HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Calcaterra, C. Articles by Balsari, A. Search for Related Content PubMed PubMed Citation Articles by Calcaterra, C. Articles by Balsari, A.

Critical Role of TLR9 in Acute Graft-versus-Host Disease¹

Claudia Calcaterra^2,*, Lucia Sfondrini^2,, Anna Rossini, Michele Sommariva, Cristiano Rumio, Sylvie Ménard^* and Andrea Balsari^3,*,

^* Molecular Biology Unit, Department of Experimental Oncology and Laboratories, National Cancer Institute, Foundation Istituto di Ricovero e Cura a Carattere Scientifico, Via Venezian, Milan, Italy; and Institute of Pathology and Department of Human Morphology, University of Milan, Via Mangiagalli, Milan, Italy

Graft-vs-host disease (GVHD) is a major complication after allogeneic bone marrow transplantation. Different studies have demonstrated that intestinal bacterial breakdown products and loss of gastrointestinal tract integrity, both induced by conditioning regiments, are critical in the pathogenesis of acute GVHD. Using C57BL/6 knockout mice, we evaluated the role of TLR4 and TLR9, which recognize bacterial LPS and DNA, respectively, in the GVHD associated with allogeneic bone marrow transplantation. When myeloablative-irradiated TLR9 knockout (TLR9^–/–) mice were used as graft recipients, survival and clinical score of acute GVHD were improved as compared with the wild-type recipient mice (18/30 vs 1/31 mice still alive at day 70 in a total of four experiments); while no differences were observed using recipient TLR4 knockout (TLR4^–/–) mice. The reduced mortality and morbidity in TLR9^–/– mice related with reduced stimulatory activity of TLR9^–/– spleen APCs after conditioning and reduced proliferation of allogeneic donor T cells. Experiments using TLR9^+/+ into TLR9^–/– and TLR9^–/– into TLR9^+/+ chimeric mice as recipients indicated a critical role for nonhematopoietic TLR9^+/+ cells interacting with bacterial breakdown products released in myeloablated mice. Altogether these data reveal a novel important role of TLR9 in GVHD, a finding that might provide tools to reduce this complication of allogeneic transplantation.

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 Associazione Italiana per la Ricerca sul Cancro.

C.C. performed the research and analyzed data; L.S. performed the research, analyzed data and contributed to write the paper; A.R. contributed to in vivo studies; S.M. contributed to interpretation of data; and A.B. designed the research and wrote the paper.

² C.C. and L.S. contributed equally to this work.

³ Address correspondence and reprint requests to Prof. Andrea Balsari, Institute of Pathology, University of Milan, Via Mangiagalli 31, 20133 Milan, Italy. E-mail address: andrea.balsari{at}unimi.it

⁴ Abbreviations used in this paper: BMT, bone marrow transplantation; GVHD, graft-vs-host disease; ODN, oligonucleotide.

⁵ The online version of this article contains supplemental material.