Background
Vascularized composite allografts (VCA) containing vascularized bone marrow (VBM) prolongs graft survival Cell populations within the co-transplanted VBM are believed to protect the skin and muscle graft components We performed experiments to define these mechanisms in our established non-human primate model of facial transplantation.
Methods
Three experimental groups were performed of facial VCA Group 1: VCA+VBM segments to MHC-mismatched cynomolgus macaques after donor irradiation (n = 4) Group 2: VCA without bone + heterotopic VBM without skin (n = 4) Group 3: VCA+VBM after donor lymphodepletion with ATGAM (n = 2) Immunosuppression consisted of tacrolimus and mycophenolate mofetil End points were graft rejection or PTLD Chimerism was assayed using donor specific anti-MHC antibodies.
Results
Group 1 recipients underwent early graft loss (mean 32 ± 21 d) from rejection (Banff IV) Chimerism was undetectable in 3 animals Donor VBM demonstrated replacement with recipient cells (50%, 70%, 100%, and 100%) Group 2 recipients also experienced early skin rejection (mean 37±18d), while one animal had PTLD Chimerism was likewise undetectable and heterotopic VBM demonstrated fibrosis and recipient replacement Of the 2 preliminary group 3 recipients one rejected early at day 12, while the other developed PTLD Complete replacement of the bone marrow was seen in the early rejecting animal These data compared to historical VCA+VBM grafts with mean survival of 348±86 days (rejection only after immunosuppression withdrawal), 75% chimerism, and viable donor VBM.
Conclusions
Facial VCA+VBM contain cell populations that protect the graft from early rejection and graft loss Our data support that these cell populations are radiosensitive, and do not confer systemic protective effects These results support a hypothesis that regulatory cell populations within VBM have local down-regulatory functions toward graft infiltrating alloreactive lymphocytes The finding that cells are noted to be susceptible to depletion or downregulation of their protective effect by irradiation should be kept in consideration when choosing pre-operative conditioning regimens and treating rejection in VCA.