Lethal hepatitis after gene transfer of IL-4 in the liver is independent of immune responses and dependent on apoptosis of hepatocytes: a rodent model of IL-4-induced hepatitis.

The putative role of IL-4 in human and animal models of hepatitis has not yet been directly determined. We now report that direct expression of IL-4 in the liver of rats or mice using recombinant adenoviruses coding for rat or mouse IL-4 (AdrIL-4 and AdmIL-4, respectively) results in a lethal, dose-dependent hepatitis. The hepatitis induced by IL-4 was characterized by hepatocyte apoptosis and a massive monocyte/macrophage infiltrate. IL-4-induced hepatitis was independent of T cell-mediated immune responses. Hepatitis occurred even after gene transfer of IL-4 into nude rats, CD8-depleted rats, cyclosporine A-treated rats, or recombinase-activating gene 2(-/-) immunodeficient mice. Peripheral depletion of leukocytes using high doses of cyclophosphamide, and/or the specific depletion of liver macrophages with liposome-encapsulated dichloromethylene diphosphonate in rats did not block lethal IL-4-induced hepatitis. Direct transduction of hepatocytes with adenoviruses was not essential, since injection of AdrIL-4 into the hind limb induced an identical hepatitis. Finally, primary rat hepatocytes in culture also showed apoptosis when cultured in the presence of rIL-4. IL-4-dependent hepatitis was associated with increases in the intrahepatic levels of IFN-gamma, TNF-alpha, and Fas ligand. Administration of AdmIL-4 to IFN-gamma, TNF-alpha receptor type I, or TNF-alpha receptor type II knockout mice also resulted in lethal hepatitis, whereas a moderate protection was observed in Fas-deficient lpr mice. IL-4-dependent hepatocyte apoptosis could be abolished by treatment with caspase inhibitory peptides. Our results thus demonstrate that IL-4 causes hepatocyte apoptosis, which is only partially dependent on the activation of Apo-1-Fas signaling and is largely independent of any immune cells in the liver.

Interleukin-10 produced by recombinant adenovirus prolongs survival of cardiac allografts in rats.

Interleukin-10 (IL-10) and interleukin-4 (IL-4), two Th2-derived cytokines, are molecules with anti-inflammatory and immunodeviating properties whose direct expression in allografts may prolong graft survival. Recombinant adenoviruses represent efficient vectors for gene transfer in quiescent cells in vivo. Adenoviral vectors encoding rat IL-10 (AdIL-10), rat IL-4 (AdIL-4) or beta-galactosidase (AdlacZ) or without transgene (Addl324) were injected directly into rat hearts at the time of transplantation in order to test their potential to prolong heart allograft survival. Expression of vectorized sequences was confirmed in heart biopsies, and kinetic analysis of beta-galactosidase showed transient expression. Cardiac allograft survival was significantly prolonged after administration of 10(9) p.f.u. of AdIL-10 (16.6 +/- 3.2 days, P < 0.05), but not AdIL-4 (9.8 +/- 1.6 days), compared with Addl324-treated (9.3 +/- 3.3 days) or untreated groups (7.8 +/- 1.5 days). Immunohistochemical analysis of allografts after gene transfer of IL-10 showed that leukocyte infiltration was quantitatively equivalent to that seen in control groups but with a strong tendency towards lower levels of CD8+ cells. Importantly, adenovirus-derived IL-10 modified the functional status of leukocytes by inducing a significant decrease in IFN-gamma production but significantly increased transforming-growth factor beta 1 (TGF-beta 1) expression within the grafts compared with those treated with Addl324. These results show that expression of IL-10 by rat hearts after gene transfer mediated by an adenoviral vector decreases allogeneic immune responses and allows prolongation of allograft survival.

[Primary muscular antro-pyloric hypertrophy in the adult: case report]. / L'hypertrophie musculaire primitive antro-pylorique de l'adulte: à propos d'un cas.

Primary hypertrophic antro-pyloric stenosis in adults is a misleading anatomic and radioclinical entity. It consists of hypertrophy of the internal muscular layer. Distal gastrectomy is the only effective treatment of the symptomatic form and allows a pathologic study of the gastrectomy, thus ruling out most causes of obstruction, including neoplastic ones. Its congenital origin has not been established. We report the case of a 59 year-old man who had primary hypertrophic pyloric stenosis.

