title: Donor pre-treatment with tacrolimus reduces transplant vasculopathy.
abstract: We tested whether transplant arteriosclerosis can be reduced by pre-treatment of the donor with immunosuppressive agents, using a rat allogeneic aorta transplantation model. Donor rats received no pre-treatment, or tacrolimus, methylprednisolone, rapamycin, or mycofenolate mofetil (MMF) 16 and 2h before explantation of the grafts. Eight weeks after transplantation, aorta allografts were harvested. Percent intima area/intima+media area (I/I+M), inflammatory cells and in situ MMP-2 and -9 activity were determined. In pre-transplantation biopsies, MMP-2 and -9 ratio, and mRNA levels for genes of interest were determined. In pre-transplantation biopsies we found no differences in MMP-2/9 ratio, and Bcl-2, Bax, TGF-beta, HO-1, p21, and HIF-1alpha mRNA expression between the groups. Aorta allografts, pre-treated with tacrolimus, showed significantly lower I/I+M ratio compared to untreated controls (p<0.01). Pre-treatment with methylprednisolone, rapamycin or MMF did not significantly reduce I/I+M ratio. In situ MMP-2/MMP-9 activity was significantly reduced in grafts treated with tacrolimus and rapamycin compared to controls (p<0.05). Immunohistochemistry revealed a high number of CD4+ cells and high CD4/CD8 ratio in grafts pre-treated with tacrolimus. Donor pre-treatment with tacrolimus significantly reduces transplant arteriosclerosis and is associated with reduced in situ MMP-2/MMP-9 activity and increased number of CD4+ cells.
authors.affiliation: Department of Surgery, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Denis
authors.initials: D
authors.lastname: Susa
authors.forename: Sandra
authors.initials: S
authors.lastname: van de Engel
authors.forename: Luc C A
authors.initials: LC
authors.lastname: van Damme
authors.forename: Henk P
authors.initials: HP
authors.lastname: Roest
authors.forename: Rob
authors.initials: R
authors.lastname: Krams
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Ijzermans
authors.forename: Ron W F
authors.initials: RW
authors.lastname: de Bruin
mesh_terms: D000818:Animals; D001011:Aorta / Q000033:anatomy & histology / Q000378:metabolism / Q000637:transplantation*; D018791:CD4 Lymphocyte Count; D003324:Coronary Artery Disease / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D017208:Rats, Wistar; D016559:Tacrolimus / Q000008:administration & dosage*; D013997:Time Factors; D014019:Tissue Donors; D017539:Tunica Intima / Q000187:drug effects
chemical_list: D007166:Immunosuppressive Agents; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D016559:Tacrolimus