Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains |
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Authors: | Semiletova Natalya V Shen Xiu-Da Feldman Daniel M Gao Feng Mhoyan Ana Liu Dhai Busuttil Ronald W Kupiec-Weglinski Jerzy W Ghobrial Rafik M |
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Affiliation: | The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 77-120 CHS, Los Angeles, CA 90095-7054, USA |
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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 -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. |
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Keywords: | MHC class I Allochimeric protein Allo-antibody Cardiac allograft Tolerance Humoral immunity |
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