Pirfenidone Inhibits T-Cell Activation, Proliferation, Cytokine and Chemokine Production, and Host Alloresponses

Abstract

Background We previously showed that pirfenidone, an anti-fibrotic agent, reduces lung allograft injury/rejection. In this study, we tested the hypothesis that pirfenidone has immune modulating activities and evaluated its effects on the function of T cell subsets, which play important roles in allograft rejection. Method We first evaluated whether pirfenidone alters T cell proliferation and cytokine release in response to T cell receptor (TCR) activation, and whether pirfenidone alters regulatory T cells (CD4+CD25+) suppressive effects using an in vitro assay. Additionally, pirfenidone effects on alloantigen-induced T cell proliferation in vivo were assessed by adoptive transfer of CFSE-labeled T cells across a parent->F1 MHC mismatch, as well as using a murine heterotopic cardiac allograft model (BALB/c->C57BL/6). Results Pirfenidone was found to inhibit the responder frequency of TCR-stimulated CD4+ cell total proliferation in vitro and in vivo, whereas both CD4 and CD8 proliferation index were reduced by pirfenidone. Additionally, pirfenidone inhibited TCR-induced production of multiple pro-inflammatory cytokines and chemokines. Interestingly, there was no change on TGF-β production by purified T cells, and pirfenidone had no effect on the suppressive properties of naturally occurring regulatory T cells. Pirfenidone alone showed a small but significant (p < 0.05) effect on the in vivo allogeneic response while the combination of pirfenidone and low dose rapamycin had more remarkable effect in reducing the alloantigen response with prolonged graft survival. Conclusion Pirfenidone may be an important new agent in transplantation, with particular relevance to combating chronic rejection by inhibiting both fibroproliferative and alloimmune responses.

Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats

“…In a bleomycin-induced murine pulmonary fibrosis model, pirfenidone also suppressed MCP-1 levels induced by bleomycin (28). An in vitro study further showed that pirfenidone inhibited T-cell receptor-induced production of multiple proinflammatory chemokines, including IP-10, MIP-1, and Mig, which suggests its inhibition of inflammatory cell recruitment (39). The functional phenotype of macrophages depends on the renal microenvironment, which changes during the pathological process (15).…”

Pirfenidone: an anti-fibrotic therapy for progressive kidney disease

“…The beneficial effect of pirfenidone may in part be associated with inhibition of the pro-apoptotic effect of TGF-β The significant renal protection noted with pirfenidone in rats was associated with down-regulation of cyclosporine-induced pro-apoptotic genes and significant reduction of apoptosis in the renal tubules and interstitium [46]. Moreover, pirfenidone may have immune modulating properties, including inhibition of T-cell activation, proliferation and attenuation of associated induction of multiple cytokines [47]. …”

Inhibitory Effects of Pirfenidone on Dendritic Cells and Lung Allograft Rejection

“…Moreover, PFD delayed acute rejection and prolonged mouse heterotopic cardiac allograft survival (9). PFD protective properties are believed to be from its inhibition of profibrotic and inflammatory cytokines (5, 10, 11).…”