title: Regulatory T cells ameliorate intrauterine growth retardation in a transgenic rat model for preeclampsia.
abstract: Preeclampsia is a multisystemic syndrome during pregnancy that is often associated with intrauterine growth retardation. Immunologic dysregulation, involving T cells, is implicated in the pathogenesis. The aim of this study was to evaluate the effect of upregulating regulatory T cells in an established transgenic rat model for preeclampsia. Application of superagonistic monoclonal antibody for CD28 has been shown to effectively upregulate regulatory T cells. In the first protocol (treatment protocol), we applied 1 mg of CD28 superagonist or control antibody on days 11 and 15 of pregnancy. In the second protocol (prevention protocol), the superagonist or control antibody was applied on days 1, 5, and 9. Superagonist increased regulatory T cells in circulation and placenta from 8.49±2.09% of CD4-positive T cells to 23.50±3.05% and from 3.85±1.45% to 23.27±7.64%, respectively. Blood pressure and albuminuria (30.6±15.1 versus 14.6±5.5 mg/d) were similar in the superagonist or control antibody-treated preeclamptic group for both protocols. Rats treated with CD28 superagonist showed increased pup weights in the prevention protocol (2.66±0.03 versus 2.37±0.05 g) and in the treatment protocol (3.04±0.04 versus 2.54±0.1 g). Intrauterine growth retardation, calculated by brain:liver weight ratio, was also decreased by the superagonist in both protocols. Further analysis of brain development revealed a 20% increase in brain volume by the superagonist. Induction of regulatory T cells in the circulation and the uteroplacental unit in an established preeclamptic rat model had no influence on maternal hypertension and proteinuria. However, it substantially improved fetal outcome by ameliorating intrauterine growth retardation.
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Lukasz
authors.initials: L
authors.lastname: Przybyl
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Tarek
authors.initials: T
authors.lastname: Ibrahim
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Nadine
authors.initials: N
authors.lastname: Haase
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Michaela
authors.initials: M
authors.lastname: Golic
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Julianna
authors.initials: J
authors.lastname: Rugor
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Ivo
authors.initials: I
authors.lastname: Bendix
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Meray
authors.initials: M
authors.lastname: Serdar
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Anne Cathrine
authors.initials: AC
authors.lastname: Staff
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Müller
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Hünig
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Ursula
authors.initials: U
authors.lastname: Felderhoff-Müser
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Florian
authors.initials: F
authors.lastname: Herse
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.).
authors.forename: Babette
authors.initials: B
authors.lastname: LaMarca
authors.affiliation: From the Experimental and Clinical Research Center, a joint cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany (L.P., N.H., M.G., J.R., F.C.L., G.W., D.N.M., F.H., R.D.); Department of Pharmacology/Toxicology, Center for Excellence in Cardiovascular and Renal Research, Jackson, MS (T.I., B.L.); Department of Pediatrics I, Neonatal Neuroscience Lab, University Hospital Essen, University Duisburg-Essen, Essen, Germany (I.B., M.S., U.F.-M.); Departments of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (A.C.S.); Institute of Virology and Immunobiology, Würzburg, Germany (T.H.); and Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany (R.D.). ralf.dechend@charite.de.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D018106:CD28 Antigens / Q000008:administration & dosage / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000503:physiopathology / Q000628:therapy*; D008213:Lymphocyte Activation / Q000187:drug effects; D011225:Pre-Eclampsia / Q000503:physiopathology / Q000628:therapy*; D011247:Pregnancy; D011256:Pregnancy Outcome; D011270:Pregnancy, Animal; D011897:Random Allocation; D051381:Rats; D055647:Rats, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens
keywords: T-lymphocytes, regulatory; fetal growth retardation; preeclampsia; pregnancy
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