Allopurinol reduces antigen-specific and polyclonal activation of human T cells

Abstract

Allopurinol is the most popular commercially available xanthine oxidase inhibitor and it is widely used for treatment of symptomatic hyperuricaemia, or gout. Although, several anti-inflammatory actions of allopurinol have been demonstrated in vivo and in vitro, there have been few studies on the action of allopurinol on T cells. In the current study, we have assessed the effect of allopurinol on antigen-specific and mitogen-driven activation and cytokine production in human T cells. Allopurinol markedly decreased the frequency of IFN-γ and IL-2-producing T cells, either after polyclonal or antigen-specific stimulation with Herpes Simplex virus 1, Influenza (Flu) virus, tetanus toxoid and Trypanosoma cruzi-derived antigens. Allopurinol attenuated CD69 upregulation after CD3 and CD28 engagement and significantly reduced the levels of spontaneous and mitogen-induced intracellular reactive oxygen species in T cells. The diminished T cell activation and cytokine production in the presence of allopurinol support a direct action of allopurinol on human T cells, offering a potential pharmacological tool for the management of cell-mediated inflammatory diseases.

Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response

“…While allopurinol can inhibit T cell activation at high doses, this is unlikely to be the explanation of the patients' negative LTT results to allopurinol as it can still induce and stimulate ALP-TCLs in our study [34]. Instead, inability of oxypurinol-specific T cells to recognize allopurinol is likely the explanation of the negative LTT results.…”

Combined treatment with benznidazole and allopurinol in mice infected with a virulentTrypanosoma cruziisolate from Nicaragua

“…Moreover, AL was able to reduce T cell activation and cytokine production by human T cells in vitro (Perez-Mazliah et al . 2012). Altogether, these findings might support the application of a combined treatment of BNZ and AL in the chronic phase of the infection, even when some degree of tissue damage has already been developed.…”

“…This might be due to higher levels of drug-induced antigen release upon administration of 2 courses of AL. A boost in humoral and cellular T cell responses was observed early after treatment of chronically T. cruzi-infected subjects with BNZ (Cooley et al 2008;Laucella et al 2009) or with a combination of AL and BNZ (Perez-Mazliah et al 2013). Therefore, a longer time might be needed for antibody clearance in this treatment schedule.…”

“…The cardioprotective effect of AL has been reported in previous studies (Pacher et al 2006) and might be related to the reduction of oxidative stress via a scavenging mechanism (Osarogiagbon et al 2000;Namazi, 2004) by suppressing TNF-α production in the heart (Pissetti et al 2011). Perez-Mazliah et al (2013) have recently reported that the combination of AL and BNZ for treatment of chronic Chagas disease in humans induced significantly altered T and B cell responses compatible with a reduction in parasite burden. Moreover, AL was able to reduce T cell activation and cytokine production by human T cells in vitro (Perez-Mazliah et al 2012).…”

Azathioprine with Allopurinol

“…While more extensive studies are needed to test for potentially confounding effects of bias from the treatment site, sample batch with respect to the LDAA/AZA comparisons or the effects of additional drugs on some patients in the AZA group, the Gene Ontology analysis, both for the shared and the full lists of differentially expressed genes, and the small number of shared genes up- or downregulated by either treatment, support the view that there are differences between LDAA and AZA in their underlying therapeutic mechanisms. An important caveat for the interpretation of the LDAA data is that allopurinol may have anti-inflammatory properties, independently of its effects on thiopurine metabolism, by scavenging free radicals, or reducing the T-cell activation 44 involved in the pathogenesis of IBD. 45 Thus, by providing complementary anti-inflammatory effects, the therapeutic value of allopurinol for IBD may extend beyond merely improving thiopurine pharmacokinetics.…”