University of Virginia Health System

Cross-talk Between the Immune System and the Brain--Implications for Disease and Health I. Immune surveillance of the CNS We, and others, have proposed that the CNS must actively mediate the delicate balance between maintenance of function and defense against pathogens and malignancy. An increasing body of evidence suggests that the CNS carefully regulates potentially damaging inflammatory responses by modulation of both lymphocyte infiltration and subsequent lymphocyte function. Modulation of intracerebral immune responses is of critical importance in the context of neurological disease arising from infection with CNS-tropic organisms (e.g. HIV) or destructive autoimmunity (e.g. multiple sclerosis). Microglia are considered to be the resident immunoregulatory or antigen presenting cells (APC) of the CNS parenchyma. Although microglia share many phenotypic and functional attributes with blood-borne monocyte/macrophages, these cells appear to represent a distinct population of immune modulatory APC with unique functional characteristics. We are currently studying the mechanisms by which macrophages and microglia modulate memory T cell responses, employing well-defined mouse models. In addition to studies on microglial APC function, we are investigating the extent to which CNS environment modulates T cell entry across the blood-brain barrier and subsequent T cell function. Elucidation of the mechanisms governing T cell migration and function within the healthy and diseased CNS, and development of effective immune-based therapies for infection and malignancy would be markedly enhanced by technologies permitting the fate of T cells in vivo to be followed in space and time. In collaboration with the Small Animal Multi-modality Imaging Center at UVa, we are developing a nuclear imaging strategy in which T cells loaded with single gamma-emitting radionuclides can be detected by photon emission computed tomography (SPECT) or single g-scintigraphy (SGS). In parallel to the radionuclear approach described, we are also exploring non-invasive optical imaging approaches to tracking T cell movement in vivo. II. Sympathetic nervous system (SNS) control of extracerebral immune responses The research described above explores how the CNS controls intracerebral immune responses. More recently we have begun to investigate how the CNS controls peripheral immune responses. Primary and secondary lymphoid organs receive extensive sympathetic innervation originating from the CNS and terminating in the direct vicinity of lymphoid cells. Catecholamines are released from these sympathetic nerve terminals following SNS activation and bind to adrenoreceptors expressed on lymphoid and associated cells. Evidence accumulated over the last twenty years indicates that stimulation of these receptors by catecholamines modulates lymphocyte trafficking and function, with attendant effects on autoimmunity and susceptibility to infection. The role of the SNS in modulating the function of primary lymphoid organs such as the adult thymus, however, remains poorly understood. We propose that catecholamines regulate thymocyte differentiation via modulation of thymic microenvironment. We are now directing our efforts to investigate the relationship between the SNS and thymopoiesis in the adult, utilizing mouse models bearing targeted knockout mutations of gene products involved in catecholamine production.