title: Prenatal Allogeneic Tolerance in Mice Remains Stable Despite Potent Viral Immune Activation.
abstract: Transplanting stem cells before birth offers an unparalleled opportunity to initiate corrective treatment for numerous childhood diseases with minimal or no host conditioning. Although long-term engraftment has been demonstrated following in utero hematopoietic cellular transplantation during immune quiescence, it is unclear if prenatal tolerance becomes unstable with immune activation such as during a viral syndrome. Using a murine model of in utero hematopoietic cellular transplantation, the impact of an infection with lymphocytic choriomeningitis virus on prenatal allospecific tolerance was examined. The findings in this report illustrate that established mechanisms of donor-specific tolerance are strained during potent immune activation. Specifically, a transient reversal in the anergy of alloreactive lymphocytes is seen in parallel with the global immune response toward the virus. However, these changes return to baseline following resolution of the infection. Importantly, prenatal engraftment remains stable during and after immune activation. Collectively, these findings illustrate the robust nature of allospecific tolerance in prenatal mixed chimerism compared with models of postnatal chimerism and provides additional support for the prenatal approach to the treatment of congenital benign cellular disease.
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Beverly S I
authors.initials: BS
authors.lastname: Strong
authors.affiliation: Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Katherine O
authors.initials: KO
authors.lastname: Ryken
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Lee
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Lucas E
authors.initials: LE
authors.lastname: Turner
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Ram K
authors.initials: RK
authors.lastname: Wadhwani
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; University of Cincinnati College of Medicine, Cincinnati, OH 45229;
authors.forename: Tess J
authors.initials: TJ
authors.lastname: Newkold
authors.affiliation: Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Amir M
authors.initials: AM
authors.lastname: Alhajjat
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; and Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Heusel
authors.affiliation: Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; University of Cincinnati College of Medicine, Cincinnati, OH 45229; aimen.shaaban@cchmc.org.
authors.forename: Aimen F
authors.identifier: http://orcid.org/0000-0002-9459-107X
authors.initials: AF
authors.lastname: Shaaban
mesh_terms: D064591:Allografts; D000818:Animals; D005260:Female; D005315:Fetal Diseases / Q000276:immunology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D051379:Mice; D011247:Pregnancy; D018183:Transplantation Chimera / Q000276:immunology*; D023001:Transplantation Tolerance