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


METHODS
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.


CONCLUSIONS
Pirfenidone may be an important new agent in transplantation, with particular relevance to combating chronic rejection by inhibiting both fibroproliferative and alloimmune responses.
Visner
Gary A
GA
Department of Medicine, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA. gary.visner@childrens.harvard.edu
Liu
Fengzhi
F
Bizargity
Peyman
P
Liu
Hanzhong
H
Liu
Kaifeng
K
Yang
Jun
J
Wang
Liqing
L
Hancock
Wayne W
WW
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D016027:Heart Transplantation; D006648:Histocompatibility / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011728:Pyridones / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
D018925:Chemokines; D016207:Cytokines; D007166:Immunosuppressive Agents; D007519:Isoantigens; D011728:Pyridones; C093844:pirfenidone; D020123:Sirolimus