Hosts lacking fms-like tyrosine kinase 3 ligand exhibit marked reductions in transplant vascular sclerosis.
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 infrarenal 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, alpha-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-gamma but with enhancement of interleukin-10 secretion in response to donor alloantigen challenge.


CONCLUSIONS
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.
Wang
Zhiliang
Z
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA.
Taner
Timuçin
T
Morelli
Adrian E
AE
Thomson
Angus W
AW
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation*; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007372:Interferons / Q000378:metabolism; D007518:Isoantibodies / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D012598:Sclerosis / Q000378:metabolism* / Q000473:pathology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014180:Transplantation; D014184:Transplantation, Homologous
D016207:Cytokines; D007074:Immunoglobulin G; D007518:Isoantibodies; D007519:Isoantigens; D008565:Membrane Proteins; C084881:flt3 ligand protein; D007372:Interferons