title: Analysis of the Th1/Th2 paradigm in transplantation: interferon-gamma deficiency converts Th1-type proislet allograft rejection to a Th2-type xenograft-like response.
abstract: The rejection mechanisms for fetal proislet allografts and pig proislet xenografts in mice are characterized by different intragraft cytokine mRNA profiles and cellular responses. Allograft rejection is predominantly CD8 T-cell-dependent and is associated with a Th1-type cytokine pattern (i.e., IFN-gamma, IL-2 but no IL-4 or IL-5 mRNA). In contrast, xenograft rejection is CD4 T-cell-dependent and is accompanied by a strong Th2-type response (i.e., enhanced expression of IL-4 and IL-5 mRNA) and by marked eosinophil accumulation at the graft site. We have now examined and compared the regulatory role of IFN-gamma in both proislet allograft and xenograft rejection processes. The histopathology and intragraft cytokine mRNA profile of BALB/c (H-2d) proislet allografts were examined in IFN-gamma-deficient and wild-type C57BL/6J recipient mice. The survival of pig proislet xenografts was also assessed in IFN-gamma -/- and wild-type hosts. Both proislet allografts and xenografts were acutely rejected in IFN-gamma -/- and wild-type mice. Unlike the conventional allograft reaction, which lacks eosinophil infiltration, the rejection of proislet allografts in IFN-gamma-deficient hosts correlated with intragraft expression of IL-4 and IL-5 mRNA (i.e., a Th2-type response) and eosinophil recruitment. The rejection of proislet allografts and xenografts can therefore occur by IFN-gamma-independent pathways; IFN-gamma, however, regulates the pathology of the allograft reaction but not the xenograft response. The immune destruction of proislet allografts is not prevented by Th2 cytokine gene expression; instead, the latter correlated with the recruitment of unconventional inflammatory cells (eosinophils), which may play an accessory role in effecting graft injury. Significantly, the Th1-to-Th2-like switch resulted in the novel conversion of an allograft rejection reaction into a xenograft-like rejection process.
authors.affiliation: Division of Molecular Medicine, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT. Charmaine.Simeonovic@anu.edu.au
authors.forename: C J
authors.initials: CJ
authors.lastname: Simeonovic
authors.forename: M J
authors.initials: MJ
authors.lastname: Townsend
authors.forename: G
authors.initials: G
authors.lastname: Karupiah
authors.forename: J D
authors.initials: JD
authors.lastname: Wilson
authors.forename: J C
authors.initials: JC
authors.lastname: Zarb
authors.forename: D A
authors.initials: DA
authors.lastname: Mann
authors.forename: I G
authors.initials: IG
authors.lastname: Young
mesh_terms: D000208:Acute Disease; D000818:Animals; D015342:DNA Probes; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D013552:Swine; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
chemical_list: D015342:DNA Probes; D012333:RNA, Messenger; D007371:Interferon-gamma