Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically...

Functional topography of rat class I major histocompatibility complex (MHC) molecule was studied. The alpha1-helical sequences that are shared by class I RT1.A(l) and RT1.A(u) were substituted in the RT1.A(a) molecule to produce the composite [alpha(1h)(l/u)]-RT1.A(a) MHC class I allochimeric molecule. Dominant immunogenic epitopes that induce accelerated rejection were identified within the hypervariable regions of the alpha1 domain of RT1.A(a), RT1.A(l), and RT1.A(u). Peri-transplant portal venous delivery of MHC class I allochimeric proteins, that included composite alpha1 helical immunodominant epitopes of RT1.A(u) and RT1.A(l), induced donor-specific tolerance to RT1(u) (Wistar Furth, WF) and RT1(l) Lewis, LEW) disparate cardiac allografts in ACI (RT1(a)) 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-gamma, 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.