title: Distinct patterns of cytokine gene suppression by the equivalent effective doses of cyclosporine and tacrolimus in rat heart allografts.
abstract: In vitro studies of the mode of action of cyclosporine (CsA) and tacrolimus have indicated that both drugs produce immunosuppression by a quite similar cellular and molecular mechanism to block T cell receptor emanated transcriptional activation of interleukin(IL)-2 and other cytokine genes. Herein, we show that there are distinct patterns of cytokine gene expression in rat heart allografts under equivalent effective doses ("optimal dose") of CsA and tacrolimus. The optimal doses of CsA (10 mg/kg/day) and tacrolimus (3.2 mg/kg/day), which induce similar mean graft survival time (MST), were administered in LEW recipients with ACI heart grafts from day 0 after grafting until sacrifice. Heart grafts were harvested at days 3, 5, and 7. The expression of various cell surface markers, cytokines, and cytotoxic factors was determined by immunohistology and reverse transcriptase-polymerase chain reaction (RFT-PCR). Cell populations that stained positively in the heart tissues of allograft control increased through day 7 for CD4+ and CD8+ T lymphocytes, NKR-Pla+ natural killer (NK) cells, and ED2+ macrophages. CsA and tacrolimus have comparable activity to block these cell local infiltrations. The mRNA levels of the majority of the factors were dramatically up-regulated in the allografts over time, peaking at day 5. The optimal doses of CsA and tacrolimus had similar inhibitory effects on Th1 type cytokine IL-2 and interferon [INF]-gamma), inflammatory cytokine (IL-1beta and tumor necrosis factor [TNF]-alpha), and cytotoxic factor (granzyme B and perforin) mRNA expression. However, the drugs had different effect on Th2 type cytokines (IL-4 and IL-10). Whereas IL-4 expression was not affected by tacrolimus and was enhanced by CsA, IL-10 expression was more significantly suppressed by tacrolimus than CsA. Differences in the suppression of Th2 type cytokine gene expression indicate that the in vivo molecular networks by which CsA and tacrolimus exert their full immunosuppressive activity are not necessarily the same.
authors.affiliation: Fujisawa Research Institute of America, Evanston Northwestern Healthcare, Northwestern University/Evanston Research Park, IL 60201, USA. hongsi_jiang@fujisawa.com
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: R N
authors.initials: RN
authors.lastname: Soriano
authors.forename: T
authors.initials: T
authors.lastname: Fujimura
authors.forename: K
authors.initials: K
authors.lastname: Krishnan
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000494:pharmacology*; D014181:Transplantation Immunology / Q000187:drug effects*; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus