Down regulation of genes involved in T cell polarity and motility during the induction of heart allograft tolerance by allochimeric MHC I.
BACKGROUND
The allochimeric MHC class I molecule [alpha1h1/u]-RT1.Aa that contains donor-type (Wistar Furth, WF; RT1u) epitopes displayed on recipient-type (ACI, RT1a) administered in conjunction with sub-therapeutic dose of cyclosporine (CsA) induces indefinite survival of heterotopic cardiac allografts in rat model. In vascularized transplantation models, the spleen contributes to graft rejection by generating alloantigen reactive T cells. The immune response in allograft rejection involves a cascade of molecular events leading to the formation of immunological synapses between T cells and the antigen-presenting cells.


RESULTS
To elucidate the molecular pathways involved in the immunosuppressive function of allochimeric molecule we performed microarray and quantitative RTPCR analyses of gene expression profile of splenic T cells from untreated, CsA treated, and allochimeric molecule + subtherapeutic dose of CsA treated animals at day 1, 3 and 7 of post transplantation. Allochimeric molecule treatment caused down regulation of genes involved in actin filament polymerization (RhoA and Rac1), cell adhesion (Catna1, Vcam and CD9), vacuolar transport (RhoB, Cln8 and ATP6v1b2), and MAPK pathway (Spred1 and Dusp6) involved in tubulin cytoskeleton reorganization and interaction between actin and microtubule cytoskeleton. All these genes are involved in T cell polarity and motility, i.e., their ability to move, scan and to form functional immunological synapse with antigen presenting cells (APCs).


CONCLUSIONS
These results indicate that the immunosuppressive function of allochimeric molecule may depend on the impairment of T cells' movement and scanning ability, and possibly also the formation of immunological synapse. We believe that these novel findings may have important clinical implications for organ transplantation.
Lisik
Wojciech
W
Department of General and Transplantation Surgery, Warsaw Medical University, Warsaw, Poland.
Tejpal
Neelam
N
Gong
Yongquan
Y
Skelton
T Spencer
TS
Ganachari
Malathesh
M
Bremer
Eric G
EG
Kloc
Malgorzata
M
Ghobrial
Rafik M
RM
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D016764:Cell Polarity / Q000187:drug effects / Q000235:genetics*; D016572:Cyclosporine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D010455:Peptides / Q000494:pharmacology; D025341:Principal Component Analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects / Q000235:genetics*
D015395:Histocompatibility Antigens Class I; D010455:Peptides; D016572:Cyclosporine