[Protective effect of an apoptosis inhibitor in a new model of hepatitis induced by interleukin-4 in the rat]. / Effet protecteur d'un peptide inhibiteur de l'apoptose dans un nouveau modèle d'hépatite induite par l'interleukine-4 chez le rat.

OBJECTIVES: Interleukin-4 is a cytokine with pleiotropic effects on many cells. The effects of its expression on the liver remain unclear. To obtain organ-localized cytokine expression and analyze its effect on the liver, recombinant adenovirus with coding sequences of interleukin-4 were transduced to rat livers. METHODS: Adenovirus with coding sequences of rat interleukin-4 were injected into the portal vein of Wistar rats. Microscopic examination of the liver was performed. The effects of interleukin-4 were confirmed in vitro on primary cultured rat hepatocytes. The same analysis was performed after intraperitoneal injection of l'YVADcmk, an inhibitor of the interleukin 1 converting enzyme. RESULTS: Interleukin-4 expression due to the recombinant adenovirus produced dose-related, potentially lethal, severe hepatitis. This hepatitis was characterized by a leucocyte infiltrate mainly composed of eosinophilic polymorphonuclear and mast cells with numerous apoptotic hepatocytes. Intraperitoneal injection of YVADcmk decreased hepatocyte apoptosis and biological hepatitis and prevented death. CONCLUSION: These results suggested that YVADcmk might be used in fulminant hepatitis in which apoptosis is predominant.

Chester-Erdheim disease: a neoplastic disorder.

Chester-Erdheim disease is a rare non-langerhans cell histiocytosis characterized by a xanthomatous infiltration of foamy macrophages. The cause and pathogenesis remain unclear. The aim of the present study was to determine whether Chester-Erdheim disease is a polyclonal reactive disease or a clonal neoplastic disorder. The clonal status of samples obtained from five patients with Chester-Erdheim disease was studied. DNA was extracted from fixed and paraffin-embedded sections after microdissection and clonal status was studied using the Xchromosome inactivation pattern of the human androgen receptor gene (HUMARA assay). One patient was homozygous for the HUMARA gene and noninformative. Three other cases were monoclonal. One was polyclonal, and this case showed a dense reactive infiltrate in association with spumous macrophages. This study suggests strongly that Chester-Erdheim disease is a monoclonal lesion consistent with neoplastic disorder. Thus, Chester-Erdheim disease may be considered as the "macrophage" counterpart of Langerhan's cell histiocytosis in the histiocytosis spectrum. Further studies are needed to establish the origin of this clonal proliferation.

[Lacrimal gland hypertrophy: revealing sarcoidosis]. / Hypertrophie des glandes lacrymales: mode de révélation d'une sarcoïdose.

We present a case of systemic sarcoidosis in a 34-year-old woman initially presenting with bilateral and symmetric proptosis caused by lacrimal gland enlargement. Based upon clinical, biological and radiological findings, sarcoidosis was suspected with lacrymal gland, parotid and pulmonary lesions. Biopsy of enlarged lacrimal gland for histological examination revealed a non caseating granuloma compatible with the diagnosis of sarcoidosis. Sarcoid lesions regressed with corticosteroid therapy.

[Pulmonary endodermal tumor resembling fetal lung. Low grade adenocarcinoma of the fetal lung type]. / Tumeur pulmonaire endodermique ressemblant au poumon foetal. Adénocarcinome de type poumon foetal de bas grade.

Pulmonary endodermal tumor resembling fetal lung is a rare pulmonary neoplasm, classified either within the pulmonary blastomas spectrum or as a subtype of adenocarcinoma. We report a case revealed by a fever in a 24-year-old woman. The tumor measured 9 cm and extended into the lower right bronchus. The diagnosis was done on a biopsy performed during fiberoptic endoscopy. The patient was treated by lobectomy. She is well without disease 6 years after surgery. This type of predominantly epithelial tumor with neuroendocrine differentiation and a scanty non malignant stromal component should be identified in young women because of its favorable outcome after surgical resection. It must not be confused with ordinary adenocarcinoma nor metastatic adenocarcinoma, especially endometrioid type.

A critical role for transforming growth factor-beta in donor transfusion-induced allograft tolerance.

