Effect of inhaled tacrolimus on cellular and humoral rejection to prevent posttransplant obliterative airway disease.
This study aimed to investigate the pharmacokinetics after tacrolimus aerosol inhalation and to assess its efficacy to suppress acute and chronic airway allograft rejection. Orthotopic tracheal transplantations were performed and tacrolimus (4 mg/kg) was administered orally (PO) or via aerosol (AER). Tracheal tissue level AUCs(0-12) were similar in both treatment groups, but blood AUCs(0-12) were approximately 5.5-fold lower with AER (p < 0.001). Interestingly, only PO animals showed elevated BUN, cholesterol and triglycerides on POD 60 (p < 0.05). Histology of grafts harvested after 6 and 60 days revealed that both treatment groups were similarly effective in suppressing graft mononuclear infiltration (p < 0.001). Cellular immune activation (assessed by IFN-gamma- and IL-4-ELISPOTS), however, was far more effectively suppressed by tacrolimus PO (p < 0.001). In both treatment groups, the vigorous alloreactive IgM-antibody surge was effectively inhibited (p < 0.001). Due to the insufficient systemic cellular immunosuppression, discontinuation of tacrolimus AER resulted in a far stronger (3.5-fold) graft infiltration on POD 8 compared to PO (p < 0.001). Tacrolimus aerosol reduces systemic side effects and effectively protects the airway graft from early cellular rejection and chronic obliterative airway disease.
Schrepfer
S
S
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA. schrepfer@standford.edu
Deuse
T
T
Reichenspurner
H
H
Hoffmann
J
J
Haddad
M
M
Fink
J
J
Fischbein
M P
MP
Robbins
R C
RC
Pelletier
M P
MP
D000280:Administration, Inhalation; D000402:Airway Obstruction / Q000517:prevention & control*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D016207:Cytokines / Q000032:analysis; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D007111:Immunity, Cellular / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D011183:Postoperative Complications / Q000517:prevention & control*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014132:Trachea / Q000637:transplantation*; D014184:Transplantation, Homologous / Q000276:immunology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D016559:Tacrolimus