Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains

Natalya V. Semiletova, Xiu Da Shen, Daniel M. Feldman, Feng Gao, Ana Mhoyan, Dhai Liu, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski, Rafik M. Ghobrial

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Functional topography of rat class I major histocompatibility complex (MHC) molecule was studied. The α1-helical sequences that are shared by class I RT1.Al and RT1.Au were substituted in the RT1.Aa molecule to produce the composite [α1 h l / u]-RT1.Aa MHC class I allochimeric molecule. Dominant immunogenic epitopes that induce accelerated rejection were identified within the hypervariable regions of the α1 domain of RT1.Aa, RT1.Al, and RT1.Au. Peri-transplant portal venous delivery of MHC class I allochimeric proteins, that included composite α1 helical immunodominant epitopes of RT1.Au and RT1.Al, induced donor-specific tolerance to RT1u (Wistar Furth, WF) and RT1l Lewis, LEW) disparate cardiac allografts in ACI (RT1a) hosts. Allochimeric generated tolerance was characterized by absence of T cell deletion or anergy. Donor specific IgM allo-Abs was not detected, while IgG alloresponse was markedly attenuated in sera of tolerant hosts. Further, long-term allografts in allochimeric-conditioned hosts exhibited moderate B cell infiltration when compared to rejecting controls. Analysis of intragraft cytokines revealed selective upregulation of IL-10 and marked inhibition of IL-2, IFN-γ, and IL-4. Our findings indicate the emergence of a peripherally induced tolerant state, afforded by the novel approach of soluble class I allochimeric conditioning that presents donor immunogenic epitopes in the context of recipient class I determinants.

Original languageEnglish (US)
Pages (from-to)48-58
Number of pages11
JournalCellular Immunology
Volume248
Issue number1
DOIs
StatePublished - Jul 2007

Keywords

  • Allo-antibody
  • Allochimeric protein
  • Cardiac allograft
  • Humoral immunity
  • MHC class I
  • Tolerance

ASJC Scopus subject areas

  • Cell Biology
  • Immunology

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