Pirfenidone inhibits T-cell activation, proliferation, cytokine and chemokine production, and host alloresponses

Transplantation. 2009 Aug 15;88(3):330-8. doi: 10.1097/TP.0b013e3181ae3392.


Background: We previously showed that pirfenidone, an anti-fibrotic agent, reduces lung allograft injury or 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 (CD4CD25) suppressive effects using an in vitro assay. Additionally, pirfenidone effects on alloantigen-induced T-cell proliferation in vivo were assessed by adoptive transfer of carboxyfluorescein diacetate succinimidyl ester-labeled T cells across a parent->F1 major histocompatibility complex 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 transforming growth factor-beta 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, whereas 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Chemokines / metabolism*
  • Cytokines / metabolism*
  • Drug Therapy, Combination
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control*
  • Heart Transplantation*
  • Histocompatibility / drug effects
  • Immunosuppressive Agents / pharmacology*
  • Isoantigens / immunology
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Culture Test, Mixed
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Pyridones / pharmacology*
  • Sirolimus / pharmacology
  • T-Lymphocyte Subsets / drug effects*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / transplantation
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Time Factors


  • Chemokines
  • Cytokines
  • Immunosuppressive Agents
  • Isoantigens
  • Pyridones
  • pirfenidone
  • Sirolimus