Marked inhibition of transplant vascular sclerosis by in vivo-mobilized donor dendritic cells and anti-CD154 mAb.
BACKGROUND
Combination of donor dendritic cells (DC) and anti-CD40 Ligand (L) (CD154) monoclonal antibody (mAb) markedly prolongs heart or skin allograft survival, but the influence of this strategy in models of chronic rejection is unknown. Our aim was to ascertain the influence of in vivo-mobilized immature donor DC plus anti-CD40L mAb on vascular sclerosis in functional murine aortic allografts.


METHODS
C3H He/J (C3H;H2k) mice received 2 x 106 freshly isolated, immunobead-purified (>90%) fms-like tyrosine kinase 3 ligand-mobilized C57BL/10 (B10;H2b) CD11c+ DC intravenously (IV), together with 500 microg of anti-CD40L mAb (MR1) intraperitoneally (IP) on days -7, 0, 4, and 10. Controls received either no donor cells, no mAb, or were untreated. B10 aortic grafts were transplanted in the abdominal aorta on day 0. At day 30, antidonor T-cell proliferative and cytotoxic responses and both complement fixing and immunoglobulin (Ig)G alloantibody levels were determined. Grafts were harvested on days 30 and 60 and examined by histology and immunohistochemistry.


RESULTS
DC infusion alone enhanced ex vivo antidonor proliferative and cytotoxic T-cell activity. By contrast, complement-fixing alloantibody levels were reduced. Anti-CD40L mAb alone strongly suppressed each of these responses. Graft inflammatory cell infiltration, intimal smooth muscle cell proliferation, fibrosis, and elastic lamina disruption observed in untreated animals were reduced in response to anti-CD40L mAb or donor DC alone. Antidonor immune reactivity, including IgG levels, and intimal proliferation were all markedly suppressed to an overall greater extent in mice given both treatments.


CONCLUSIONS
Whereas blockade of the CD40-CD40L pathway ameliorated transplant vasculopathy, preservation of near-normal vessel architecture was achieved by simultaneous administration of donor DC. This strategy represents a novel application of DC for suppression of chronic rejection.
Wang
Zhiliang
Z
Thomas E Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Morelli
Adrian E
AE
Hackstein
Holger
H
Kaneko
Katsuhiko
K
Thomson
Angus W
AW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001011:Aorta / Q000637:transplantation*; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D006084:Graft Rejection / Q000517:prevention & control; D007150:Immunohistochemistry; D007518:Isoantibodies / Q000032:analysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011183:Postoperative Complications; D012598:Sclerosis / Q000473:pathology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000473:pathology / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007518:Isoantibodies; D023201:CD40 Ligand