Heart, but Not Skin, Allografts from Donors Lacking Flt3 Ligand Exhibit Markedly Prolonged Survival Time

Abstract

Fms-like tyrosine kinase 3 ligand (Flt3L) administration leads to dramatic increases in dendritic cells (DC) in lymphoid and nonlymphoid tissues. Conversely, mice lacking Flt3L (Flt3L−/−) show severe reductions in both myeloid (CD11c+CD8α−) and lymphoid-related DC (CD11c+CD8α+) in the thymus and secondary lymphoid organs. In this study marked reductions in CD11c+ interstitial cardiac DC and in dermal, but not epidermal, DC (Langerhans cells) were also observed. CD11c+ cells that migrated from Flt3L−/− skin explants expressed lower surface MHC class II and costimulatory molecules and naive T cell allostimulatory activity than migratory wild-type (wt) C57BL/6 (B6) CD11c+ cells. We examined the survival of Flt3L−/− heart or tail skin grafts (H2b) in allogeneic wt (BALB/c; H2d) recipients. The outcome of transplantation of BALB/c organs into Flt3L−/− recipients was also determined. Flt3L−/− mice rejected BALB/c heart or skin grafts with similar kinetics as B6 wt recipients. Trafficking of donor DC into host spleens or draining lymph nodes was markedly reduced after transplantation of Flt3L−/− heart, but not skin grafts, respectively. Compared with wt hearts, survival of Flt3L−/− hearts was markedly prolonged in BALB/c recipients (median survival time, 37 and 15 days, respectively; p < 0.001). Skin graft survival was unaffected. Rejection of Flt3L−/− hearts was precipitated by infusion of wt donor DC at the time of transplant. Thus, severe depletion of interstitial heart DC resulting from targeted gene disruption prolongs, but does not indefinitely extend, heart survival. Acute rejection of wt grafts in Flt3L−/− recipients reflects presumably an intact role of the direct pathway of allorecognition.

Hosts Lacking Fms-Like Tyrosine Kinase 3 Ligand Exhibit Marked Reductions in Transplant Vascular Sclerosis

“…Our observations contrast with the normal kinetics of acute vascularized heart allograft rejection in Flt3L -/-recipients (15), which indicate normal functioning of T-cell effector mechanisms in these animals. Thus, although a substantial deficit in host DC numbers does not seem to affect the acute rejection of cardiac allografts, severe depletion of these highly special-FIGURE 1.…”

“…Notably, wild-type donor DC infusion at the time of transplant fully restores the acute rejection response in wildtype recipients of Flt3L -/-cardiac allografts (15). On the other hand, the half-life of (bulk) DC in the spleen is approximately 2 to 3 days (21).…”

“…Mice lacking Flt3L (Flt3L -/-) as the result of targeted gene disruption show severe reductions in DC subsets, both in the thymus and secondary lymphoid organs (14). Recently, we reported that heart allografts from Flt3L -/-donors, deficient in interstitial DC, exhibited markedly prolonged graft survival time, but that Flt3L -/-mice rejected heart grafts with similar kinetics as in wild-type recipients (15). This study examines the role of host DCs that are implicated in the indirect pathway of allorecognition in the development of vascular sclerosis in wild-type C57BL/6 (B6) or Flt3L -/-B6 (H2 b ) recipients of functioning aortic allografts from normal BALB/c (H2 d ) donors.…”

Exhaustive Depletion of Graft Resident Dendritic Cells: Marginally Delayed Rejection but Strong Alteration of Graft Infiltration

“…In the rat, for example, tolerance can be achieved by kidney graft parking prior to transplantation, which depleted the graft in donor dendritic cells (21,22) and can be reversed by donor dendritic cell infusion into the recipient (5,6). Prolongation of cardiac allograft survival has also been observed in rats after DDC depletion (23,24) or in mice when donors lacking Flt3 ligand were used (25). However, these effects, which appear to suggest a "universal" mechanism of early acute graft rejection, are restricted to only certain strains (23,26), indicating that the actual role of donor APC in acute rejection should be interpreted with caution.…”

Dendritic cell homeostasis and trafficking in transplantation

“…Thus, for cellular transplants, depletion of donor DCs could inhibit subsequent anti-alloantigen responses, resulting in functional tolerance [78]. For vascularized transplants, depletion of donor DCs can partially inhibit priming and prolong graft survival, although immunity is eventually generated and tolerance is not achieved [79]. Therefore, these findings suggest a dominant role for indirect alloantigen presentation by recipient DCs to prime the immune response for subsequent rejection [75][76][77].…”