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Lymphocytes Support Oval Cell-Dependent Liver Regeneration¹

Hélène Strick-Marchand^*,, Guillemette X. Masse^*,, Mary C. Weiss^, and James P. Di Santo^2,*,

^* Cytokines and Lymphoid Development Unit, Immunology Department, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, Unité 668, Unité de Recherche Associée 2578, Centre National de la Recherche Scientifique, Institut Pasteur, and Institut National de la Santé et de la Recherche Médicale, Unité 845, Pathogénèse des Hépatites Virales B et Immunothérapie, Paris, France

In case of hepatic damage, the liver uses a unique regeneration mechanism through proliferation of hepatocytes. If this process is inhibited, bipotent oval stem cells proliferate and differentiate to hepatocytes and bile ducts, thus restoring liver mass. Although oval cell accumulation in the liver is often associated with inflammatory processes, the role of lymphocytes in oval cell-mediated hepatic regeneration is poorly understood. We treated wild-type and immunodeficient mice with an oval cell-inducing diet: in the absence of T cells (CD3^–/– and Rag2^–/–) there were fewer oval cells, whereas in alymphoid mice (Rag2^–/–_c^–/–) a strongly reduced oval cell response and higher mortality, due to liver failure, was observed. Adoptive transfer of T cells into alymphoid mice protected them from liver failure, but was insufficient to restore the oval cell response. Treatment of Rag2^–/– mice with an NK cell-depleting Ab resulted in a significantly diminished oval cell response. These genetic experiments point to a major role for NK and T cells in oval cell expansion. In wild-type mice, oval cell proliferation is accompanied by an intrahepatic inflammatory response, characterized by the recruitment of Kupffer, NK, NKT, and T cells. Under these conditions, lymphocytes produce T_H1 proinflammatory cytokines (IFN- and TNF-) that are mitogenic for oval cells. Our data suggest that T and NK lymphocytes stimulate oval cell expansion by local cytokine secretion. This beneficial cross-talk between the immune system and liver stem cells operates under noninfectious conditions and could promote tissue regeneration following acute liver damage.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, and a Grand Challenges in Global Health Grant from the Bill & Melinda Gates Foundation.

² Address correspondence and reprint requests to Dr. James P. Di Santo, Cytokines and Lymphoid Development Unit, Institut National de la Santé et de la Recherche Médicale, Unité 668, Institut Pasteur, 25 rue du Docteur Roux, 75742 Paris, France. E-mail address: disanto{at}pasteur.fr

³ Abbreviations used in this paper: CDE, choline-deficient ethionine-supplemented; _c, common chain; LDH, lactate dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; WT, wild type.