Nicholas W. Lukacs

CXL10 (IFN-γ-inducible protein-10) control of encephalitogenic CD4+ T cell accumulation in the central nervous system during experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a CD4+ Th1-mediated demyelinating disease of the CNS that serves as a model for multiple sclerosis. A critical event in the pathogenesis of EAE is the entry of both Ag-specific and Ag-nonspecific T lymphocytes into the CNS. In the present report, we investigated the role of the CXC chemokine CXCL10 (IFN-γ-inducible protein-10) in the pathogenesis of EAE. Production of CXCL10 in the CNS correlated with the development of clinical disease. Administration of anti-CXCL10 decreased clinical and histological disease incidence, severity, as well as infiltration of mononuclear cells into the CNS. Anti-CXCL10 specifically decreased the accumulation of encephalitogenic PLP139–151 Ag-specific CD4+ T cells in the CNS compared with control-treated animals. Anti-CXCL10 administration did not affect the activation of encephalitogenic T cells as measured by Ag-specific proliferation and the ability to adoptively transfer EAE. These results demonstrate an important role for the CXC chemokine CXCL10 in the recruitment and accumulation of inflammatory mononuclear cells during the pathogenesis of EAE.

The Function of Chemokines in Health and Disease

The cascade of events that dictate the normal physiologic processes leading to the initiation, maintenance, and final resolution of inflammation is the result of the host responding to a variety of direct or indirect stimuli. Although these stimuli may represent either infectious agents (viruses, bacteria, and protozoans) or noninfectious processes (trauma, autoimmune disorders, and ischemia/reperfusion injury), they all result in the activation and directed migration of leukocytes into an area of tissue injury. Our current understanding of inflammation suggests that the recruitment of leukocytes from the lumen of a vessel into a localized area of injury depends on an interrelated network of events, which must occur with some fidelity in order for the cells to arrive successfully at a site of inflammation. Although many of the steps involved in leukocyte activation and elicitation have been identified, a complete understanding of these processes, including the subsequent tissue injury, are not entirely known.