3-Deazaadenosine prevents leukocyte invasion by suppression of adhesion molecule expression during acute cardiac allograft rejection: involvement of apoptotic cell death.
BACKGROUND
In the initial phase after cardiac transplantation, mononuclear cells infiltrate the graft, initiating a relevant impulse for rejection. 3-Deazaadenosine (c3Ado), an analog of adenosine, has proven anti-inflammatory properties both in vitro and in vivo. We hypothesized that c3Ado can serve as a therapeutic tool to reduce cellular infiltration in cardiac allograft transplantation.


METHODS
Using the Wistar-Furth-to-Lewis rat cardiac allograft model, animals were treated with 5 mg c3Ado subcutaneously twice per day. Allografts of untreated animals served as controls. Grafts were harvested on Days 1, 3 and 6 after transplantation for further examination (n = 4 per group and timepoint).


RESULTS
Immunohistochemical examination of c3Ado-treated grafts revealed up to 80% reduction of infiltrating major histocompatability complex (MHC) II-positive cells and T-cell-receptor-positive cells (R73) as well as ED1-positive monocytes and macrophages at Days 3 and 6 after transplantation. Adhesion molecule (ICAM-1 and VCAM-1) expression at Days 1 and 3 was almost completely abolished in c3Ado-treated grafts. However, c3Ado treatment did not prevent apoptotic cell death (TUNEL assay, DNA laddering) at Day 6, nor did it prolong allograft survival. As in controls, grafts were rejected at Day 7.


CONCLUSIONS
c3Ado significantly reduces graft infiltration by preventing leukocyte invasion, most likely through suppression of adhesion molecule expression. Although graft survival was not prolonged, treatment with c3Ado may still serve as a strategy to protect hearts from early damage after transplantation. Further studies will show whether peri-operative use of c3Ado can bridge the critical phase after transplantation when standard immunosuppression is not yet completely efficacious.
Department of Internal Medicine, Division of Cardiology, School of Medicine, University Hospital Giessen, Klinikstrasse 36, 35392 Giessen, Germany.
Horst
H
Fingerhuth
Hans
H
Hölschermann
Helmut
H
Grimm
Harald
H
Tillmanns
Werner
W
Haberbosch
Ruediger C
RC
Braun-Dullaeus
Thomas H W
TH
Stadlbauer
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000032:analysis* / Q000378:metabolism; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control*; D016027:Heart Transplantation; D000949:Histocompatibility Antigens Class II / Q000032:analysis / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D014184:Transplantation, Homologous; D014372:Tubercidin / Q000494:pharmacology* / Q000627:therapeutic use; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism
D015815:Cell Adhesion Molecules; D000949:Histocompatibility Antigens Class II; D019010:Vascular Cell Adhesion Molecule-1; C018258:3-deazaadenosine; D018799:Intercellular Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D014372:Tubercidin