Acute multiple sclerosis characterized by extensive mononuclear phagocyte infiltration.

In this study, we examine the clinical, neuroradiological, and immunohistochemical findings of a 51 year old white female who died 27 months after onset of acute multiple sclerosis despite treatment with interferon-beta, azathioprine, corticosteroids, and cyclophosphamide. Immunohistochemical studies revealed extensive gliosis and mononuclear phagocyte infiltration with corresponding upregulation of proinflammatory cytokines (eg. IFN-alpha, TNF-alpha). The significance of immunohistochemical findings with respect to clinical presentation is discussed.

New treatment strategies for malignant gliomas.

Although survival in patients with malignant gliomas remains limited, there is renewed optimism with the emergence of novel treatment strategies. Cytotoxic agents such as temozolomide and CPT-11 have shown promising clinical activity. Biological treatments for brain tumors, including antisense oligonucleotides, gene therapy, and angiogenesis inhibitors, are also being evaluated in clinical trials. Delivery strategies have been developed to overcome challenges presented by the blood-brain barrier. These noteworthy treatments, alone or in combination, may ultimately prolong survival and enhance quality of life in this group of patients.

SCID mice with HIV encephalitis develop behavioral abnormalities.

Severe combined immunodeficient (SCID) mice inoculated intracerebrally (i.c.) with HIV-infected human monocytes develop brain pathology similar to that in humans with HIV encephalitis. This includes HIV-positive macrophages and multinucleated giant cells, astrogliosis, microglial nodules, and neuronal dropout. These xenografts survive about 1 month. To develop a model of chronic HIV encephalitis and to assay the resulting behavioral abnormalities, we reinoculated SCID mice i.c. every 4 weeks for 3 months with either HIV-infected human monocytes (n = 5) or uninfected human macrophages (n = 4) or administered no inoculation (n = 6); these three groups were monitored for behavioral abnormalities. Tests of cognitive function in a Morris water maze 3.5 months after the first inoculation suggested that HIV-infected mice performed poorly compared with controls. Following testing in the water maze on days 4 and 5 of acquisition, motor activity of infected mice was reduced in comparison with that of controls. Retention of goal location when tested 1 week later was impaired in HIV-infected mice compared with controls. Histopathologic analysis of brains revealed significant astrogliosis and strongly suggested higher numbers of major histocompatibility complex (MHC) class II-positive multinucleated macrophages in HIV-infected compared with control mice. Thus, our preliminary studies indicate that SCID mice with HIV encephalitis develop behavioral abnormalities reminiscent of human disease. These behavioral abnormalities are associated with significantly increased astrogliosis, the presence of HIV, and probably multinucleated giant cells. These studies further support the use of this SCID animal model system for studies of the pathogenesis of HIV encephalitis and for drug interventions.

Potential relationships between the presence of HIV, macrophages, and astrogliosis in SCID mice with HIV encephalitis.

The pathogenesis of HIV encephalitis (HIVE) has not been determined although increased numbers of mononuclear phagocytes (macrophages and microglia), some of which are HIV-infected, and reactive astrogliosis are important pathological findings in this condition. For this experiment, fifty-one SCID mice were inoculated intracerebrally either with human cells and HIV-1, human cells only or HIV only and then sacrificed at various time points. HIV gag mRNA was detected by reverse transcriptase polymerase chain reaction (PCR) distant from the site of inoculation in 73% of mouse brains inoculated with HIV and human cells attesting to the pervasiveness of HIV infection in SCID brain. HIV mRNA was detected as long as 91 days after inoculation of human cells and virus and the presence of HIV gag, nef, and tat/rev mRNA in HIV-infected SCID brains indicates ongoing HIV mRNA synthesis. Brain tissue sections were immunostained for HIV, human macrophages, and astrocytes from a subset of mice (n = 29) from the above groups and qualitatively assessed. PCR data for HIV mRNA was correlated with staining results and these data suggested that the greatest astrogliosis was present in mice inoculated with HIV and human cells, consistent with previously reported data. The data further suggest that astrogliosis is greater when HIV is detected. Taken together the data are consistent with a synergistic effect between macrophages and HIV in the development of astrogliosis.