Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains1

• Published in: Cellular immunology Vol. 248; no. 1; pp. 48 - 58
• Main 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.
• Format: Journal Article
• Language: English
• Published: 01-07-2007
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1016/j.cellimm.2007.04.008

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
. Peri-transplant 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.