Donor-specific (DST) or nonspecific blood transfusions administered before transplantation can enhance survival of vascularized allografts both in humans and animals but the immunological mechanisms of this effect remain unclear. We have analyzed the expression and the role of endogenous TGF-beta1 in a model of heart allograft tolerance, induced by pregraft DST in adult rats. We reported previously that this tolerance occurs despite a strong infiltration of leukocytes into the graft that are unable to produce both Th1- and Th2-related cytokines in vivo. Allografts from DST-treated rats express high levels of TGF-beta1 mRNA and active protein. This phenomenon is correlated with the rapid infiltration of leukocytes producing high amounts of TGF-beta1. TGF-beta1-producing cells are virtually absent among early infiltrating cells in rejected grafts but are found at a later time point. The induction of allograft tolerance in vivo is abrogated by administration of neutralizing anti-TGF-beta mAb. Moreover, overexpression of active TGF- beta1 in heart allografts using a recombinant adenovirus leads to prolonged graft survival in unmodified recipients. Taken together, our results identify TGF-beta as a critical cytokine involved in the suppression of allograft rejection induced by DST and suggest that TGF-beta-producing regulatory cells are also involved in allograft tolerance.

Anti-adenovirus immune responses in rats are enhanced by interleukin 4 but not interleukin 10 produced by recombinant adenovirus.

Recombinant adenoviruses can be used for in vivo gene transfer with great efficiency. However, the duration of transgene expression and the possibility of readministering the virus are severely limited by the host anti-adenovirus immune response, which is controlled mainly by cytokine networks. Adenoviruses encoding IL-4 (AdIL-4) or IL-10 (AdIL-10) were administered to rats through the portal vein and the anti-adenovirus immune response was studied. As compared with administering adenoviruses without transgene (Addl324) or with the lacZ gene (AdlacZ), AdIL-4, but not AdIL-10, resulted in a significant increase in leukocytes in the liver, with a predominance of macrophages that peaked on days 7 and 14 after gene transfer and gradually returned to normal by day 28. AdIL-4 induced a significant increase in both neutralizing and ELISA-detected anti-adenovirus antibodies, whereas AdIL-10 caused an increase in ELISA-detected antibodies alone. Anti-adenovirus antibodies were predominantly of Th1-dependent immunoglobulin subclasses in rats receiving Addl324, AdlacZ, or AdIL-10, whereas animals receiving AdIL-4 showed a predominance of Th2-dependent immunoglobulin subclasses. Type 1 (IFN-gamma) and type 2 (IL-5) cytokines were increased only in livers from rats receiving AdIL-4. Rats receiving AdIL-4 showed increased anti-adenovirus cytotoxic T lymphocyte activity and CD8+ cell depletion prevented leukocyte infiltration in the liver. These results show that IL-4 increases local and systemic immune responses against recombinant adenoviruses.

[Pancreatic metastasis of a renal adenocarcinoma. Apropos of 2 cases]. / Métastase pancréatique d'un adénocarcinome rénal. A propos de 2 cas.

The pancreas is an uncommon site of metastasis for renal cell carcinoma. We report 2 cases of patients who underwent total and subtotal pancreatectomy 13 and 10 years after resection of the primary tumor. One of the patients already had liver and cerebellum metastasis, the second one had a solitary metastasis to the pancreas. In both cases, tumoral proliferation invaded the lumen of the Wirsung, and in one case was prominent through the papillae.

Pathology of the central nervous system in Chester-Erdheim disease: report of three cases.

Chester-Erdheim disease is a rare form of non-Langerhans cell histiocytosis consisting of disseminated xanthogranulomatous infiltration and fibrosis that primarily involves the bones, visceral organs and systemic fatty spaces. Involvement of the central nervous system is variable, and neuropathological features have seldom been documented. We report the neuropathological findings in 3 autopsy cases. One patient had radiological and pathological bone changes characteristic of Chester-Erdheim disease. Neuropathology revealed multiple characteristic xanthogranulomas disseminated in the cerebral hemispheres, hypothalamus, cerebellum, and brainstem. The second patient presented first with cutaneous lesions characteristic of Langerhans cell histiocytosis. She subsequently developed bone abnormalities suggestive of Chester-Erdheim disease, which was confirmed by autopsy, raising the possibility of a common spectrum of histiocytosis including both diseases. Gross examination of the brain was normal, however, microscopy showed infiltration of the brain by characteristic non-Langerhans cell xanthogranulomas. The third patient presented with systemic features characteristic of Chester-Erdheim disease. Neurological signs included gait disturbance, seizures and confusion. Examination of the brain did not show any histiocytic infiltration, but did show changes suggestive of Hallervorden-Spatz syndrome. Association of Chester-Erdheim disease and Hallervorden-Spatz syndrome has not been previously reported. The relationship between both conditions is unclear.

