In vitro and in vivo immunosuppressive potential of thalidomide and its derivative, N-hydroxythalidomide, alone and in combination with cyclosporin A.
Thalidomide (Thd) has been shown to have interesting immunosuppressive properties and strong action against TNF-alpha. It is used for treating a variety of immune-mediated pathology and inflammatory diseases. The purpose of this work was to evaluate the in vitro and in vivo immunosuppressive effects of Thd and its derivative, N-Hydroxythalidomide (H-Thd), alone and in combination with cyclosporin A (CsA), upon different in vitro lymphocyte activation pathways and in vivo local graft-versus-host-reaction (GvHR). At different concentrations, both Thd and H-Thd alone inhibited the lymphocyte proliferation induced by alloantigen (MLR), mitogens (Con A, PWM) and superantigen (SEB) with an activity of 50-75% that of CsA, however, in some tests, immunosuppressive potency of H-Thd was shown to be higher than that of Thd. In vivo using GvHR, Thd and H-Thd alone proved as active as CsA. The association in vitro and in vivo of each compound with CsA at different low concentrations, produced an additive effect as strong as CsA used alone at high therapeutic concentrations. In summarizing, this study revealed that: (1) despite its weaker potency in vitro than that of CsA, H-Thd presents interesting immunosuppressive properties similar to, and in some cases, better than Thd, and (2) the combination of H-Thd or Thd with CsA at suboptimal concentrations leads to high activity.
Chuong
P H
PH
Laboratoire de Toxicologie, Faculté de Pharmacie, Université de Paris V, France.
Galons
H
H
Voisin
J
J
Zhu
J
J
Righenzi
S
S
Warnet
J M
JM
Claude
J R
JR
Huynh-Thien
D
D
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006087:Graft vs Host Reaction / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology*
D007166:Immunosuppressive Agents; C060554:N-hydroxythalidomide; D013792:Thalidomide; D016572:Cyclosporine