The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology.

The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d-negative antibody-mediated rejection (ABMR) from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor-specific antibody tests (anti-HLA and non-HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i-IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell-mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus-based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next-generation clinical trials.

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.

Interferon-gamma acts directly on rejecting renal allografts to prevent graft necrosis.

In transplant rejection interferon (IFN)-gamma regulates the recipient immune response but also acts directly on IFN-gamma receptors in the graft. We investigated these direct actions by comparing rejecting kidneys from donors lacking IFN-gamma receptors (GRKO mice) or control donors (129Sv/J) in CBA recipients. Beginning day 5, 129Sv/J kidneys displayed high major histocompatibility complex (MHC) expression, progressive infiltration by inflammatory cells, but no thrombosis and little necrosis, even at day 21. GRKO kidneys showed increasing fibrin thrombi in small veins, peritubular capillary congestion, hyaline casts, and patchy parenchymal necrosis, progressing to near total necrosis at day 10. Terminal dUTP nick-end labeling assays were positive only in the interstitial infiltrate, confirming that massive cell death in GRKO transplants was not apoptotic. Paradoxically, GRKO kidneys showed little donor MHC induction and less inflammatory infiltration. Both GRKO and 129Sv/J allografts evoked vigorous host immune responses including alloantibody and mRNA for cytotoxic T cell genes (perforin, granzyme B, Fas ligand), and displayed similar expression of complement inhibitors (CD46, CD55, CD59). GRKO kidneys displayed less mRNA for inducible nitric oxide synthase and monokine inducible by IFN-gamma but increased heme oxygenase-1 mRNA. Thus IFN-gamma acting on IFN-gamma receptors in allografts promotes infiltration and MHC induction but prevents early thrombosis, congestion, and necrosis.

The role of the class II transactivator (CIITA) in MHC class I and II regulation and graft rejection in kidney.

Class II transactivator (CIITA) induces transcription of MHC class II genes, and induces class I in some cell lines. We examined the effect of CIITA deficiency on class I and II expression in mouse kidney. In CIITA knockout (CIITAKO) mice, basal class II was absent, but class I levels were mildly but significantly increased. Allogeneic stimulation or ischemic injury increased class I and II expression in kidneys of control (wild-type, WT) mice but induced only class I in CIITAKO mice. Thus, in kidney, all basal and induced class II expression was CIITA-dependent, but neither basal nor induced class I was CIITA-dependent. Rejecting kidney allografts from CIITAKO mice in CBA hosts manifested intense induction of donor class I but no donor class II expression. Rejecting kidneys from both WT and CIITAKO donors showed predominantly CD8 T-cell infiltration at days 7 and 21, with increasing tubulitis and arteritis at day 21. CIITAKO kidneys showed fewer infiltrating cells than WT kidneys at day 21. Thus CIITA-deficient kidneys have no basal and induced class II expression but display intense induction of class I expression, and evoke typical rejection lesions, although some indices of infiltration are reduced at day 21.

Renal transplant biopsy: what does it tell?

The value of the renal allograft biopsy has been significantly enhanced by several developments in 1997 including the following: the first convincing demonstration that molecular biology techniques can be applied to renal allograft tissue to obtain a diagnosis of acute rejection with high sensitivity and specificity; the development of an improved, internationally agreed classification of kidney transplantation pathology ('Banff 1997'); and significant new insights into the specific pathology of chronic rejection, involving splitting and lamination of peritubular capillary basement membranes and the presence of increased apoptotic cell death. Although it is predictable that long-term technology might eliminate the need for renal allograft biopsies altogether, in the short term these new breakthroughs will greatly increase the value of this procedure in the management of renal transplant patients.