High-level endothelial expression of human CD59 prolongs heart function in an ex vivo model of xenograft rejection.

BACKGROUND: Hyperacute rejection of discordant xenografts is dependent on activation of the complement system of the recipient. Transgenic expression of recipient complement regulatory factors in donor tissue has proved to be a promising approach to dealing with hyperacute rejection, although the relationship between the level of complement regulatory factor expression and the degree of protection is not well established. Here, we examine this relationship using CD59 transgenic mouse hearts in an ex vivo model of xenograft rejection. METHODS: The level of expression of CD59 in two lines of transgenic mice, in which CD59 is expressed under the control of either the murine H2Kb (MHC class I) promoter (line CA-17) or the endothelium-specific human intercellular adhesion molecule-2 promoter (line 237-7), was compared by immunohistochemistry and flow cytometry. Hearts from both groups and wild-type controls were perfused ex vivo with human plasma, and mean heart work for each group was compared over a 60-min period. RESULTS: CD59 expression on cardiac endothelial cells isolated from homozygous CA-17 mice was 25- to 30-fold lower than that on cardiac endothelial cells from heterozygous 237-7 mice. CA-17 hearts perfused with 6% human plasma exhibited a reduction in deposition of the membrane attack complex, but not a prolongation of function, compared with nontransgenic mouse hearts. In contrast, 237-7 hearts showed significantly prolonged function during perfusion with 20% plasma. CONCLUSIONS: High-level endothelial-specific expression of CD59 was effective in prolonging the function of mouse hearts perfused with 20% human plasma, whereas low-level, broader expression did not provide protection from 6% plasma.

Future directions in transplantation: xenotransplantation.

Xenotransplantation would overcome the worldwide shortage of organs for transplantation. However, xenotransplantation using primate organs is unpracticable, and xenotransplantation between phylogenetically disparate species results in hyperacute rejection. This fulminant form of rejection is mediated by both naturally occurring xeno-antibodies and by direct activation of the alternative pathway of complement. The precise specificities of the xeno-antibodies are incompletely understood and better characterization of these antibodies and their target antigens is needed to allow the development of therapeutic maneuvers, such as immunoadsorption of the relevant antibodies. The direct activation of the alternative pathway of complement by xenogeneic tissue is due, at least in part, to the lack of appropriate (human) membrane bound regulators of complement on the xenogeneic cells. These regulatory molecules, called homologous restriction factors, are species specific, and act to favor inactivation of the complement cascade if the complement is of the same species. Human homologous restriction factors are capable of protecting xenogeneic cells from lysis mediated by human complement. The study of cell-mediated rejection in xenotransplantation has been largely overshadowed by hyperacute rejection. Resolution of the barriers to xenotransplantation will benefit the ever growing number of patients awaiting transplantation.

Non-dilated urinary tract obstruction.

OBJECTIVE: To describe the occurrence of obstructive uropathy in the absence of dilatation of the urinary tract. CLINICAL FEATURES: Five cases of non-dilated obstructive nephropathy are described. All patients were uraemic on presentation. Obstruction was caused by retroperitoneal malignancy in two patients and uric acid lithiasis in the remaining three. All patients had at least one ultrasound examination. Isotope renography and computed tomography were performed in three and four patients respectively. None of these imaging techniques suggested obstruction in any of the cases. Radionuclide scans were characterised by unusually poor perfusion and parenchymal phase images. INTERVENTION AND OUTCOME: An immediate diuresis and a rapid return of normal renal function occurred after relief of the obstruction in all cases. CONCLUSION: The absence of dilatation in obstructive nephropathy is uncommon but may be responsible for delayed diagnosis and management of a readily treatable cause of acute renal failure.