title: Donor cell replacement in mice transplanted in utero is limited by immune-independent mechanisms.
abstract: In utero transplantation (IUTx) therapy with allogeneic cells results in negligible peripheral blood (PBL) chimerism in nonablated humans with progressive diseases. IUTx has been successful only in immunocompromised fetuses. Because early treatment has great potential for halting disease progression, mechanisms preventing cell expansion must be identified and corrected. The hypothesis that factors in addition to allogenicity are responsible for low-level expansion is tested here by transplanting congenic cells into nonablated normal and mucopolycaccharidosis type VII (MPSVII) murine fetuses. MPSVII mice lack the enzyme beta-glucuronidase (GUSB-), accumulate glycosaminoglycans, and progressively develop severe storage disease. Low levels of enzyme can reverse storage. Evidence presented elsewhere showed that allogeneic donor cells overexpressing GUSB are negligible and their corrective effects are lost post-IUTx in MPSVII mice. We find that (1) congenic donor PBL cells, like allogeneic cells, are negligible in PBL of normal GUSB+ and MPSVII GUSB- hosts post-IUTx; (2) congenic, unlike allogeneic cells, are retained long term in both GUSB+ and GUSB- recipients; and (3) sufficient GUSB is produced to alleviate storage for up to 11.5 months in multiple tissues of GUSB- hosts. GUSB+ and GUSB- animals repopulate to a similar extent, indicating that donor GUSB enzyme does not initiate an immune response in the MPSVII null recipients. We conclude that the initial expansion of congenic and allogeneic cells is limited post-IUTx by non-immune-related mechanisms and the level of PBL cells is not necessarily indicative of graft failure following congenic IUTx. The mechanism limiting initial expansion may differ from that supporting long-term cell retention.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA. jeb@jax.org
authors.forename: J E
authors.initials: JE
authors.lastname: Barker
authors.forename: A J T
authors.initials: AJ
authors.lastname: Schuldt
authors.forename: M D
authors.initials: MD
authors.lastname: Lessard
authors.forename: C D
authors.initials: CD
authors.lastname: Jude
authors.forename: C A
authors.initials: CA
authors.lastname: Vogler
authors.forename: B W
authors.initials: BW
authors.lastname: Soper
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D001773:Blood Cells / Q000637:transplantation*; D002454:Cell Differentiation; D017690:Cell Transplantation; D005260:Female; D005315:Fetal Diseases / Q000628:therapy; D005333:Fetus / Q000737:chemistry / Q000166:cytology* / Q000276:immunology; D005966:Glucuronidase / Q000172:deficiency / Q000276:immunology; D051379:Mice; D016538:Mucopolysaccharidosis VII / Q000628:therapy*; D011247:Pregnancy; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000637:transplantation; D014018:Tissue Distribution; D014181:Transplantation Immunology
chemical_list: D005966:Glucuronidase