Thorac Cardiovasc Surg 2007; 55 - MP_66
DOI: 10.1055/s-2007-967422

Use of tacrolimus, sirolimus, and FK778 in experimental xenotransplantation – a detailed analysis of drug efficacy on cellular and humoral xenorejection

T Deuse 1, S Schrepfer 2, F Koch-Nolte 3, T Krieger 3, M Haddad 4, H Schaefer 5, H Reichenspurner 1
  • 1University Heart Center Hamburg, Cardiovascular Surgery, Hamburg, Germany
  • 2Stanford University, Cardiothoracic Surgery, Stanford, United States of America
  • 3University Hospital Hamburg, Immunology, Hamburg, Germany
  • 4University Hospital Hamburg, Clinical Chemistry, Hamburg, Germany
  • 5University Hospital Hamburg, Pathology, Hamburg, Germany

Aims: Aimed to investigate and to compare the efficacies of tacrolimus, sirolimus and FK778 on xenograft rejection.

Methods: The concordant hamster-to-rat aortic xenotransplantation model was used to examine host cellular and humoral responsiveness as well as histologic xenograft rejection. Recipients were treated for 14 days with tacrolimus, sirolimus, FK778, or combination regimens at varying doses.

Results: Drug trough levels were 12.4±6.7mg/l (tacrolimus 4mg/kg), 1.6±0.6mg/l (tacrolimus 1mg/kg), 8.2±1.7mg/l (sirolimus 2mg/kg), 2.9±1.2mg/l (sirolimus 0.5mg/kg), 104.8±56.5mg/l (FK778 20mg/kg), and 31.6±14.1mg/l (FK778 5mg/kg), respectively. In untreated rats, a huge infiltrative response was observed within the xenografts that widened the mean adventitial diameter from 143±93mm to 809±209mm (p<0.01) and caused extensive myocyte necrosis. Tacrolimus > FK778 >> sirolimus dose-dependently diminished xenograft infiltration and in the same order reduced vessel wall myocyte necrosis. Tacrolimus 4mg/kg significantly suppressed CD4+ cells compared with sirolimus 2mg/kg (p=0.008), and CD8+ (p≤0.015) and ED1+ cells (p=0.001) compared with FK778 20mg/kg and sirolimus 2mg/kg, respectively. Tacrolimus >> FK778 > sirolimus reduced in vivo lymphocyte activation (T-cell CD25 surface expression) and Tacrolimus > FK778 >> sirolimus diminished mixed lymphocyte reactions (p=0.06 tacrolimus 4mg/kg vs. FK778 20mg/kg; p=0.043 tacrolimus 4mg/kg vs. sirolimus 2mg/kg). Xeno-reactive antibody production was vigorously upregulated few days after transplantation (p<0.001), and tacrolimus > FK778 >> sirolimus significantly reduced circulating xeno-reactive IgM as well as IgG. Combination regimens revealed no significant benefit when compared with the corresponding monotherapy groups.

Conclusions: Tacrolimus is most powerful and so far, no other single drug protocol has shown a comparable efficacy on the different mechanisms during xenograft rejection.