Intragraft gene expression profile associated with the induction of tolerance by allochimeric MHC I in the rat heart transplantation model.
The MHC class I allochimeric protein containing donor-type epitopes on recipient-type heavy chains induces indefinite survival of heterotopic cardiac allografts in rats. We analyzed gene expression profile of heart allograft tissue. Mutated peptide [alpha1h1/u]-RT1.Aa that contains donor-type (Wistar Furth, WF; RT1u) immunogenic epitopes displayed on recipient-type (ACI, RT1a) was delivered into ACI recipients of WF hearts at the time of transplantation in addition to a 3 days course of oral cyclosporine. Microarray analysis was performed using Affymetrix Rat 230 2.0 Microarray. Allochimeric molecule treatment caused upregulation of genes involved in structural integrity of heart muscle, downregulation of IL-1beta a key modulator of the immune response, and downregulation of partitioning defective six homolog gamma PAR6, which is involved in T cell polarity, motility, and ability to scan dendritic cells (DC). These indicate that the immunosuppressive function of allochimeric molecule and/or the establishment of allograft tolerance depend on the induction of genes responsible for the heart tissue integrity, the suppression of cytokine pathway(s), and possibly the impairment of T cells mobility and their DC scanning ability. These novel findings may have important clinical implications for inhibition of chronic rejection in transplant recipients.
Lisik
Wojciech
W
Department of General and Transplantation Surgery, Warsaw Medical University, Warsaw, Poland.
Gong
Yongquan
Y
Tejpal
Neelam
N
Skelton
Thomas S
TS
Bremer
Eric G
EG
Kloc
Malgorzata
M
Ghobrial
Rafik M
RM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D016572:Cyclosporine / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D016027:Heart Transplantation; D006649:Histocompatibility Antigens / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011919:Rats, Inbred Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023001:Transplantation Tolerance / Q000235:genetics* / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D006649:Histocompatibility Antigens; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; C504908:Pard6a protein, rat; C038353:histocompatibility antigens RT, rat; D016572:Cyclosporine