IFN-gamma alters the pathology of graft rejection: protection from early necrosis.
We studied the effect of host IFN-gamma on the pathology of acute rejection of vascularized mouse heart and kidney allografts. Organs from CBA donors (H-2k) were transplanted into BALB/c (H-2d) hosts with wild-type (WT) or disrupted (GKO, BALB/c mice with disrupted IFN-gamma genes) IFN-gamma genes. In WT hosts, rejecting hearts and kidneys showed mononuclear cell infiltration, intense induction of donor MHC products, but little parenchymal necrosis at day 7. Rejecting allografts in GKO recipients showed infiltrate but little or no induction of donor MHC and developed extensive necrosis despite patent large vessels. The necrosis was immunologically mediated, since it developed during rejection, was absent in isografts, and was prevented by immunosuppressing the recipient with cyclosporine or mycophenolate mofetil. Rejecting kidneys in GKO hosts showed increased mRNA for heme oxygenase 1, and decreased mRNA for NO synthase 2 and monokine inducible by IFN-gamma (MIG). The mRNA levels for CTL genes (perforin, granzyme B, and Fas ligand) were similar in rejecting kidneys in WT and GKO hosts, and the host Ab responses were similar. The administration of recombinant IFN-gamma to GKO hosts reduced but did not fully prevent the effects of IFN-gamma deficiency: MHC was induced, but the prevention of necrosis and induction of MIG were incomplete compared with WT hosts. Thus, IFN-gamma has unique effects in vascularized allografts, including induction of MHC and MIG, and protection against parenchymal necrosis, probably at the level of the microcirculation. This is probably a local action of IFN-gamma produced in large quantities in the allograft.
Halloran
P F
PF
Departments of. Medicine, Surgery, and Laboratory Medicine and Anatomical Pathology, University of Alberta, Edmonton, Alberta, Canada. phil.halloran@ualberta.ca
Miller
L W
LW
Urmson
J
J
Ramassar
V
V
Zhu
L F
LF
Kneteman
N M
NM
Solez
K
K
Afrouzian
M
M
D000208:Acute Disease; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics; D000961:Antilymphocyte Serum / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007106:Immune Sera / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007668:Kidney / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D009336:Necrosis; D011994:Recombinant Proteins / Q000008:administration & dosage
D000961:Antilymphocyte Serum; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007106:Immune Sera; D011994:Recombinant Proteins; D007371:Interferon-gamma