Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice.
The lack of fetal immune responses to foreign antigens, i.e., fetal immunologic tolerance, is the most compelling rationale for prenatal stem cell and gene therapy. However, the frequency of engraftment following in utero hematopoietic cell transplantation (IUHCT) in the murine model is reduced in allogeneic, compared with congenic, recipients. This observation supports the existence of an immune barrier to fetal transplantation and challenges the classic assumptions of fetal tolerance. Here, we present evidence that supports the presence of an adaptive immune response in murine recipients of IUHCT that failed to maintain engraftment. However, when IUHCT recipients were fostered by surrogate mothers, they all maintained long-term chimerism. Furthermore, we have demonstrated that the cells responsible for rejection of the graft were recipient in origin. Our observations suggest a mechanism by which IUHCT-dependent sensitization of the maternal immune system and the subsequent transmission of maternal alloantibodies to pups through breast milk induces a postnatal adaptive immune response in the recipient, which, in turn, results in the ablation of engraftment after IUHCT. Finally, we showed that non-fostered pups that maintained their chimerism had higher levels of Tregs as well as a more suppressive Treg phenotype than their non-chimeric, non-fostered siblings. This study resolves the apparent contradiction of induction of an adaptive immune response in the pre-immune fetus and confirms the potential of actively acquired tolerance to facilitate prenatal therapeutic applications.
Merianos
Demetri J
DJ
Children's Center for Fetal Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Tiblad
Eleonor
E
Santore
Matthew T
MT
Todorow
Carlyn A
CA
Laje
Pablo
P
Endo
Masayuki
M
Zoltick
Philip W
PW
Flake
Alan W
AW
D000818:Animals; D005260:Female; D005333:Fetus / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D007108:Immune Tolerance; D007112:Immunity, Maternally-Acquired; D066298:In Vitro Techniques; D007518:Isoantibodies / Q000378:metabolism*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology; D014184:Transplantation, Homologous
D007518:Isoantibodies