Role of FK778 alone or in combination with tacrolimus or mTOR inhibitors as an immunomodulator of immunofunctions: in vitro evaluation of T cell proliferation and the expression of lymphocyte surface antigens.
We evaluated the in vitro capacity of FK778, alone or in combination with other immunosuppressive drugs: Tacrolimus (TRL); Sirolimus (SRL), Everolimus (EVL), to inhibit clonal expansion of T-lymphocytes and expression of lymphocyte-activation surface antigens; secondly, we compared the immunosuppressive potential of FK778 combined with TRL, SRL and EVL with the same combinations using Mycophenolic acid (MPA) as antimetabolite. Lymphocyte proliferation was assessed by 3H-Thymidine incorporation, in whole blood cultures stimulated with ConA. The effect of FK778 on alloresponse was evaluated by MLC and the expression of lymphocyte surface antigens by cytometry. FK778, TRL, SRL and EVL showed a high in vitro capacity to inhibit lymphocyte proliferation in a concentration-dependent way. Combinations of FK778 with TRL, SRL, or EVL presented an additive effect, especially FK778+TRL. Similar inhibition capacity of the clonal expansion was observed, when FK778 was combined with TRL, SRL or EVL, respecting the same combinations but using MPA instead of FK778. In addition, FK778 inhibited the expression of lymphocyte surface antigens involved in activation, co-stimulatory and apoptosis signals. In conclusion, FK778 inhibits the proliferative response induced by mitogeneic and allogeneic stimuli and the expression of surface antigens. Combinations of FK778 with TRL or mTOR inhibitors presented an additive effect and their action on T cell proliferation was similar to that of combinations with MPA. Since FK778, TRL and mTOR inhibitors present different action mechanisms and involve different cellular targets, these combinations may help prevent episodes of allorejection in organ transplants. FK778 and mTOR inhibitors may represent an alternative treatment for patients with renal failure.
Millán
O
O
Pharmacology Laboratory (CDB), Hospital Clinic, University of Barcelona, C/Villaroel 170, 08036 Barcelona, Spain.
Jiménez
O
O
Fortuna
V
V
Barceló
J J
JJ
Brunet
M
M
D000480:Alkynes; D000954:Antigens, Surface / Q000096:biosynthesis*; D000963:Antimetabolites / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D000068338:Everolimus; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007555:Isoxazoles; D008934:Mitogens; D009173:Mycophenolic Acid / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus / Q000494:pharmacology*
D000480:Alkynes; D000954:Antigens, Surface; D000963:Antimetabolites; D017252:CD3 Complex; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D008934:Mitogens; D009570:Nitriles; D015375:Receptors, Interleukin-2; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus