Everolimus but not mycophenolate mofetil therapy is associated with soluble HLA-G expression in heart transplant patients.
BACKGROUND
Human leukocyte antigen-G (HLA-G), a protein primarily expressed during pregnancy, helps maintain maternal-fetal immune tolerance. Myocardial and/or soluble HLA-G (sHLA-G) expression confers protection against rejection and vasculopathy after heart transplantation. Although the precise mechanisms remain unclear, immunosuppressive therapy has been reported to influence this expression.


METHODS
We compared sHLA-G expression in heart transplant recipients receiving two different anti-proliferative agents: mycophenolate mofetil (MMF) and everolimus (RAD). Twelve-hour pharmacokinetic (PK) studies were conducted in patients after cyclosporine (CsA) administration in conjunction with RAD or MMF, during which plasma HLA-G concentrations were measured by enzyme-linked immunoassay (ELISA).


RESULTS
Among patients receiving RAD, 78% expressed detectable levels of plasma HLA-G (1,002 +/- 511 ng/ml) compared with 25% of patients receiving MMF (612 +/- 438 ng/ml, p = 0.03). In all sHLA-G(+) patients, expression remained constant, with no significant changes in HLA-G levels throughout the 12-hour PK study period. CsA did not appear to influence sHLA-G expression, as there was no correlation between HLA-G levels and CsA exposure (R(2) = 0.43, p = 0.08).


CONCLUSIONS
These preliminary findings suggest a disproportionate expression of HLA-G in patients under two distinct immunosuppression strategies after heart transplantation. Although CsA administration does not influence sHLA-G levels, RAD but not MMF is associated with sHLA-G expression. Larger prospective clinical investigations are required to confirm whether RAD is independently associated with increased HLA-G expression.
Heart Transplant Program, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, 585 University Avenue, Toronto, Ontario, Canada.
Rohit
R
Sheshgiri
Finn
F
Gustafsson
Jill
J
Sheedy
Vivek
V
Rao
Heather J
HJ
Ross
Diego H
DH
Delgado
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016572:Cyclosporine / Q000097:blood / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006680:HLA Antigens / Q000097:blood / Q000235:genetics*; D059951:HLA-G Antigens; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008431:Maternal-Fetal Exchange / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011241:Prednisone / Q000627:therapeutic use; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D011257:Pregnancy Proteins; D016572:Cyclosporine; D000068338:Everolimus; D009173:Mycophenolic Acid; D011241:Prednisone; D020123:Sirolimus