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

Background. Mice lacking fins-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 (H2(b)) recipients of aortic allografts from normal BALB/c (H2(d)) 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 enzymelinked immunosorbent assay or graft immunohistochemistry). Results. Sixty days posttransplant, BALB/c allografts in wild-type 136 recipients showed severe chronic arteriopathy (intimal thickening, a-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 antigenspecific 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. 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.