“In vitro” azathioprine-induced changes in peripheral T cell apoptosis and IFN-γ production associate with drug response in patients with Crohn's Disease

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Abstract

Background and aim: The use of the highly effective thiopurines as early therapeutic option in Crohn's Disease (CD) may be discouraged by the long time interval required to obtain clinical efficacy as also by their potential side effects. The development of non-invasive markers of responsiveness to thiopurines represents a major attempt in the clinical management of CD patients. Azathioprine is able to induce apoptosis of T cells. We studied the effect of thiopurines on “in vitro” T cell apoptosis, IFN-γ and IL-10 production in a group of CD patients with known response to a previous treatment with AZA.

Methods: Heparinized blood samples were drawn from 25 CD patients showing or not a previous responsiveness to a conventional azathioprine treatment (n = 17 and n = 8, respectively). CD4 + T cells were stimulated “in vitro” with aCD3/28 mAbs in the presence or absence of azathioprine, 6-mercaptopurine or 6-thioguanine. Apoptosis was assessed using Annexin V staining, and IFN-γ and IL-10 production in cell culture supernatants was evaluated by ELISA.

Results: Apoptosis stimulation index (% of apoptotic cells in the presence of thiopurine/% of apoptotic cells in the absence of thiopurine) and IFN-γ stimulation index (IFN-γ production in the presence of thiopurine/IFN-γ production in the absence of thiopurine) were, respectively, significantly lower and higher in non-responder when compared to responder patients. No variation was observed in IL-10 production.

Conclusions: Evaluation of apoptosis and IFN-γ stimulation index of peripheral CD4 + T cell may be useful for a proper selection of CD patients candidate to thiopurine treatment.

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