title: Postnatal donor lymphocytes enhance prenatally-created chimerism at the risk of graft-versus-host disease.
abstract: The major barrier to clinical application of in utero hematopoietic stem cell transplantation is insufficient chimerism for phenotypic correction of target diseases or induction of graft tolerance. Postnatal donor lymphocyte infusion (DLI) may enhance donor cell levels so as to further facilitate tolerance induction. We created murine mixed chimeras in utero. Chimeras with <10% donor cells were subjected to postnatal DLI to evaluate the effects of DLI on chimerism augmentation and skin tolerance induction. Within one day after DLI, recipients experienced a transient peaking of donor chimerism, which could be as high as 20~40%. However, the transient chimerism peaking didn't benefit donor skin survivals despite immediate skin placement after DLI. In case of fruitful DLI, chimerism augmentation was usually observed after a latent period of 2~4 weeks. Otherwise, chimerism would return to around pre-DLI levels by days 7~14. Peripheral chimerism of >3% could be consistently boosted up to >10%, whereas chimerism of <0.2% hardly showed any significant enhancement. As for chimerism levels of 0.2~3%, chimerism augmentation up to >10% succeeded in 3(15%) of 20 recipients. Notably, chimerism augmentation by postnatal DLI was often associated with unexpected death or graft-versus-host disease (GVHD). In conclusion, transient chimerism augmentation by DLI played no role in facilitating graft tolerance. Substantial augmentation by DLI demanded a threshold chimerism level and posed a serious risk of GVHD to the recipients. It raised the concern about using postnatal DLI to broaden therapeutic horizons of in utero hematopoietic stem cell transplantation.
authors.affiliation: Department of Surgery, Chang Gung Children's Hospital, College of Medicine, Chang Gung University Taoyuan, Taiwan.
authors.forename: Jeng-Chang
authors.initials: JC
authors.lastname: Chen
authors.affiliation: Department of Allergy, Asthma and Rheumatology, Chang Gung Children's Hospital, College of Medicine, Chang Gung University Taoyuan, Taiwan.
authors.forename: Liang-Shiou
authors.initials: LS
authors.lastname: Ou
authors.affiliation: Pediatric Research Center, Chang Gung Children's Hospital Taoyuan, Taiwan.
authors.forename: Hsiu-Yueh
authors.initials: HY
authors.lastname: Yu
authors.affiliation: Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University Taoyuan, Taiwan.
authors.forename: Ming-Ling
authors.initials: ML
authors.lastname: Kuo
authors.affiliation: Department of Surgery, Chang Gung Children's Hospital, College of Medicine, Chang Gung University Taoyuan, Taiwan.
authors.forename: Pei-Yeh
authors.initials: PY
authors.lastname: Chang
authors.affiliation: Pediatric Research Center, Chang Gung Children's Hospital Taoyuan, Taiwan.
authors.forename: Hsueh-Ling
authors.initials: HL
authors.lastname: Chang
keywords: Chimerism augmentation; donor lymphocyte infusion; graft-versus-host disease; in utero transplantation; tolerance induction