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

Abstract

Functional topography of rat class I major histocompatibility complex (MHC) molecule was studied. The α 1 -helical sequences that are shared by class I RT1.Al and RT1.A u were substituted in the RT1.A a molecule to produce the composite [α 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 α 1 domain of RT1.A a , RT1.A l , and RT1.A u . Peritransplant portal venous delivery of MHC class I allochimeric proteins, that included composite α 1 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-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.

Intensity of transplant chronic rejection correlates with level of graft-infiltrating regulatory cells

“…All sections were analyzed in a single-blind fashion for the presence of characteristic lesions, as described elsewhere. 11 Briefly, the degree of neo-intimal formation within each identifiable vessel was calculated using the IMAGEPRO Plus 5.1 (Media Cybernetics, Silver Spring, MD) computerized morphometric analysis software. Area, diameter, and neo-intimal formation, represented as neo-intimal index (NI ϭ intima area/(lumen area ϩ intima area) ϫ 100), were assessed.…”

New concepts in alloimmune recognition

“…Bharat and Mohanakumar [19] review the mechanisms by which allogeneic peptides exert such exquisite specificity and propose approaches by which those peptides might be used to engender allogeneic tolerance. These approaches are more than theoretical, because as Semiletova et al [20] show, allogeneic peptides can be engineered to modify immune responses to a considerable extent. In this seminal work, one can begin to imagine that some day the clinical immunologist will select a set of peptides, rather than a set of immunosuppressive drugs, to specifically and more safely modify immune responses.…”