Thalidomide was developed in the 1950s as a sedative having only a low toxicity. However, McBride and Lenz reported in 1961 a close correlation between oral administration of thalidomide by pregnant women and a particular deformity (phocomelia) of their babies. In the 1990s, the biological activities of thalidomide were determined to include the control of tumor necrosis factor-alpha production and inhibition of angiogenesis. In 1994, Folkman et al. reported that thalidomide exhibited a strong inhibition of angiogenesis in their experiments with rabbits and that this effect had a significant relationship to phocomelia. They suggested a utility of thalidomide as a therapeutic agent for diseases that involve angiogenesis, particularly tumorous diseases. Furthermore, in 1994, Vacca et al. reported that the bone marrow of multiple myeloma (MM) patients was rich in blood vessels and that there is a causal relationship between the activity of MM and marrow angiogenesis. According to these data, thalidomide was tested in many countries as a new therapeutic agent for MM. In this review, new pharmacological availability of thalidomide is described on the basis of our experiences.
Multinucleated giant cells (MGC) are characteristic cells in granulomatous disorders such as sarcoidosis and leprosy. There are two types of MGC; foreign body-type and Langhans-type cells. The exact mechanisms of the formation and the functional significance of MGC are not determined, although their morphological features are well understood. MGC are also formed in vitro from peripheral blood mononuclear cells by stimulation with cytokines and lectins. Particularly IFN-γ is considered to play a pivotal role in monocyte fusion. IL-3, IL-4, IL-13, and GM-CSF are other reported cytokines involved in MGC formation. In addition to such inflammatory mediators, a factor derived from the pathogens of granulomatous disorders may be necessary for MGC formation. Muramyl dipeptide, a peptidoglycan portion of bacterial cell walls, is one of the candidates and can preferentially induce Langhans-type cells in in vitro MGC formation system. Although the exact mechanisms of in vitro MGC formation remains unknown, cell surface molecules such as P2X7 receptor, integrins, CD98, and macrophage fusion protein are considered to be involved in fusion process. Monocytes of sarcoidosis patients expressed higher levels of P2X7 and had a higher ability to induce MGC than those of healthy controls. Effective agents for sarcoidosis such as tranilast, alloprinol, and captopril inhibited in vitro MGC formation, suggesting their therapeutic effects through the direct effects on monocytes . Thus, an in vitro MGC formation model would be a useful tool to understand the relevance of MGC in granulomatous disorders.
As an obligate intracellular pathogen, the principal host cells for Mycobacterium leprae are mononuclear phagocytes or macrophages. The macrophage is a primitive cell type being found in both early and advanced life forms, and possesses a variety of functions, such as phagocytosis of invaded bacteria, production of cytokines, antigen presentation and tumor killing. Hansen's disease is a chronic infectious disease characterized by specific host immune responses against M. leprae. In this article the macrophage is focused to dissect its functions in the disease.