Calcineurin Inhibitors Suppress Cytokine Production from Memory T Cells and Differentiation of Naïve T Cells into Cytokine-Producing Mature T Cells

Abstract

T cells have been classified as belonging to the Th1 or Th2 subsets according to the production of defining cytokines such as IFN-γ and IL-4. The discovery of the Th17 lineage and regulatory T cells shifted the simple concept of the Th1/Th2 balance into a 4-way mechanistic pathway of local and systemic immunological activity. Clinically, the blockage of cytokine signals or non-specific suppression of cytokine predominance by immunosuppressants is the first-line treatment for inflammatory T cell-mediated disorders. Cyclosporine A (CsA) and Tacrolimus (Tac) are commonly used immunosuppressants for the treatment of autoimmune disease, psoriasis, and atopic disorders. Many studies have shown that these compounds suppress the activation of the calcium-dependent phosphatase calcineurin, thereby inhibiting T-cell activation. Although CsA and Tac are frequently utilized, their pharmacological mechanisms have not yet been fully elucidated.In the present study, we focused on the effects of CsA and Tac on cytokine secretion from purified human memory CD4+T cells and the differentiation of naïve T cells into cytokine-producing memory T cells. CsA or Tac significantly inhibited IFN-γ, IL-4, and IL-17 production from memory T cells. These compounds also inhibited T cell differentiation into the Th1, Th2, and Th17 subsets, even when used at a low concentration. This study provided critical information regarding the clinical efficacies of CsA and Tac as immunosuppressants.

Cyclosporine A Regulates Pro-Inflammatory Cytokine Production in Ulcerative Colitis

“…IL-4 is known to play an important role in IBD (Sanchez-Munoz et al 2008). In connection with CsA IL-4 production is reduced in different in vitro studies (Andersson et al 1992;Tsuda et al 2012). We could show, that in the case of IBD patients and controls, IL-4 levels are reduced in all groups investigated.…”

Immunosuppressive Compounds Exhibit Particular Effects on Functional Properties of Human Anti-Aspergillus T H 1 Cells

“…Therefore, our data suggest that the concomitant use of CsA with adoptively transferred donor-derived anti-Aspergillus T H 1 cells may result in an insufficient number of effector cells in vivo. In addition, our results show that CsA in subtherapeutic levels significantly inhibited the production of IFN-␥ upon restimulation with naturally processed Aspergillus antigens, which is in line with recently reported data on purified memory CD4 ϩ T cells stimulated with PMA and ionomycin (20), as well as with data on CMV-specific CD8 ϩ T cells (21). This is an important observation, since IFN-␥ is well known as one of the key molecules in the combat against Aspergillus (6).…”

Lung parenchyma-derived IL-6 promotes IL-17A–dependent acute lung injury after allogeneic stem cell transplantation

“…27 More recently, CsA has actually been shown to promote Th17 differentiation in vivo, and subsequent bronchiolitis obliterans after experimental lung transplantation although effects on IL-6 were not studied. 28 It was interesting to note in our clinical cohort, unlike IL-6, Figure 7.…”