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IFN- Alters the Pathology of Graft Rejection: Protection from Early Necrosis¹

Philip F. Halloran^2,*, Leslie W. Miller^3,*, Joan Urmson^*, Vido Ramassar^*, Lin-Fu Zhu, Norman M. Kneteman, Kim Solez and Marjan Afrouzian^*

Departments of ^* Medicine, Surgery, and Laboratory Medicine and Anatomical Pathology, University of Alberta, Edmonton, Alberta, Canada

We studied the effect of host IFN- on the pathology of acute rejection of vascularized mouse heart and kidney allografts. Organs from CBA donors (H-2^k) were transplanted into BALB/c (H-2^d) hosts with wild-type (WT) or disrupted (GKO, BALB/c mice with disrupted IFN- genes) IFN- 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- (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- to GKO hosts reduced but did not fully prevent the effects of IFN- deficiency: MHC was induced, but the prevention of necrosis and induction of MIG were incomplete compared with WT hosts. Thus, IFN- 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- produced in large quantities in the allograft.

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