IMMUNOMODULATION BY THALIDOMIDE - SYSTEMATIC REVIEW OF THE LITERATUREAND OF UNPUBLISHED OBSERVATIONS

Three decades of immunological investigations using thalidomide are re viewed Both in vitro and in vivo investigations are in accordance with the clinical finding that thalidomide does not impede T-cell competen ce in the control of infection by mycobacteriae. The term immunosuppre ssant does not apply. The immunomodulatory effects of thalidomide are evident in a myriad of phenomenological changes, and a molecularly def ined common denominator of these activities is not known at present. C ritical assessment with the objective to account for the clinical acti vity of thalidomide in specific human diseases leads to a focus on eff ects of thalidomide on phagocytic leukocytes and endothelia. The forme r are responsive to thalidomide by modulation of cytokine synthesis in vitro and in vivo; this activity can be shown using monocyte-specific stimuli in peripheral blood mononuclear cells but also in other phago cytic cells like microglia. For technical reasons, endothelial cells h ave until now been tested primarily in vitro. However, there is solid evidence now from intravital microscopy that the induction of adhesivi ty in postcapillary venules by LPS is modulated by thalidomide. Altere d surface antigen expression has been described on leukocytes obtained from humans and experimental animals treated with thalidomide, but co nvincing evidence is lacking for in vitro modulation of surface antige n expression on leukocytes (as opposed to the modulation of adhesion a ntigens on endothelial cells stimulated by LPS or exogenous TNF alpha in the presence of thalidomide). Therefore, in vivo redistribution is likely to account for some, if not all changes in circulating leukocyt e phenotypes. The immunopathological conditions most clearly responsiv e to thalidomide are vasculitic alterations of post-capillary venules either in the context of mycobacterial infection (in the case of eryth ema nodosum leprosum) or mucocutaneous aphths. In both instances (as i n the majority of focal inflammatory lesions), leukocyte infiltration and cytokine responses, in particular TNF alpha, are present. Thalidom ide acts clinically not only by palliation of existing lesions but als o by prevention of recurrence. The mechanism operates in skin, mucosa and parts of the nervous system and is most readily explained by syner gism of TNF alpha modulation and a separate point of action on leukocy te migration patterns. (C) 1996 Wiley-Liss, Inc.