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Evidence for an Adaptive Immune Barrier after in Utero Hematopoietic Cell Transplantation.

Publication ,  Conference
Peranteau, WH; Endo, M; Adibe, OO; Flake, AW
Published in: Blood
November 16, 2006

In utero hematopoietic cell transplantation (IUHCT) is a nonmyeloablative approach that takes advantage of normal immunologic development to achieve donor specific tolerance. Despite the many potential advantages of the fetal recipient, IUHCT across MHC barriers has been limited by low levels of engraftment and the inability to consistently achieve allochimerism.Although the immature immune system of the developing fetus has long been appreciated as a principal advantage of IUHCT, the competence of the fetal immune system to act as a barrier to IUHCT has been a source of debate. Until now, comparisons of allogeneic and congenic engraftment have been inconclusive due to methodologic limitations resulting in minimal and inefficient engraftment. In this study, a new intravascular technique that allows definitive administration of much higher doses of donor cells was employed to directly compare the incidence and levels of engraftment following in utero transplantation of either congenic or allogeneic bone marrow (BM) or enriched hematopoietic stem cells (HSCs). 20E+06 B6 GFP BM cells (H2Kb+, GFP+) or 1E+05 cKit+Sca-1+Lin- B6 GFP cells (H2Kb+, GFP+) were intravenously injected via the vitelline vein into gestational day 14 Balb/c (H2Kd+, allogeneic) or C57Bl/6 (H2Kb+, congenic) fetal mice. The peripheral blood (PB) of recipients was serially analyzed by flow cytometry for GFP+ donor cells at 1, 2, 4 and 6 months of age. A separate group of animals was harvested at 1 week of age (2 weeks after injection) to assess donor chimerism in PB and BM. Our results demonstrate that 100% of surviving recipients of whole BM demonstrate engraftment at 1 week of age, but that 70% of allogeneic recipients lose engraftment by 1 month of age, and 80% ultimately fail to sustain long-term chimerism. In contrast, all congenic recipients maintain engraftment at 6 months of age (Table 1). Chimerism levels in allogeneic recipients drop significantly after 1 month of life while those in congenic recipients remain stable. This results in a significant difference in engraftment levels in allogeneic and congenic recipients beyond 1 month of life (Fig 1). Similar results were seen when enriched HSCs were the donor cell source. 100% (2/2) of congenic recipients of enriched HSCs demonstrated stable low level PB engraftment up to 6 months of life (0.14–0.55% GFP+ donor cells). In contrast, no allogeneic recipients (0/9) of enriched HSCs were chimeric from 1 to 6 months of life. In combination, these results demonstrating a 100% efficiency of long-term engraftment in congenic recipients and loss of engraftment by 1 month of age in the majority of allogeneic recipients strongly implicate an adaptive immune barrier to allogeneic engraftment after IUHCT. Better understanding of the immune mechanisms limiting allogeneic engraftment after IUHCT is required to allow the development of successful strategies for IUHCT.Efficiency of Engraftment after IUHCT in Congenic and Allogeneic Recipients 1 week of age (BM) 1 week of age (PB) 1 month of age (PB) 6 months of age (PB) congenic 100% (8/8) 100% (8/8) 100% (25/25) 100% (25/25) allogeneic 100% (8/8) 100% (8/8) 29% (9/31) 19% (6/31) Figure Figure

Duke Scholars

Published In

Blood

DOI

EISSN

1528-0020

ISSN

0006-4971

Publication Date

November 16, 2006

Volume

108

Issue

11

Start / End Page

3179 / 3179

Publisher

American Society of Hematology

Related Subject Headings

  • Immunology
  • 3213 Paediatrics
  • 3201 Cardiovascular medicine and haematology
  • 3101 Biochemistry and cell biology
  • 1114 Paediatrics and Reproductive Medicine
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology
 

Citation

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Peranteau, W. H., Endo, M., Adibe, O. O., & Flake, A. W. (2006). Evidence for an Adaptive Immune Barrier after in Utero Hematopoietic Cell Transplantation. In Blood (Vol. 108, pp. 3179–3179). American Society of Hematology. https://doi.org/10.1182/blood.v108.11.3179.3179
Peranteau, William H., Masayuki Endo, Obinna O. Adibe, and Alan W. Flake. “Evidence for an Adaptive Immune Barrier after in Utero Hematopoietic Cell Transplantation.” In Blood, 108:3179–3179. American Society of Hematology, 2006. https://doi.org/10.1182/blood.v108.11.3179.3179.
Peranteau WH, Endo M, Adibe OO, Flake AW. Evidence for an Adaptive Immune Barrier after in Utero Hematopoietic Cell Transplantation. In: Blood. American Society of Hematology; 2006. p. 3179–3179.
Peranteau, William H., et al. “Evidence for an Adaptive Immune Barrier after in Utero Hematopoietic Cell Transplantation.Blood, vol. 108, no. 11, American Society of Hematology, 2006, pp. 3179–3179. Crossref, doi:10.1182/blood.v108.11.3179.3179.
Peranteau WH, Endo M, Adibe OO, Flake AW. Evidence for an Adaptive Immune Barrier after in Utero Hematopoietic Cell Transplantation. Blood. American Society of Hematology; 2006. p. 3179–3179.

Published In

Blood

DOI

EISSN

1528-0020

ISSN

0006-4971

Publication Date

November 16, 2006

Volume

108

Issue

11

Start / End Page

3179 / 3179

Publisher

American Society of Hematology

Related Subject Headings

  • Immunology
  • 3213 Paediatrics
  • 3201 Cardiovascular medicine and haematology
  • 3101 Biochemistry and cell biology
  • 1114 Paediatrics and Reproductive Medicine
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology