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 All Versions of this Article: jimmunol.0900454v1 183/1/462    most recent 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 Google Scholar Articles by Cao, T. M. Articles by Shizuru, J. A. PubMed PubMed Citation Articles by Cao, T. M. Articles by Shizuru, J. A.

Identification of a Major Susceptibility Locus for Lethal Graft-versus-Host Disease in MHC-Matched Mice¹

Thai M. Cao^2,*, Laura C. Lazzeroni, Schickwann Tsai^*, Wendy W. Pang, Amy Kao, Nicola J. Camp, Alun Thomas and Judith A. Shizuru

^* Blood and Marrow Transplantation Program, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132; Department of Psychiatry and Behavioral Sciences, Stanford University of School of Medicine, Stanford, CA 94305; Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305; and Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84132

Graft-vs-host disease (GVHD) is the major cause of morbidity and mortality after allogeneic hemopoietic cell transplantation. From a genetic perspective, GVHD is a complex phenotypic trait. Although it is understood that susceptibility results from interacting polymorphisms of genes encoding histocompatibility Ags and immune regulatory molecules, a detailed and integrative understanding of the genetic background underlying GVHD remains lacking. To gain insight regarding these issues, we performed a forward genetic study. A MHC-matched mouse model was used in which irradiated recipient BALB.K and B10.BR mice demonstrate differential susceptibility to lethal GHVD when transplanted using AKR/J donors. Assessment of GVHD in (B10.BR x BALB.K)F₁ mice revealed that susceptibility is a dominant trait and conferred by deleterious alleles from the BALB.K strain. To identify the alleles responsible for GVHD susceptibility, a genome-scanning approach was taken using (B10.BR x BALB.K)F₁ x B10.BR backcross mice as recipients. A major susceptibility locus, termed the Gvh1 locus, was identified on chromosome 16 using linkage analysis (logarithm of the odds, 9.1). A second locus was found on chromosome 13, named Gvh2, which had additive but protective effects. Further identification of Gvh genes by positional cloning may yield new insight into genetic control mechanisms regulating GVHD and potentially reveal novel approaches for effective GVHD therapy.

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 in part by Grants P01CA049605 and R01HL087240 (to J.A.S.) and K08HL067847 (to T.M.C.) from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Thai M. Cao, Blood and Marrow Transplant and Myeloma Program, Division of Hematology, University of Utah School of Medicine, 30 North 1900 East, Room SOM 5C402, Salt Lake City, UT 84132. E-mail address: thai.cao{at}hsc.utah.edu

³ Abbreviations used in this paper: GVHD, graft-vs-host disease; HAg, histocompatibility Ag; BC, backcross; BM, bone marrow; TBI, total-body irradiation; LOD, logarithm of the odds.

⁴ The online version of this article contains supplemental material.