不良研究所

Immune regulation and brain-immune interactions, autoimunity and multiple sclerosis

Our studies focus on the mechanisms underlying the interactions between the immune system and central nervous system (CNS) and how such interactions contribute to the tissue injury observed in such human neurologic disorders as multiple sclerosis, HIV encephalopathy, and Alzheimer's disease.听The studies are conducted using human peripheral blood derived immune cells and human neural cells (astrocytes, microglia, oligodendrocytes (OLs)), derived from surgically resected adult human CNS tissues.听

Specific questions being studied are:听

1. What effects the endogenous glial cells of the CNS (astrocytes, microglia) have on T cells which infiltrate this compartment?听
Continued recruitment and activation of Glial cells can serve as antigen presenting cells (APCs) to T cells but whether they promote or inhibit T cell responses seems dependent on the production of specific cytokines and expression of surface co-stimulatory molecules by the glial cells. By defining the precise properties of human adult glial cells which determine their APC capacities, we hope to learn how to modulate these functions for therapeutic purposes.听

2.听What effects infiltrating T cells have on the endogenous glial cells?听
How will the array of soluble and cell surface molecules expressed by T cells modulate the properties of the glial cells? Our specific approaches are to determine whether T cells induced in vivo (patients receiving immunomotherapies) or in vitro to express distinct cytokine profiles differentially effect glial cell functions and to selectively interfere with molecules mediating T cell-glial interactions using specific antibodies or receptor antagonists. Most of the latter reagents are being considered for clinical trials.听

3.听How do infiltrating T cells and activated glia contribute to the actual tissue injury as occurs in neurologic diseases?听
Such injury selectively directed at myelinating cells (OLs) is regarded as the primary mechanism of injury in multiple sclerosis. A specific focus of our work is what cell surface or intra cellular properties of the OLs determines their apparent selective vulnerability to injury mediated via the tumor necrosis factor (TNF) receptor (R) superfamily (fas, TNF-R, p75 nerve growth factor R). Products of activated microglia and astrocytes are implicated as secondary mediators of neuronal injury in Alzheimer's disease and AIDs encephalopathy.