Induction of lethal experimental allergic encephalomyelitis in nonhuman primates and guinea pigs with human glioblastoma multiforme tissue

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✓ The introduction of active specific immunotherapy as an adjunct to conventional therapy of the brain-tumor patient creates the risk of the concomitant induction of experimental allergic encephalomyelitis (EAE). The lack of resolution concerning the total group of central nervous system (CNS) antigens which may be encephalitogenic, and the lack of definition of the necessary conditions for the induction of an anti-CNS myelin response complicate the design of an immunotherapeutic regimen for brain-tumor patients. We report here the ready induction of EAE in four of four guinea pigs and both of two nonhuman primates (Macaca fascicularis) with human glioblastoma multiforme (GBM) tissue injected with either complete or incomplete Freund's adjuvant (CFA, IFA). Immunization protocols utilizing encephalitogenic GBM tissue and adjuvant which did not result in EAE induction were established in both of two macaques, and the production of significant levels of antibodies specifically reactive with immunizing GBM-derived cultured cell lines in all of 12 macaques without EAE induction was demonstrated. As the lower detection limit of the sodium dodecyl sulfate-polyacrylimide gel electrophoresis (SDS-PAGE) assay for human myelin basic protein (HBP) was 0.6 µg HBP/gel, and an extract prepared from WR-GBM tumor tissue contained less than 0.6 µg of detectable HBP/25 µg of pH 3 extractable protein, and as 100 to 1000 µg of purified human basic protein (HBP) failed to induce EAE in three of three macaques, it was hypothesized that 1) GBM tissue may act as an adjuvant and markedly lower myelin basic protein (MBP) threshold doses for EAE induction, that 2) MBP encephalitogenic fragments capable of EAE induction may be present in GBM tissue but difficult to quantitate in precipitates by in vitro methods, or that 3) secondary encephalitogenic antigens unrelated to MBP may be present in GBM tissue. The threat of EAE induction and the potential difficulty of its detection in the deteriorating brain-tumor patient receiving active specific immunotherapy warrants a biological screen in immunizing CNS material in experimental animals prior to administration to patients in immunotherapy protocols.

Article Information

Address reprint requests to: Darell D. Bigner, M.D., Departments of Pathology and Experimental Surgery, Duke University Medical Center, Durham, North Carolina 27710.

© AANS, except where prohibited by US copyright law.

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    Monkey 111. A: Coronal whole-mount section of the brain and transverse sections of the brain stem and cervical, dorsal, lumbar, and sacral spinal cord displaying hemorrhagic necrosis. B: Perivascular infiltration in the area of hemorrhagic necrosis. H & E, × 100. C: Area of hemorrhagic necrosis. H & E, × 400 D: Myelin destruction within an area of leukocyte infiltration. H & E, × 100.

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    Monkey 418. A: Coronal whole-mount section of the brain displaying widespread perivascular infiltration and diffuse cellular infiltration of both white and gray matter, and generalized edema. B: Massive myelin destruction in areas of cell infiltration. Luxol fast blue. C: Photomicrograph showing perivascular round cell cuffing in the area of myelin destruction. H & E, × 100.

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