CTLA4Ig gene transfer alleviates abortion in mice by expanding CD4+CD25+ regulatory T cells and inducing indoleamine 2,3-dioxygenase |
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| Institution: | 1. Department of Obstetrics and Gynecology, Center of Reproductive Medicine, The Second West China Hospital, Sichuan University, Sichuan Province 610041, China;2. Department of Pharmacology, College of Pharmaceutical, Third Military Medical University, Chongqing 400038, China;1. First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China;2. Affiliated Hospital of Hainan Medical University, Haikou 570102, Hainan Province, China;1. Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819, Japan;2. National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709, USA;3. Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan;1. Liver Research Center and the Division of Gastroenterology, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 55 Claverick St, Providence, RI, 02903, USA;2. Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy St, Providence, RI, 02903, USA;1. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands;2. Department of Gynaecology, Leiden University Medical Center, Leiden, the Netherlands;3. Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands;1. Transplantation Research Center, Harvard Medical School, LMRC #316, 221 Longwood Avenue, Boston, MA 02115, USA;2. HLA Tissue Typing Laboratory, Renal Transplant Program, Division of Renal Medicine, Transplantation Research Center, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis Street, PBB 161G, Boston, MA 02115, USA;1. Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois;2. Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois;3. Women''s Health Research Institute, Northwestern University, Chicago, Illinois |
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| Abstract: | Successful pregnancy requires a state of immunological tolerance since normally the maternal immune system does not reject the semi-allogeneic conceptus. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a ligand for B7, delivers negative signals to antigen presenting cells (APCs) to compete with CD28 for binding to B7 molecules and down-regulate proinflammatory responses, thus inhibiting T cell activation. Using CBA/J × DBA/2 matings as an abortion-prone model, we observed that adenovirus-mediated CTLA4Ig (Ad-CTLA4Ig) gene transfer improves pregnancy outcome. Ad-CTLA4Ig therapy skewed the ability of serum cytokine production toward a Th2 bias. Flow cytometry revealed that Ad-CTLA4Ig administration expanded peripheral CD4+CD25+ regulatory T cell populations in CBA/J × DBA/2 matings. Furthermore, Ad-CTLA4Ig administration induced indoleamine 2,3-dioxygenase (IDO) and Foxp3 mRNA expression at the materno-fetal interface. Our results demonstrate that adenovirus-mediated CTLA4Ig gene transfer improves pregnancy outcome in a murine model of abortion by expanding the CD4+CD25+ regulatory T cell population and inducing IDO mRNA expression. |
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