF from patient sera collected during PP was purified and characterized. Native gel electrophoresis of IIF indicates a single protein band; further analysis on SDS gels indicates two bands at the 200 and 21-kD range. ELISA failed to reveal the presence of any anti-IFN antibodies. This study demonstrates the presence of IIF in MS patients' sera which are removed from the circulation by PP. Removal of IIF from circulation was associated with increased IFN levels and clinical improvement as measured by Kurtzke's disability status scale (KDSS).

Immunomodulatory activity of human leukocyte interferon in cancer patients: results obtained during pulse therapy schedule.

We evaluated and previously reported the efficacy of alpha-interferon (alpha-IFN) in 84 cancer patients (19). IFN was administered in a pulse fashion given for 3 consecutive days every 4 weeks. We also evaluated the immunomodulatory effect of IFN which constitutes the basis for the current report. Before, during and after courses of IFN treatment, the immune status of the patients was assessed by: (i) circulating immune complexes, (ii) change in lymphocyte type including (a) natural killer (NK) cells, (b) T-cell subsets (suppressor, helper) and (c) HLA-Dr antigen positivity, (iii) myelopoietic differentiation, (iv) macrophage-dependent tumor cytotoxicity with measurements of macrophage-derived growth factor (MDGF), (v) granulocyte functions, (vi) antibody formation against IFN, and (vii) antiproliferative activity of IFN. In addition, LDH, beta-2 microglobulin, and CEA as tumor markers were obtained. High serum or plasma IFN levels were associated with increased activity of T suppressor cells, increased HLA-Dr antigen, and increased NK activity. The increase of these three parameters was directly related to tumor response. In vitro inhibition of tumor cells in tissue culture by IFN culture was predictive of objective tumor response in those patients whose tumor cells were tested. In addition, IFN induced release of MDGF by monocytes. It is apparent that in addition to direct antitumor effect, IFN has multiple modulatory effects on the immune system in man that may aid in tumor control when given in a pulse schedule.