Altered microRNA expression after infection with human cytomegalovirus leads to TIMP3 downregulation and increased shedding of metalloprotease substrates, including MICA.

Proteolytic shedding of ligands for the NK group 2D (NKG2D) receptor is a strategy used by tumors to modulate immune recognition by NK cells and cytotoxic T cells. A number of metalloproteases, especially those of the A disintegrin and metalloprotease (ADAM) family, can mediate NKG2D ligand cleavage and this process can be modulated by expression of the thiol isomerase ERp5. In this article, we describe that an increased shedding of the NKG2D ligand MICA is observed postinfection with several strains of human CMV due to an enhanced activity of ADAM17 (TNF-α converting enzyme) and matrix metalloprotease 14 caused by a reduction in the expression of the endogenous inhibitor of metalloproteases tissue inhibitors of metalloproteinase 3 (TIMP3). This decrease in TIMP3 expression correlates with increased expression of a cellular miRNA known to target TIMP3, and we also identify a human CMV-encoded microRNA able to modulate TIMP3 expression. These observations characterize a novel viral strategy to influence the shedding of cell-surface molecules involved in immune response modulation. They also provide an explanation for previous reports of increased levels of various ADAM17 substrates in the serum from patients with CMV disease. Consistent with this hypothesis, we detected soluble MICA in serum of transplant recipients with CMV disease. Finally, these data suggest that it might be worthwhile to prospectively study ADAM17 activity in a larger group of patients to assay whether this might be a useful biomarker to identify patients at risk for development of CMV disease.

Prostatic aspergillosis in a heart transplant recipient: case report and review.

In this study we report the first case of invasive prostatic aspergillosis (IPRA) in a heart recipient with post-transplantation antibody deficiency, and review the other 11 cases described in the medical literature. Seven patients were immunocompromised and 6 had dissemination to other sites. Examination of the prostate usually revealed enlargement, with or without nodular lesions. Transrectal ultrasonography or computed tomography scan can provide the diagnosis, although this should be confirmed with biopsy and culture of the lesion. Urine culture can be negative and treatment should include long-term systemic anti-fungal therapy and, in most cases, prostatectomy.

Clostridium difficile-associated diarrhea in heart transplant recipients: is hypogammaglobulinemia the answer?

BACKGROUND: Information regarding Clostridium difficile-associated diarrhea (CDAD) after solid-organ transplantation (SOT) is scarce, particularly after heart transplantation (HT). Although host immune response to C. difficile plays a substantial role in the outcome of this infection, the responsibility of hypogammaglobulinemia (HGG) as a predisposing condition for CDAD has not been studied in SOT. We analyzed the incidence, clinical presentation, outcome and risk factors, including HGG, of CDAD after HT. METHODS: Two hundred thirty-five patients who underwent HT (1993 to 2005) were included. Transplantation procedure and immunosuppression were standard. From January 1999 HGG was systematically searched and corrected when IgG levels were <400 mg/dl or severe infection was present. Toxin-producing C. difficile was detected by means of cytotoxin assay and culture of stool samples. Patients with and without CDAD were compared for identification of risk factors. RESULTS: CDAD was detected in 35 patients (14.9%). Incidence decreased significantly since HGG was sought and treated: 29 (20.6%) in the first period, and 6 (6.4%) in the second (p = 0.003). CDAD appeared a mean of 32 days (range 5 to 3,300 days) after HT. No related death or episode of fulminant colitis was detected. At least one episode of recurrence was noted in 28.6% of patients. Severe HGG was found to be the only independent risk factor for CDAD after HT (RR 5.8; 95% CI: 1.05 to 32.1; p = 0.04). CONCLUSIONS: C. difficile is a significant cause of diarrhea in HT recipients and post-transplant HGG is independently associated with an increased risk. The potential role of immunoglobulin administration in this population requires further study.

Inhibition of brush border dipeptidase with cilastatin reduces toxic accumulation of cyclosporin A in kidney proximal tubule epithelial cells.

BACKGROUND: Cilastatin reduces nephrotoxicity associated with cyclosporin A (CyA) in solid organ and bone marrow transplantation. This appears to be unrelated to changes in renal haemodynamics or CyA metabolism. How cilastatin induces this protection is unclear, but it could result from changes on accumulation of CyA proximal cells. METHODS: We investigated the effects of cilastatin on primary cultures of pig kidney proximal tubule epithelial cells (PTECs) treated with CyA and FK506. Cell membrane fluidity and membrane-bound cholesterol-rich raft (MBCR) distribution were evaluated by fluorescence microscopy, and CyA transport by radioimmunoassay. Changes in CyA- and FK506-induced apoptosis were also evaluated by electron and light microscopy, flow cytometry, and detection of cytoplasmic nucleosones by enzyme-linked immuosorbent assay. RESULTS: CyA caused a dose-dependent reduction of cell membrane fluidity, which was prevented by pre-treating PTECs with cilastatin. Cilastatin also inhibited CyA transport across membranes and reduced recovery of CyA in mitochondria and membrane-bound fractions from cilastatin-treated PTECs. This effect was not related to an altered distribution of MBCRs, which are essential for CyA transport. Cilastatin protected against CyA- and FK506-induced apoptosis. CONCLUSIONS: Prevention of CyA-induced reduction of cell membrane fluidity and inhibition of CyA transport are features of cilastatin's direct effects on PTECs. Unaltered distribution of MBCRs in the presence of cilastatin suggests that cilastatin binding to raft-bound dipeptidases, rather than MBCR modifications, causes interference with CyA transport. These results provide additional insight into the mechanisms and scope of cilastatin nephroprotection.