Adenovirus-mediated gene transfer in rat liver of interleukin 4 but not interleukin 10 produces severe acute hepatitis.

Several immune responses are either limited to or concentrated in a given organ. Cytokines produced during ongoing immune responses have organ-localized effects that can be only partially mimicked upon their systemic delivery. Recombinant adenoviruses are efficient vectors to induce transient organ-localized cytokine expression. This allows in vivo analysis of the effects of cytokines produced spatially and temporally in a manner comparable to that observed during immune responses. The authors generated recombinant adenovirus for rat IL-4 (AdIL-4) and IL-10 (AdIL-10) to analyse the in vivo effects of these two important immunoregulatory molecules after gene transfer in the liver. It was first established that AdIL-4 and AdIL-10 were able to direct the production of biologically active cytokines by different rat cell types in vitro. Intraportal injection of doses of up to 10(10) pfu of AdIL-10 or control non-coding recombinant adenovirus were well tolerated, and hepatic histology showed only mild alterations. Conversely, animals receiving more than 2.5 x 10(9) pfu of AdIL-4 showed dose-dependent mortality, with clinical signs of hepatic dysfunction. Liver histology in animals receiving 2.5 x 10(9) pfu of AdIL-4 showed severe acute hepatitis with maximal lesions between day 7 and 14 and almost complete normalization by day 28 after gene transfer. The leukocyte infiltrate was composed primarily of mononuclear cells, but eosinophils and mast cells were significantly increased as compared to control animals. Hepatic function was also altered in animals that received AdIL-4, with kinetics similar to that of histological lesions. Our study describes a model for investigating cytokine function in vivo through liver-localized transgene expression mediated by adenoviral vectors and demonstrates that liver production of IL-4 but not IL-10 results in acute severe hepatitis.

[Pathologic study with immunohistochemistry of 61 pancreatic endocrine tumors in 16 patients suffering from multiple endocrine neoplasia type I (MEN I). Review of the literature]. / Etude anatomopathologique avec immunohistochimie de 61 tumeurs endocrines pancréatiques chez 16 patients atteints de néoplasies endocriniennes multiples de type I (NEM I). Revue de la littérature.

The Multiple Endocrine Neoplasia (MEN I) or Wermer's syndrome is an uncommon disease which is most often inherited and affects mainly parathyroid glands, pancreatic islets and pituitary gland. The aim of this study concerning 61 pancreatic tumors in 16 patients suffering from MEN I was to define the macroscopic, histological and immunohistochemical characteristics of these tumors. The pancreatic endocrine tumors as part of the MEN I syndrome concern multiple tumors of small size, localized most often to the pancreas's tail. In 79% of cases, these tumors have a different predominating peptidic hormonal secretion in a same patient though most of them have plurihormonal secretions. The pancreatic polyendocrinopathy detection imposes a family investigation to look for a type I polyendocrinopathy.

[Immunohistochemical study of 17 cases of rectal neuroendocrine tumors]. / Etude immunohistochimique de 17 cas de tumeurs neuro-endocrines rectales.

Seventeen rectal neuroendocrine tumors ("Rectal Carcinoids") were studied by immunohistochemistry using antibodies directed against neuroendocrine markers: chromogranin A, neuron-specific enolase, synaptophysin, neuroendocrine peptides (ACTH, glicentin, glucagon, pancreatic polypeptide, somatostatin, vasoactive intestinal peptide) and antibody against serotonin. All patients with tumors measuring 1 cm or less had no specific symptoms and survived between fifteen months and eight years. Only one patient with a 6 cm poorly differentiated neuroendocrine carcinoma died less than one year after diagnosis. Only five out of seventeen tumors secreted serotonin. Most tumors were derived from L cell secreting glucagon, glicentin or pancreatic polypeptide.