Thalidomide Costimulates Primary Human T Lymphocytes, Preferentially Inducing Proliferation, Cytokine Production, and Cytotoxic Responses in the CD8+ Subset

Abstract

The efficacy of thalidomide (α-phthalimido-glutarimide) therapy in leprosy patients with erythema nodosum leprosum is thought to be due to inhibition of tumor necrosis factor α. In other diseases reported to respond to thalidomide, the mechanism of action of the drug is unclear. We show that thalidomide is a potent costimulator of primary human T cells in vitro, synergizing with stimulation via the T cell receptor complex to increase interleukin 2–mediated T cell proliferation and interferon γ production. The costimulatory effect is greater on the CD8+ than the CD4+ T cell subset. The drug also increases the primary CD8+ cytotoxic T cell response induced by allogeneic dendritic cells in the absence of CD4+ T cells. Therefore, human T cell costimulation can be achieved pharmacologically with thalidomide, and preferentially in the CD8+ T cell subset.

Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma

“…Its antiangiogenic effects are hypothesized to result from the blocking of bFGF and VEGF. 8 Acting as an immunomodulator, thalidomide enhances cell-mediated immunity by directly costimulating T cells, 20 and it also alters adhesion molecule expression. 21,22 Recently, Fujita et al demonstrated the inhibitory effects of thalidomide on cyclooxygenase-2 expression.…”

Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers

“…Immunomodulatory drug analogues are able to costimulate T cells (Haslett et al, 1998;Corral et al, 1999) and are highly antiangiogenic (Dredge et al, 2002a). The ability to costimulate T cells has been associated with an increased Th1-type cytokine response and suggests that in certain clinical settings, IMiD analogues are likely to act as adjuvants to promote T-cell responses, thereby contributing to antitumour activity in vivo.…”

An evaluation of factors predicting long-term response to thalidomide in 234 patients with relapsed or resistant multiple myeloma

“…The exact mechanism of THAL action on MM is still unclear. Some postulated effects of THAL are: the inhibition of proangiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF) (Dmoszynska et al, 2000;Kyle and Rajkumar, 2001) and the downregulation of the secretion of proinflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor (TNF) (Moreira et al, 1993;Turk et al, 1996); upregulation of adhesion molecules (Geitz et al, 1996) and the stimulation of cytotoxic T-cell proliferation and the secretion of interferon-g and interleukin-2 (Haslett et al, 1998). First reports concerning the application of THAL in MM were published in 1999 by Singhal et al (1999).…”