Heart transplants in interferon-gamma, interleukin 4, and interleukin 10 knockout mice. Recipient environment alters graft rejection

J Clin Invest. 1997 Nov 15;100(10):2449-56. doi: 10.1172/JCI119787.

Abstract

To study the role of cytokines in long-term cardiac allografts we have used recipient mice with targeted gene deletions (-/-) in IFN-gamma, IL-4, or IL-10. In wild-type and IL-4 -/- recipients immunosuppressed with a 30-d course of anti-CD4 and anti-CD8, graft survival was > 87 d. This time was significantly reduced in IFN-gamma -/- (62 +/- 19 d, P < 0.05) and IL-10 -/- recipients (55 +/- 4 d, P < 0.0001). Histology showed mononuclear cell infiltration, patchy necrosis, fibrosis, and vascular thickening in all groups. Intragraft transcript levels measured by 32P-reverse transcriptase PCR showed different inflammatory patterns. IFN-gamma -/- recipients had higher IL-2 transcripts and selective alteration in macrophage activation that may have contributed to decreased graft survival. Decreased graft survival in IL-10 -/- recipients was associated with increases in iNOS and IFN-gamma-driven responses. Finally, in grafts from IL-4 -/- recipients, there were increases in CD3 transcripts concurrent with TNF-alpha levels. This increase suggests that IL-4 may regulate T cell infiltration through TNF-alpha-mediated inflammatory cell recruitment. Concurrent evaluation of these three isolated cytokine deletions has shown that the recipient environment caused distinct graft modifications.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CD3 Complex / biosynthesis
  • CD4 Antigens / immunology
  • CD8 Antigens / immunology
  • Graft Rejection / genetics
  • Graft Rejection / immunology*
  • Graft Rejection / pathology
  • Graft Survival / genetics
  • Graft Survival / immunology*
  • Heart Transplantation / immunology*
  • Heart Transplantation / pathology
  • Immunosuppression
  • Interferon-gamma / deficiency*
  • Interferon-gamma / physiology
  • Interleukin-10 / deficiency*
  • Interleukin-10 / physiology
  • Interleukin-2 / biosynthesis
  • Interleukin-4 / deficiency*
  • Interleukin-4 / physiology
  • Macrophage Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred CBA
  • Mice, Knockout
  • Transcription, Genetic
  • Transplantation, Homologous
  • Transplantation, Isogeneic
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • CD3 Complex
  • CD4 Antigens
  • CD8 Antigens
  • Interleukin-2
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-4
  • Interferon-gamma