title: 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 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.
authors.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.
authors.forename: Natalya V
authors.initials: NV
authors.lastname: Semiletova
authors.forename: Xiu-Da
authors.initials: XD
authors.lastname: Shen
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Feldman
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Ana
authors.initials: A
authors.lastname: Mhoyan
authors.forename: Dhai
authors.initials: D
authors.lastname: Liu
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.forename: Rafik M
authors.initials: RM
authors.lastname: Ghobrial
mesh_terms: D000818:Animals; D014644:Genetic Variation / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D007519:Isoantigens / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology*; D050506:Mutant Chimeric Proteins / Q000138:chemical synthesis / Q000276:immunology*; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000276:immunology*; D016415:Sequence Alignment; D013045:Species Specificity; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007376:Interleukin-2; D007519:Isoantigens; D050506:Mutant Chimeric Proteins; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma