title: LF 15-0195 immunosuppressive agent enhances activation-induced T-cell death by facilitating caspase-8 and caspase-10 activation at the DISC level.
abstract: The deoxyspergualin derivative LF 15-0195 has demonstrated some efficacy in animal models of autoimmune and graft-versus-host diseases and is currently tested in clinics. The molecular mechanisms of LF 15-0195 immunosuppressive activity remained unknown. We show that exposure to LF 15-0195 sensitizes Jurkat T cells to apoptosis induced by an agonistic anti-CD95 antibody (CH11 clone) and by the cytokine TNF-related apoptosis-inducing ligand. LF 15-0195 does not demonstrate any significant effect on the postmitochondrial activation of caspases, nor does it modify overall expression of CD95, Fas-associated death domain, and procaspase-8. The compound facilitates the recruitment of these molecules to the death-inducing signaling complex (DISC) and enhances caspase-8 and -10 activation, thus increasing cytochrome c and direct IAP binding with low pI (DIABLO)/Smac mitochondrial release. LF 15-0195 also sensitizes Jurkat T cells to CD3-mediated apoptosis, an in vitro model for activation-induced T-cell death (AICD). LF 15-0195-mediated sensitization to AICD was further confirmed in human peripheral T cells exposed to anti-CD3 antibodies, then cultured in the presence of interleukin-2. In these cells, LF 15-0195 increased apoptosis triggered by either anti-CD95 antibodies or CD3 restimulation, whereas no effect was observed on "passive apoptosis." Finally, in bone marrow recipient mice, LF 15-0195 enhanced allogeneic donor T-cell death, which required a functional CD95 pathway. These results suggest that LF 15-0195 sensitizes T cells to AICD by increasing caspase activation at the DISC level in response to CD95 engagement. This original mechanism, together with LF 15-0195 efficacy in various disease models, makes this compound a promising immunosuppressive drug.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U517, IFR 100, Faculties of Medicine and Pharmacy, Dijon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ducoroy
authors.forename: Olivier
authors.initials: O
authors.lastname: Micheau
authors.forename: Sylvain
authors.initials: S
authors.lastname: Perruche
authors.forename: Laurence
authors.initials: L
authors.lastname: Dubrez-Daloz
authors.forename: Daniel
authors.initials: D
authors.lastname: de Fornel
authors.forename: Patrick
authors.initials: P
authors.lastname: Dutartre
authors.forename: Philippe
authors.initials: P
authors.lastname: Saas
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
mesh_terms: D000818:Animals; D001773:Blood Cells; D016026:Bone Marrow Transplantation / Q000276:immunology; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D053418:Death Domain Receptor Signaling Adaptor Proteins; D006086:Graft vs Host Disease / Q000517:prevention & control; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D023421:Models, Animal; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D019014:fas Receptor / Q000502:physiology
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; D006146:Guanidines; D007166:Immunosuppressive Agents; C434185:LF 150195; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C506438:CASP10 protein, human