Efectos inmunomoduladores del glatirámero acetato y su potencial papel en la reactivación de la tuberculosis pulmonar / Immunomodulating effects of glatiramer acetate and its potential role in pulmonary tuberculosis reactivation

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Maleic vinyl ether anhydride nephropathy: altered glomerular permeability due to an immunomodulating agent.

The polyanionic immunomodulatory polymer, maleic vinyl ether anhydride (MVE-2), enhances antitumor macrophage activity and causes heavy proteinuria. The effects of this compound on renal function and renal morphology were investigated in a rat model. Rats were given daily intravenous infusions of MVE-2, 100 mg/kg, over 2-4 hr on each of three consecutive days. Renal function and morphology in MVE-2-infused rats were examined by standard techniques and compared to control rats given saline. On the average, MVE-2 rats had a significant reduction in inulin clearance to 62% of control values. MVE-2 rats developed heavy proteinuria 1-3 days after the first infusion (mean +/- 1 SEM, 387 +/- 91 mg/24 hr). By light microscopy, the only finding was intratubular protein casts; glomeruli were normal. Immunofluorescence showed no deposition of antibody, complement, or fibrin. Electron microscopy revealed foot process effacement, epithelial cell vacuolization, and subepithelial ring-shaped structures; no immune-complex deposits were present. MVE-2 rats had no increase in the number of glomerular Ia(+) cells. To examine further the mechanism of MVE-2 nephropathy, the ability of MVE-2 to induce proteinuria in animals pretreated with radiation (750 rad), methylprednisolone (MP) or cyclosporine (CyA) was determined. Animals pretreated with radiation or MP had significantly less proteinuria after MVE-2 treatment compared to animals receiving no immunosuppressive therapy, while CyA pretreated rats developed heavy proteinuria. These results are compatible with the hypothesis that MVE-2 induces proteinuria via an effect on steroid- and radiation-sensitive cells, perhaps related to production of circulating factors which alter glomerular permeability.

Phase I study of MVE-2 evaluating toxicity and biologic response modification capability.

A total of 21 patients were treated in a phase I trial using the biological response modifier MVE-2, a low molecular weight component of pyran copolymer. All patients received weekly IV MVE-2 infused over 2 h. Proteinuria, sometimes of nephrotic proportions, was the dose limiting toxicity, and was seen with increasing incidence as the cumulative dose of MVE-2 exceeded 2500 mg. Other toxicity with MVE-2 was minimal. Biologic response modification at tolerable doses was inconsistent, although several assays, particularly natural cell-mediated cytotoxicity, indicated enhanced activity at higher dosages of MVE-2. No objective tumor responses were observed. MVE-2 is not useful as a biological response modifier using our initial method of administration, since the dose limiting toxicity occurred at lower levels than were necessary to induce consistent biologic response modification. Following completion of the phase I study, we administered MVE-2 by 30-min infusion to 8 additional patients and did not detect proteinuria, in spite of large cumulative doses. It is possible that alternate schedules of MVE-2 administration could minimize proteinuria and allow the administration of dosages necessary for immunologic modification.

Evaluation of the immunological and toxicological properties of MVE-2 in phase I trials.

Pyran copolymer enhances resistance to infections and transplantable tumors in mice. It induces interferon, activates macrophages, increases antibody-dependent cellular cytotoxicity (ADCC), functions as an adjuvant, and has direct antitumor effects. MVE-2, a low-molecular-weight (15,000) component of pyran copolymer, exhibited less toxicity and essentially the same positive biological effects as pyran copolymer. MVE-2 was, therefore, chosen for clinical trials. This study was designed to determine the toxicity and immunological effects of MVE-2 in humans. Fourteen patients who received biweekly MVE-2 had lymphocyte and monocyte ADCC, natural killer activity, and monocyte to macrophage maturation measured 2, 3, 7, 10, and 13 days after each of the first three doses of MVE-2. Lymphocyte antibody-dependent cellular cytotoxicity and monocyte maturation increased significantly following MVE-2 administration and the effect persisted at least 4 weeks. Although numbers were small, the enhanced ADCC seemed related to both single dose and cumulative dose of MVE-2. Five of six patients receiving more than 2 g of MVE-2 had improvement in lymphocyte ADCC. Increases in lymphocyte and monocyte natural killer activity approached, but did not attain statistical significance. Proteinuria was the dose-limiting toxicity, but was reversible. MVE-2 induced a modest, but real enhancement of lymphocyte and monocyte function at doses that were well tolerated.