K. Zwingenberger et S. Wnendt, IMMUNOMODULATION BY THALIDOMIDE - SYSTEMATIC REVIEW OF THE LITERATUREAND OF UNPUBLISHED OBSERVATIONS, Journal of inflammation, 46(4), 1996, pp. 177-211
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.