title: Association of down-regulation of cytokine activity with rat hind limb allograft survival.
abstract: Cytokines are short-acting protein modulators of many physiologic processes including graft rejection. An understanding of the production, action, and interaction of cytokines may lead to better appreciation of the complex mechanism of graft rejection. The potential would then exist for more selective and less-toxic means of modulating the immune response. A rat hind limb allograft model with major immunohistoincompatibility was used to study the local mRNA expression of IL-1 alpha, IL-2, IL-6, gamma interferon (gamma INF), platelet-derived growth factor-alpha (PDGF-alpha), basic fibroblast growth factor (FGF), and transforming growth factor-beta (TGF-beta) during acute allograft rejection. A 14-day postoperative course of immunosuppressive therapy with FK506 or rapamycin was administered. In situ hybridization was performed on serial full-thickness skin punch biopsies of the untreated rejecting limb allograft and compared with tissue from treated allografts, isografts, and to normal limb tissue. A sequential pattern of cytokine mRNA expression was demonstrated which progressed in a time-dependent manner and paralleled observed clinical rejection. Maximal cytokine mRNA expression correlated with peak graft rejection. Cellular expression of IL-1 alpha, IL-2, IL-6, gamma-INF, FGF, and TGF-beta mRNA was suppressed with FK506 to below isograft levels, and clinical rejection was not observed with the doses, routes, and schedules used. Rapamycin was ineffective in suppressing cytokine expression, and allograft rejection was not prevented. Isografts demonstrated no evidence of rejection. The in situ hybridization technique demonstrates a time-dependent, selective expression of cytokines within rejecting allograft tissue, and the modification of this response with immunosuppressive therapy. Down-regulation of cytokine expression is associated with clinical allograft survival.
authors.affiliation: Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, California, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Fealy
authors.forename: D
authors.initials: D
authors.lastname: Most
authors.forename: P
authors.initials: P
authors.lastname: Huie
authors.forename: M
authors.initials: M
authors.lastname: Wolf
authors.forename: R K
authors.initials: RK
authors.lastname: Sibley
authors.forename: R E
authors.initials: RE
authors.lastname: Morris
authors.forename: B H
authors.initials: BH
authors.lastname: Press
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics* / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D015870:Gene Expression; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000502:physiology*; D006614:Hindlimb / Q000637:transplantation*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D017403:In Situ Hybridization / Q000379:methods; D007371:Interferon-gamma / Q000032:analysis; D007375:Interleukin-1 / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D015850:Interleukin-6 / Q000032:analysis / Q000502:physiology; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011090:Polyenes / Q000627:therapeutic use; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020123:Sirolimus; D016559:Tacrolimus / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000235:genetics; D014181:Transplantation Immunology
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D010982:Platelet-Derived Growth Factor; D011090:Polyenes; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D007371:Interferon-gamma; D020123:Sirolimus; D016559:Tacrolimus