Increased expression of transforming growth factor-beta and eosinophil infiltration is associated with the development of transplant arteriosclerosis in long-term surviving cardiac allografts.
BACKGROUND
Transplant arteriosclerosis is a major limiting factor for long-term function of allografts in clinical transplantation. This study investigated the impact of three different protocols capable of inducing long-term allograft survival on the development of transplant arteriosclerosis and immune response in cardiac allografts.


METHODS
CBA.Ca (H2k) recipients of fully allogeneic C57/BL10 (H2b) heart grafts received a short-term course of anti-CD154 antibody or were pretreated with anti-CD4 antibody in combination with donor alloantigen in the form of CBK (H2k+Kb) bone marrow or C57BL/10 donor-specific transfusion (DST). Grafts were analyzed on day 40 or 100 after transplantation for transplant arteriosclerosis and expression of interferon-gamma, interleukin (IL)-2, IL-4, IL-10, IL-12p40, inducible nitric oxide synthase, and transforming growth factor (TGF)-beta1 mRNA. Serum was analyzed for the presence of alloantibodies.


RESULTS
Intimal proliferation was 62%+/-11% on day 40 in the anti-CD154 group, progressed from 31%+/-10% on day 40 to 68%+/-8% on day 100 in the CBK-bone marrow group, but remained stable at 39%+/-4% in the DST group. Increased transplant arteriosclerosis on day 100 was associated with high intragraft TGF-beta1 mRNA production and eosinophil infiltration, but not alloantibody production. Progressing transplant arteriosclerosis was associated with increased IL-4 expression.


CONCLUSIONS
Treatment protocols for the induction of long-term allograft survival can differ substantially in the extent and kinetics of transplant arteriosclerosis. IL-4 and TGF-beta1 may be two potential therapeutic targets to attenuate the development of transplant arteriosclerosis in the long term.
Spriewald
Bernd M
BM
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, United Kingdom.
Ensminger
Stephan M
SM
Billing
J Stephen
JS
Morris
Peter J
PJ
Wood
Kathryn J
KJ
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism; D001803:Blood Transfusion; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism; D004804:Eosinophils / Q000473:pathology*; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects*; D015847:Interleukin-4 / Q000378:metabolism; D007519:Isoantigens / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014019:Tissue Donors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014184:Transplantation, Homologous
D000906:Antibodies; D015704:CD4 Antigens; D016207:Cytokines; D007519:Isoantigens; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D023201:CD40 Ligand; D015847:Interleukin-4