2ND-SET REJECTION OF MOUSE-LIVER ALLOGRAFTS IS DEPENDENT ON RADIATION-SENSITIVE NONPARENCHYMAL CELLS OF GRAFT BONE-MARROW ORIGIN

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.