Fm. Fu et al., 2ND-SET REJECTION OF MOUSE-LIVER ALLOGRAFTS IS DEPENDENT ON RADIATION-SENSITIVE NONPARENCHYMAL CELLS OF GRAFT BONE-MARROW ORIGIN, Transplantation, 61(8), 1996, pp. 1228-1233
Livers are accepted spontaneously when transplanted orthotopically fro
m B10 (H2(b)) or BALB/c (H2(d)) to C3H (H2(k)) mice without host immun
osuppression. Presensitization to donor can, however, be induced by sk
in grafting two weeks prior to liver transplantation, resulting in sec
ond-set or ''accelerated'' liver graft rejection, within 4-5 days. In
this study, the role of liver nonparenchymal cells (NPC) in second-set
rejection was tested by donor whole-body irradiation and replacement
of donor B10 liver NPC with those of either third-party (BALB/c) or re
cipient strain (C3H) bone marrow. Irradiation alone (9.5 Gy) of normal
B10 donors before liver transplantation significantly prolonged graft
survival in presensitized CSII recipients. Three months after bone ma
rrow transplantation (BMT), chimeric Livers expressing third-party or
recipient haplotype, were transplanted orthotopically into unmodified
C3H recipients. Graft survival was prolonged significantly compared wi
th livers from normal or syngeneically reconstituted B10 donors. Prolo
nged survival of chimeric (BALB/c->B10) livers was also evident in C3R
mice presensitized to alloantigens expressed on both the liver parenc
hymal (B10) and third-party NPC (BALB/c) by simultaneous grafting of s
kin from each donor strain. Determination of graft cytokine mRNA profi
les 4 days posttransplant showed that replacement of donor with third-
party or recipient strain BM-derived cells was associated with reduced
expression of IL-2 and IFN-gamma mRNA compared with that in grafts fr
om syngeneically reconstituted donors. IL-10 transcripts, however, wer
e not significantly affected, The results are consistent with a key ro
le of radiation-sensitive, donor-specific NPC of bone marrow origin in
second-set liver rejection in presensitized hosts. In this process, c
ompetent donor-strain NPC appear to augment the activity of primed T c
ells responsible for the second-set rejection.