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. While long-term engraftment has been demonstrated following in utero hematopoietic cellular transplantation (IUHCT) 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 IUHCT, the impact of an infection with lymphocytic choriomenigitic virus (LCMV) 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 to models of postnatal chimerism and provides additional support for the prenatal approach to the treatment of congenital benign cellular disease.

Extrinsic allospecific signals of hematopoietic origin dictate iNKT cell lineage-fate decisions during development

“…Next, the requirement for iNKT cell support for allospecific NK and T cell education was compared between B6.CD1d −/− chimeras and B6 chimera controls 33 34 . No differences were observed in the pattern of NK or T cell education between control and B6.CD1d −/− chimeras.…”

“…8e ). Furthermore, T cell populations expressing TCRvβ5, 11, and 12 react with endogenous mammary tumor virus-derived superantigens bound to I-E family MHC class II molecules on donor Balb/c cells resulting in the deletion of these populations in Balb/c → B6 chimeras 34 36 37 38 . Both wild-type and B6.CD1d −/− chimeras displayed deletion of allospecific TCRvβ5, 11, and 12 T cells ( Fig.…”

Maternal and Fetal Immune Response to In Utero Stem Cell Transplantation

“…Here, NK cell education hinged on allorecognition by the activating receptor and subsequent upregulation of the inhibitory receptors in a developmentally-limited window (29). These changes were proven to be remarkably stable in mature chimeras even in the face of a potent viral infection (31) and were supported by adjunct mechanisms such as MHC transfer (trogocytosis) that provided sustained cisrecognition of donor ligand in the absence of trans- interaction (32). The essence of this quantitative model for NK cell education is that a minimal amount of donor chimerism is required for induction and maintenance of NK cell tolerance thereby establishing a theoretical explanation for many of the observations of clinical IUHCT.…”

Depletion of murine fetal hematopoietic stem cells with c-Kit receptor and CD47 blockade improves neonatal engraftment

“…1 Proposed benefits include transplanting into an immunologically naive fetal host with the ability to form donor-specific tolerance. [2][3][4] Despite success in animal models, [5][6][7][8][9][10][11] success in human clinical applications has been limited. 12 Multiple barriers to engraftment have been elucidated, including the maternal immune system.…”