Downregulation of intragraft ifn-y expression correlates with increased iggl alloantibody response following intrathymic immunomodulation of sensitized rat recipients

Jochen Binder, Elmara Graser, Wayne W. Hancock, Barbara Wasowska, Mohamed H. Sayegh, Hans Dieter Volk, Jerzy W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

Abstract

A single intrathymic injection of donor-specific spleen cells (2xl07) abrogates accelerated (24 hr) rejection of LBNF1 cardiac allografts in presensitized LEW rats and prolongs graft survival to about 11 days. This effect is donor-specific, γ-irradiation-sensitive, thymus-dependent, and requires no concomitant therapy. We have recently shown that following intrathymic alloantigen administration, there is an earlier and increased systemic production of alloreactive IgM, and subsequently a premature isotype switching to IgG with the predominant IgGl and IgG2a alloanti-body responses. There is also a preferential binding of these IgG subclasses to the endothelium of well-func-tioning allografts. In this work, we analyzed the early cell activation and related cytokine elaboration patterns at the mRNA and protein levels by competitive template RT-PCR and immunohistochemistry, respectively. We found that prolonged cardiac allograft survival following intrathymic administration of donor spleen cells in presensitized rats was associated with markedly depressed intragraft IFNγ mRNA and protein expression. Moreover, intrathymic allostimula-tion has led to a defect in the IL-2 pathway as the expression of IL-2 and IL-2R protein at the graft site was inhibited despite stable IL-2 mRNA levels. The inhibition of cell activation was also demonstrated by reduced MHC class II and the lack of ICAM-1, and TNF-α expression by immunohistochemistry. The expression of biologically active IL-12 (p70) by mononuclear and endothelial cells was detected in rejecting grafts between 3 and 12 hr. The well-functioning grafts after intrathymic allostimulation were devoid of IL-12 (p70), which in turn may have contributed to the downregulation of IFN-γ mRNA and protein. Treatment with r.IFN-γ, but not with r.IL-2, recreated the rejection response, and the characteristic IgG subclass pattern associated with accelerated graft loss. Hence, intrathymic immunomodulation with alloanti-gen results in selective inhibition of IFN-γ-producing cells and a preferential upregulation of IgGl alloanti-bodies. These data support the notion of the interlocked immunoregulatory roles of cytokine and al-loantibody networks in rat allograft recipients.

Original languageEnglish (US)
Pages (from-to)1516-1524
Number of pages9
JournalTransplantation
Volume60
Issue number12
StatePublished - Dec 27 1995
Externally publishedYes

ASJC Scopus subject areas

  • Transplantation
  • Immunology

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