Experimental Pathological Analysis of Intractable Inflammatory Disease:Role of mutant genes and macrophage functions

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Intractable inflammatory diseases are histopathologically characterized by granulomatous lesions associated with the accumulation of macrophages as effector cells. Owing to the immunological concepts developed in a last few years, pathogenesis of these diseases is suggested to be under the unusual host-immune response rather than the kind of pathogens. That is, the functions of macrophages and other cells belonging to mononuclear phagocyte system are regulated by unusual immune products including some lymphokines or immune complexes, and several chemical mediators released from these cells induce tissue-destruction directly or via intrinsic cell stimulation. On the other hand, these cells-play feedback actions against host immune system and modify it. Intractable inflammatory diseases may be associated with such unusual homeostatic situation.The first object in our project is to verify the propriety of this hypothesis by using several strains of immune disease mice. Thus, we have studied; 1) quantitative effect of immune complexes on the development of inflammatory lesions associated with macrophages, 2) influence of the lymphoproliferative mutant gene, lpr or gld, inducible of immunological dysfunctions upon macrophage functions, and 3) molecular characteristics of cytokines acting on macrophages, released from spleen cells in association with the lymphoproliferative gene expression or from a human T cell line.The second is to clarify the genetic factors responsible for these diseases. We have analyzed the pathologic features and macrophage functions in several strains of mice congenic of the lpr or gld gene. Moreover, it was found that particular segregated background genes contribute to the development of these diseases in association with the lymphoproliferative gene.