The goal of the project is to investigate the biological roles of members of the chemokine family of cytokines by studying chemokine actions in vivo, primarily in animal models of infectious disease. Through differential screening of a cDNA library prepared from lymphokine-activated macrophages, this laboratory discovered two mouse chemokines, Crg-2 and Mig. Crg-2 is the mouse homologue of the human chemokine IP-10, and the murine Mig (MuMig) was used to identify a human homologue, HuMig. Crg-2/IP-10 and Mig are related, interferon-gamma inducible chemokines that preferentially target T lymphocytes, acting as chemotactic factors for activated T cells. Following injection of mice with interferon-gamma, mig was induced dramatically in multiple organs. In analyses of animal models of infectious disease, infection of mice with the malarial parasite P. yoellii induced mig in liver, spleen, lung and heart. Infection of mice with the protozoa T gondii led to induction of mig early after infection in liver, lung, spleen and heart and at later times in brain. Infection of mice with vaccinia virus induced mig in liver, ovary, uterus, spleen, heart and lung. Using interferon-gamma knockout mice or anti-interferon-gamma antibodies, we demonstrated that inductions of mig by infection with T. gondii and vaccinia virus were dependent absolutely on interferon gamma. Expression patterns of mig and crg-2/IP-10 differed. In each model the highest level of expression of mig was in the liver while crg-2 was expressed at the highest level in different tissues concordant with the expression of interferon-gamma. In order to evaluate the roles of mig and crg-2/IP-10 in host defense we have produced recombinant vaccinia virus producing these chemokines as well as mice with targeted deletion/disruption of the mig gene and studies using these biological reagents are underway.
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