Differential Effects of Calcineurin and Mammalian Target of Rapamycin Inhibitors on Alloreactive Th1, Th17, and Regulatory T Cells. Issue 9 (September 2015)

• Record Type: Journal Article
• Authors: Gallon, Lorenzo; Traitanon, Opas; Yu, Yuming; Shi, Bo; Leventhal, Joseph R.; Miller, Joshua; Mas, Valeria; L, Xu; Mathew, James M.
• Is Part Of: Transplantation. Volume 99:Issue 9(2015)
• Publication Date: 2015-09
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000000717
• Languages: English
• ISSNs: 0041-1337

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background</title> <p>Previously, we had reported the role of tacrolimus (TAC) versus sirolimus (SRL) on the generation of regulatory T cells (Tregs) in primary MLR assays with SRL, demonstrating a uniquely supportive effect. However, the mechanisms associated with their actions on alloreactive human T cells are not fully understood. Therefore, we tested whether TAC and SRL differentially affect already alloactivated human CD4<sup>+</sup> T-cell subsets.</p> </sec> <sec> <title>Methods</title> <p>Alloreactive CD4<sup>+</sup>CD45RA<sup>−</sup>/CD45RO<sup>+</sup> T cells generated in 9-day MLR were cocultured with anti-CD3 and autologous antigen presenting cells plus interleukin (IL)-2 in presence of TAC, SRL, or both, and the Tregs generated after another 5 to 6 days were phenotypically, molecularly, and functionally characterized.</p> </sec> <sec> <title>Results</title> <p>Tacrolimus significantly and SRL modestly inhibited interferon (IFN)-γ (Th1) and IL-17 (Th17)–producing cells. At clinical therapeutic concentrations, SRL, however, significantly increased forkhead/winged helix transcription factor P3 (FOXP3<sup>+</sup>) Tregs, whereas TAC inhibited this T-cell population dose dependently and significantly. When used in combination, TAC and SRL had additive effects on inhibition of IFN-γ– and IL-17–producing cells. This was in contrast to the ability of SRL to reverse TAC-mediated inhibition of FOXP3-expressing cells. Proinflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor-α) added to cultures caused significant decrease in FOXP3<sup>+</sup> Tregs that was again reversed by SRL. Sirolimus-derived Tregs were phenotypically normal, anergic to allostimulation, and suppressed proliferation of allogeneic effector T-cells.</p> </sec> <sec> <title>Conclusions</title> <p>Thus, although TAC inhibits all alloreactive T cells, SRL promotes the differentiation and expansion of donor-specific Tregs without secondary reprogramming to IFN-γ<sup>+</sup>FOXP3<sup>+</sup> and IL-17<sup>+</sup>FOXP3<sup>+</sup> Treg subsets. These results, although performed in an artificial in vitro model, add clinically applicable information on how these agents affect T-cell subpopulations.</p> </sec> </abstract>