Advances in neuroimmunology最新文献

Human immunodeficiency virus type 1 (HIV-1) infection is highly specific for its human host. In order to study HIV-1 infection of the human nervous system, we have established a small animal model in which second-trimester (11–17.5 weeks) human fetal brain or neural retina is transplanted into the anterior chamber of the eye of immunosuppressed adult rats (Epstein et al., 1992; Cvetkovich et al., 1992), and more recently in immunodeficient (SCID) mice. The human xenografts survive for many months, vascularize and form a blood-brain barrier. Immunohistochemistry with PGP 9.5 identified neuronal cell bodies and neuritic processes. Electron microscopy revealed axonal growth cones and synaptic junctions. Infection of these xenografts with cell-free HIV-1 proved difficult, however co-engraftment with HIV-1-infected human monocytes resulted in characteristic pathological changes, including the formation of syncytial giant cells, neuronal loss, and astroglial proliferation, supporting the hypothesis that these cells can mediate neurotoxicity. In other studies, xenografts of human fetal retinal tissue were readily infected with cell-free human cytomegalovirus (HCMV) strain AD169. These grafts contained cells with intracytoplasmic and intranuclear inclusions typical of HCMV infection. Productive infection within these grafts was demonstrated by the presence of immediate early, and late (capsid) HCMV antigens, by recovery of HCMV on human fibroblast cultures, and by serial passage of virus to additional retinal xenografts (DiLoreto et al., 1994). The aim of these studies is to develop a small animal model to study direct and indirect effects of HIV-1 infection on human neural tissues, and to study interactions between HIV-1 and other opportunistic pathogens such as HCMV. This model should prove useful in evaluating antiviral therapies.

Approximately one quarter of AIDS patients develop neurologic symptoms attributable to HIV infection within the brain. Previous studies suggest that HIV associated neurologic damage may be mediated by immune factors secreted by activated/infected CNS macrophages. We developed an in vivo system in which human embryonic brain tissue can be infected with HIV and the associated pathology monitored. In this model, dissociated human brain tissue is grown in vitro as single cell suspension in serum free medium. Fetal neural cells aggregate and form “brain microspheres” that are then transplanted into SLID mice. Pilot studies suggest that “brain microspheres” injected in the fat pad of SCID mice differentiate and survive for several months in vivo. Study of these grafts shows presence of functional neural cells and vascular organization suggesting a blood-brain barrier. When brain microspheres are co-cultured in vitro with HIV-infected human macrophages, virus is detected inside the human neural tissue grafts in SCID mice and measurements of viral and immune factors can be performed. To promote physiologic neuronal differentiation within the human grafts, implantation in the brain of SCID mice is being tested at the present time.

Human Immunodeficiency Virus type-1 (HIV-1)-associated neurologic disease occurs as the initial presenting clinical manifestation of acquired immunodeficiency syndrome (AIDS) in 3–7% of infected patients, but in up to 18% of children and adolescents (Janssen, 1992; Janssen et al., 1992; Scott et al., 1989; Mintz et al., 1989a; Epstein et al., 1986). The overall prevalence of dementia in adult AIDS patients is 7.3–11.3% (Janssen, 1992), but up to 30–60% of children with AIDS manifest an analogous progressive encephalopathy (Epstein et al., 1986; Belman et al., 1988; Mintz, 1992; The European Collaborative Study, 1990). As a result of both direct and indirect effects of HIV-1 infection of the central nervous system (CNS), a distinct clinical and pathologic picture has emerged of insidious and severe neurologic deterioration, termed “AIDS Dementia Complex” (ADC) in adults, and “HIV-1-associated Progressive Encephalopathy” (PE) in children (Working Group, 1991) (see Table 1). In the severe manifestations of this pariah, there is little dispute as to the necessity of CNS HIV-1 infection for precipitating the cascade of adverse neurologic symptoms, although the pathogenic mechanisms of neurologic dysfunction and destruction— whether a result of direct cellular infection of HIV, secondarily produced and upregulated cytotoxic cytokines, or co-infection with opportunistic pathogens— remains an area of active research (Epstein and Gendelman, 1993; Fiala et al., 1993; Wiley and Nelson, 1988; Saito et al., 1994; Koenig et al., 1986; Sharer, 1992). Furthermore, the existence of systemic immune deficiency renders the CNS susceptible to opportunistic infection (OI), particularly in adult patients, adding further to morbidity and mortality (Clifford and Campbell, 1992). With the introduction of antiretroviral nucleoside analogues, there have been reports of a decreasing incidence of ADC (Portegies et al., 1989; Day et al., 1992), and amelioration—at least temporarily of PE in children (Pizzo et al., 1988; Mintz and Epstein, 1992; Brouwers et al., 1990; Mintz et al., 1990). This appends further evidence to the central precipitating role of CNS HIV-1 infection.

There is much debate whether there exists any subclinical neurologic dysfunction during the asymptomatic stages of systemic infection (Janssen et al., 1989; Karlsen et al., 1993; McArthur et al., 1989a; Selnes et al., 1990). Perplexities are injected from the many environmental confounders impacting on psychometric testing (McArthur et al., 1989a; Satz et al., 1993; Wilkins et al., 1990).

Although many analogies exist between ADC and PE, there are interesting differences and distinct contrasts between the two populations. Careful study and comparisons of these divergences are important for understandin