Up-regulation of macrophage migration inhibitory factor in acute renal allograft rejection in the rat

Recent studies have identified a key role for macrophage migration inhibito ry factor (MIF) in a number of immune cell-mediated diseases. The current s tudy investigated the potential role of MIF in acute allograft rejection. L ewis rats underwent bilateral nephrectomy and then received an orthotopic D A renal allograft or an orthotopic Lewis renal isograft. Groups of six anim als were killed at day 1 or 5 after transplantation. No immunosuppression w as used. Animals receiving a renal allograft exhibited severe rejection on day 5, as shown by high levels of serum creatinine, very low rates of creat inine clearance, and severe tubulitis with a dense macrophage and T cell in filtrate. In contrast, isografts had normal renal function on day 5 with no histological evidence of rejection. Northern blotting showed that renal MI F mRNA expression was unchanged at day 1, but was increased 3.5-fold on day 5. In situ hybridization showed a marked increase in MIF mRNA expression b y tubular cells and MIF mRNA expression by many infiltrating mononuclear ce lls in day 5 allografts. Immunostaining confirmed an increase in tubular MI F protein expression, particularly in areas of severe tubular damage with p rominent leucocytic infiltration. Double staining showed that many infiltra ting macrophages and T cells expressed the MIF protein in day 5 allografts. There was only a minor increase in MIF expression in day 5 isografts, demo nstrating that neither surgical injury nor stress cause significant up-regu lation of MIF expression in allograft rejection. In conclusion, this study has demonstrated that local MIF production is specifically increased in acu te renal allograft rejection. These results suggest that MIF may play an im portant role in the cellular immune response mediating acute allograft reje ction.