Survival, function, morphology and serological aspects of rat renal allografts. Effect of short‐term treatment with cyclosporine A, anti‐CD4 and anti‐interleukin‐2 receptor monoclonal antibodies

Abstract

Survival, function, morphology and serological aspects of rat renal allografts. Effect of short-term treatment with cyclosporine A, anti-CD4 and anti-interleukin-2 receptor monoclonal antibodies. APMIS 100:The aim of this study was to investigate the effect of short-term treatment with cyclosporine A (CyA) combined with anti-CD4 (OX-38) and anti-interleukin-2 receptor (OX-39) monoclonal antibodies (MAbs) on graft survival, graft function, morphology, and anti-donor antibody levels in a BN-to-LEW rat kidney transplantation model. Spontaneous rejection occurred at 9.3 days (range 9-10 d). Administration of CyA (12.5 mg/kg/d) for 14 days prolonged graft survival to 33 days (range 2 3 4 0 d, P<O.O2). Supplementing with OX-38 and OX-39 100 pg/kg/d, given i.p. from days 0 to 7, further prolonged graft survival to 70 days (range 38-> 100 d, P < 0.02 vs controls and CyA group). One of seven recipients had good graft function for more than 100 days. A three-fold increase of the MAb dosage did not improve mean graft survival (53.5 d), but three of eight recipients had well functioning grafts for > 100 days. Kidney function was characterized by reduced creatinine clearance, also in the recipients with long-term graft survival, and a defect in concentrating urine creatinine with subsequent pronounced increase in urinary output. Graft histology showed a complex pattern of interstitial alterations including mononuclear cell infiltration, fibrosis, tubular atrophy and vascular damage with intimal /endothelial cell hyperplasia and perivascular inflammation. In nine of 10 MAbtreated recipients with graft survival > 60 days, granular deposits of immunoglobulins and C3 were found by immunofluorescence microscopy (IFM). The deposits were localized in the glomerular capillaries and mesangium. IFM in MAb-treated control animals could not demonstrate any deposits. Flow cytometric evaluation of posttransplant serum samples against donor target cells showed increasing amounts of anti-donor antibodies until the time of rejection, while recipients with longterm graft function had moderately positive cross-matches up to two months after transplantation. Hereafter antibody titres decreased and cross-matches at the time of sacrifice were again negative. The morphological findings and the flow cytometric cross-match results seem to indicate a postponed antibody-mediated type of rejection. The reason why some kidney recipients showed decreasing antibody titres and stable long-term graft function is unclear.

Acute Kidney Graft Rejection Morphology and immunology

“…It is therefore tempting to assume that tubular cells under the influence of similar cytokines produced by infiltrating lymphocytes and macrophages express MHC class I1 and associated molecules such as VCAM-1 and ICAM-1 leading to destruction of the tubular epithelium (200,96,229). In coculture experiments and in animal experiments blocking of adhesion molecules and their ligands by antibodies is followed by diminished adhesion, cytotoxicity (136,200,13) and prolonged graft survival (95, 97,196,39,48,159). Furthermore, tubular cells apart from being target cells may contribute as antigen-presenting cells which add to the complexity of their function (99).…”

“…Glomerulopathy, induction of MHC class I1 antigens with subsequent acute rejection or changes in the ratio of CD4+/ CDg+ T-lymphocytes are some of the changes described (219,63,179,61,192,184). We were unable to based on pharmaceutical agents (69, 101) should include the use of specific monoclonal antibodies targeting lymphocyte populations and adhesion molecules (13, 97,196,39,48,159,42,212,182). This has proven possible in experimental animal studies and in humans.…”