Hosts lacking Fms-like tyrosine kinase 3 ligand exhibit marked reductions in transplant vascular sclerosis

Zhiliang Wang, Timuçin Taner, Adrian E. Morelli, Angus W. Thomson

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background. Mice lacking fms-like tyrosine kinase 3 ligand (Flt3L -/-) as the result of targeted gene disruption show severe reductions in dendritic cell (DC) subsets. We examined the development of vascular sclerosis and alloimmune reactivity in wild-type C57BL/6 (B6) and Flt3L -/- B6 (H2b) recipients of aortic allografts from normal BALB/c (H2d) donors. Methods. DC deficiency was confirmed by flow cytometric analysis. Aortic allografts were anastomosed to the infra-renal portion of the recipient's abdominal aorta. No immunosuppressive therapy was administered. Transplant outcome was assessed 60 days postgrafting by histologic and immunohistochemical examination of the grafts. Host reactivity to donor alloantigens was determined by assaying splenic T-cell proliferation and T-cell infiltration within the grafts, immunoglobulin-G subclass alloantibody levels (by flow cytometry), and cytokine production (by enzyme-linked immunosorbent assay or graft immunohistochemistry). Results. Sixty days posttransplant, BALB/c allografts in wild-type B6 recipients showed severe chronic arteriopathy (intimal thickening, α-smooth muscle actin+ cell proliferation, fibrosis, and elastic lamina disruption). In contrast, profound deficiency of host myeloid, "lymphoid-related," and pre-plasmacytoid DC subsets was accompanied by marked reductions in each feature of chronic rejection. Improvement in graft appearance was associated with antigen-specific suppression of ex vivo anti-donor T-cell proliferative activity and reductions in interferon-γ but with enhancement of interleukin-10 secretion in response to donor alloantigen challenge. Conclusion. Permanent deficiency of host DC subsets resulting from targeted gene disruption markedly inhibits the development of transplant vascular sclerosis, associated with striking reductions in both anti-donor T-cell reactivity and immunoglobulin-G alloantibody production.

Original languageEnglish (US)
Pages (from-to)869-875
Number of pages7
JournalTransplantation
Volume79
Issue number8
DOIs
StatePublished - Apr 27 2005

Keywords

  • Dendritic cells
  • Flt3 ligand
  • Transplantation
  • Vascular sclerosis

ASJC Scopus subject areas

  • Transplantation

Fingerprint Dive into the research topics of 'Hosts lacking Fms-like tyrosine kinase 3 ligand exhibit marked reductions in transplant vascular sclerosis'. Together they form a unique fingerprint.

  • Cite this