Thalidomide derivatives and the immune system. I. Changes in the pattern of integrin receptors and other surface markers on T lymphocyte subpopulations of marmoset blood

Abstract

Treatment of marmosets (Callithrix jacchus) with thalidomide (Thd) or its derivative EM12 (which is also teratogenic, but more stable to hydrolysis) resulted in the lack of reaction of adhesion surface receptors (integrins) on T lymphocytes in venous blood. Lymphocyte subsets appeared, for example CD4+CD2-, which are not found under normal conditions. (a) There was no clear effect of the treatments on the total number of leukocytes or lymphocytes or on the total number of CD4+ or CD8+ T lymphocytes. (b) A decrease in the percentage of the cytotoxic T cells carrying the CDw29 marker (CD8+CD56+CDw29+) at a dose as low as 5 mg EM12/kg bw, and an increase in the percentage of suppressor cells carrying the CDw29 marker (CD8+CD56-CDw29+) at 10 mg EM12/kg bw were found. Similar effects were induced by Thd at somewhat higher doses, while supidimide (Sup) was less active even at the very high dose of 100 mg/kg bw. Especially at the lower doses these effects occurred with a lag phase and persisted after discontinuation of the dosing. Alterations induced in helper T cell subpopulations by Thd or EM12 were less impressive (no significant effect was observed with 5 mg EM12/kg bw). Some changes were observed at higher dose levels in the CD4+CD45RA+CDw29+ cells and the CD4+CD45RACDw29+ cells. (c) The most significant effect, reduction in the reactivity of CD2+, was detectable subsequent to daily oral doses as low as 10 mg Thd/kg or 1 mg EM12/kg bw. Peak plasma concentrations to be expected under these experimental conditions are less than 1 micrograms/ml. (d) The surface receptors found to be affected include among others: CD2 (LFA-2) and CD11a (LFA-1 alpha) and CD18 (LFA-1 beta). Clearly, CD4+ cells were found to be more susceptible to the loss of the integrin receptors than CD8+ cells. (e) The effect persisted for several weeks subsequent to the discontinuation of the dosing. (f) A rough estimate of the relative potency to reduce the CD2 receptor in the marmoset suggests EM12 to be five to ten times more potent than Thd. Sup, a Thd derivative reported to exhibit no or a low teratogenic potency, was found to be at least five times less potent than Thd. (g) The alterations of surface adhesion receptors by the substances studied in this investigation were not confined to T lymphocytes. We also observed similar effects on B lymphocytes, monocytes, and neutrophils, and many other cell types carrying such receptors might be affected.(ABSTRACT TRUNCATED AT 400 WORDS)

Long-term thalidomide use in refractory cutaneous lesions of systemic lupus erythematosus

“…More recently it was refered that thalidomide was associated with a decrease in CD4+ cells in 2 patients with erythema nodosum leprosum 29 , but not in healthy volunteers 30 . Reduced expression of integrin receptors in CD4 cells during thalidomide treatment was observed in laboratory animals 31 , but not in healthy volunteers 30 . Reduced expression of major histocompatibility complex class II antigens and ICAM-1 on keratinocytes from erythema nodosum leprosum lesions was observed during thalidomide treatment 32 .…”

Thalidomide and Its Metabolites Have No Effect on Human Lymphocyte Proliferation

“…It has been proposed that thalidomide blocks the produc tion of human macrophage-derived TNF-a [4] and that af fects the expression of adhesion molecules on marmoset lymphocytes [6], so the conclusion that thalidomide does not affect lymphocyte proliferation is a valuable informa tion for a drug the use of which is being extended to diseases with a strong immunological component [1][2][3].…”

“…In vivo administration of thalidomide causes a decrease in the CD4/CD8 lymphocyte ratio in healthy humans [5] and a decrease in lymphocyte adhesion molecules in mar mosets, although in the latter CD4 and CD8 lymphocyte levels were unaffected [6].…”

Mechanism of immunomodulatory drugs' action in the treatment of multiple myeloma

“…IMiDs activate NFAT transcriptional pathways [125], thereby inhibiting cancer cell migration. In addition, the treatment with IMiDs decreased the expression of integrin subunits and/ or integrin receptors [192][193][194][195][196]. Since integrins are crucial for cell-matrix interactions and mediate cell adhesion to endothelium, decreased the expression of integrins, upon treatment with IMiD, will result in inhibition of cell migration.…”