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+CD45RA-CDw29 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 μ/ml. (d) The surface receptors found to be affected include among others: CD2 (LFA-2) and CD11 a (LFA-1α) and CD18 (LFA-1β). 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. Interferences with the many functions of integrins with fundamental biological importance may open a new dimension of pharmacological or toxic effects.