Use of type I and type IV hypersensitivity responses to define the immunopharmacological profile of drugs.
Administration of antigen suspended in incomplete Freund's adjuvant supplemented with either heat-killed Mycobacterium tuberculosis (complete Freund's adjuvant, CFA) or Bordetella pertussis toxin sensitizes animals so that subsequent antigen challenge leads to delayed-type (DTH) or immediate type hypersensitivity (ITH) responses, named type IV and type I, respectively. Appropriate timing of administration of drugs with respect to immunization or antigen challenge allowed to detect predominantly immunosuppressive, antiinflammatory or antianaphylactic activities. Among the reference drugs tested, only cyclosporin A (CsA) and dexamethasone (Dex) markedly inhibited DTH reaction, due to their immunosuppressive and antiinflammatory activities, respectively, whereas leflunomide and indomethacin resulted less potent. On the other hand, only dexchlorpheniramine, a histamine-receptor antagonist, afforded significant protection against anaphylactic shock, a form of ITH. Two new chemical entities were studied according to this protocol: ITF 1697, a chemically stabilized C-reactive protein-derived tetrapeptide, and ITF 2018, a leflunomide analogue. Data obtained with these new compounds showed that ITF 1697 has antianaphylactic activity, while ITF 2018 is endowed, mainly, with antiinflammatory activity. These results show that, through appropriate timing of administration, established in vivo models of immunologically mediated disease states allow an accurate profiling of the effects of pharmacologically active molecules and the detection of unsuspected activities for new drugs.
Di Pierro
F
F
Centro Ricerche Italfarmaco S.p.A., Milan, Italy.
d'Atri
G
G
Marcucci
F
F
Leoni
F
F
D000818:Animals; D002097:C-Reactive Protein / Q000031:analogs & derivatives; D016572:Cyclosporine / Q000276:immunology / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D006968:Hypersensitivity, Delayed; D006969:Hypersensitivity, Immediate; D007166:Immunosuppressive Agents / Q000276:immunology* / Q000494:pharmacology; D007213:Indomethacin / Q000276:immunology / Q000494:pharmacology; D007555:Isoxazoles / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D000077339:Leflunomide; D051379:Mice; D008807:Mice, Inbred BALB C
D007166:Immunosuppressive Agents; D007555:Isoxazoles; D016572:Cyclosporine; D002097:C-Reactive Protein; D000077339:Leflunomide; D007213:Indomethacin