Intragraft expression of cytokine transcripts during pig proislet xenograft rejection and tolerance in mice.

  • Morris C
  • Simeonovic C
  • Fung M
  • et al.
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Abstract

The rejection of pig proislet (islet precursor) xenografts in CBA/H mice is a CD4+ T cell-dependent process. The molecular mechanisms of xenograft rejection, xenograft survival during anti-CD4 mAb therapy and xenograft tolerance post-withdrawal of anti-CD4 mAb administration, were examined by using a semiquantitative PCR method. Temporal analysis of intragraft cytokine mRNA demonstrated a Th0-like pattern of expression (IL-2, IFN-gamma, IL-3, IL-4, IL-5, and IL-10) on day 4 of the acute xenograft rejection process. From day 5, however, only Th2-associated transcripts (IL-3, IL-4, IL-5, and IL-10) were enhanced in xenografts compared with isograft controls. Immunohistochemistry showed that the principal participants in the rejection infiltrate were CD4+ T cells and eosinophils, with smaller numbers of CD8+ T cells. In vivo depletion of CD4+ T cells prevented xenograft rejection but had minimal effect on the peak levels of IL-2, IFN-gamma, and IL-10 mRNA; in contrast, the enhanced expression of IL-3, IL-4, and IL-5 transcripts seen in rejecting xenografts was abrogated. This established a positive correlation between acute xenograft rejection, presence of CD4+ T cells, and enhanced intragraft expression of mRNA for the Th2-type cytokines IL-3, IL-4, and IL-5. In tolerant hosts, long-term proislet xenograft survival and function (> 190 days) was accompanied by intragraft expression of IL-2 and IL-10 mRNA; IFN-gamma, IL-3, IL-4, and IL-5 mRNA were either undetected or not enhanced. The induced rejection of long-term functioning xenografts (> 170 days) in nontolerant hosts resulted in selective enhancement of IL-4 transcript expression. This study suggests that Th2-like CD4+ T cells are differentially activated in response to xenoantigen and that xenograft tolerance is associated with lack of expression of the Th2 cytokine, IL-4.

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Morris, C. F., Simeonovic, C. J., Fung, M. C., Wilson, J. D., & Hapel, A. J. (1995). Intragraft expression of cytokine transcripts during pig proislet xenograft rejection and tolerance in mice. The Journal of Immunology, 154(5), 2470–2482. https://doi.org/10.4049/jimmunol.154.5.2470

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