C. Giannini

Liver-Stage Development of Plasmodium falciparum in a Humanized Mouse Model

BACKGROUNDnThe liver stage of the human malaria parasite Plasmodium falciparum is the least known, yet it holds the greatest promise for the induction of sterile immunity and the development of novel drugs. Progress has been severely limited by the lack of adequate in vitro and in vivo models.nnnMETHODSnRecently, it was found that immunodeficient mice transgenic for the urokinase plasminogen activator allow survival of differentiated human hepatocytes. We confirm this finding but show that hepatocyte survival is short lived unless nonadaptive defenses are simultaneously depleted.nnnRESULTSnBy controlling macrophages and NK cells, we readily effected the long-term secretion of human serum albumin and human alpha-1 antitrypsin in mouse serum (at 3 months, the proportion of repopulated mice increased from 0% to 60% and from 22% to 80%, respectively; P<.0001). P. falciparum sporozoites delivered intravenously into mice readily infected transplanted human hepatocytes and developed into liver schizonts. Their size was twice as large as what was seen in vitro and was comparable to that found in humans and chimpanzees.nnnCONCLUSIONnThese results emphasize the importance of nonadaptive defenses against xenotransplantation and lead to development of small laboratory models that, because they can harbor human hepatocytes, provide novel opportunities to study intrahepatic pathogens, such as those causing malaria and hepatitis.

Low serum tryptophan levels, reduced macrophage IDO activity and high frequency of psychopathology in HCV patients.

Summary.u2002 Indoleamine 2,3‐dioxygenase (IDO), a key enzyme of tryptophan (TRP) metabolism, is induced in various tissues of patients with bacterial and viral infection or with neoplastic diseases. This induction is considered the main cause of the decreased serum TRP levels, the reduced brain serotonin synthesis and the occurrence of psychopathological disorders often detected in patients with chronic infections or different forms of cancer. We studied 89 subjects including: (a) 39 patients with chronic hepatitis C virus (HCV) infection and mild liver damage (b) 40 healthy controls, and (c) 10 patients with chronic hepatitis B virus (HBV) infection. We measured serum TRP and kynurenine levels and IDO activity in macrophages. Furthermore, each patient had an accurate psychopathological evaluation. HCV‐infected patients had lower (−28%) serum TRP concentrations than healthy volunteers or HBV‐infected patients with comparable liver damage. Depression and anxiety symptoms were particularly common in HCV patients. Unexpectedly, serum kynurenine levels and IDO activity in cultured macrophages (under both basal or stimulated conditions) were lower in HCV patients than in controls. Our study shows that HCV patients have reduced serum TRP levels and confirms that they frequently suffer from anxiety and depression‐related symptoms. The reduced IDO activity found in the macrophages of these patients suggest that HCV infection may hamper macrophage functions.

Serum HCV-RNA and Liver Histologic Findings in Patients with Long-Term Normal Transaminases

In this study we aimed to correlate liverhistology and the presence of hepatitis C virus (HCV)viremia, genotype, and quantity of HCV genome in 19positive and 11 RIBA II indeterminate patientspresenting persistently normal ALT values over 24 monthsbefore biopsy. In addition, after biopsy serum ALTvalues were monitored monthly for a mean follow-upperiod of 24.8 months, after which patients werereevaluated for RIBA II and the presence of viremia.Sixteen patients (53%) were serum HCV-RNA-positive; 13of them (68%) were confirmed positive and 3 (27%)indeterminate on RIBA II. Histology of the HCV-RNA-positive patients showed eight cases of CPH (one case ofgenotype 1a; four cases type 1b; three cases type 2),six cases of CAH (three cases type 1b, three cases type2), one case of CLH (type not determined), and one case of normal liver (NL) (type 1b).Histology of the HCV-RNA-negative patients showed fourcases of CPH, one case of CAH, two cases of CLH, andseven cases of NL. During the follow-up period ninepatients (30%) presented slight increases in ALT values(<2 × N), and in particular, flares of ALT wereobserved four times in the CAH and five times in the CPHpatients, who were all viremic, but never in the NL subjects. These results indicate that subjectspositive on RIBA II, but with persistently normal ALTvalues, had a high probability of being serumHCV-RNA-positive and that almost all these viremicsubjects presented histologic signs of liver disease. Incontrast, RIBA II indeterminate subjects had a moderateprobability of being HCV-RNA-positive, but a number ofthese may present signs of liver disease. In both cases there was no association withgenotype or HCV-RNA serum levels. The other nonviremiccases included subjects with hepatic changes goingtoward resolution or with normal liver in whom hepatic biopsy can be avoided. Only one case was a truecarrier since he was viremic with normal liver andpersistently normal ALT values.