Immune Ontogeny and Engraftment Receptivity in the Sheep Fetus

Abstract

Objective: The biologic explanation for fetal receptivity to donor engraftment and subsequent long-term tolerance following transplantation early in gestation is not known. We investigated the role fetal immune ontogeny might play in fetal transplantation tolerance in sheep. Methods: Engraftmentof allogeneic and xenogeneicHSC was determined 60 days following transplantation at different time points in sheep fetal gestation. Parallel analysis of surface differentiation antigen expression on cells from lymphoid organs of timed gestational age fetal sheep was determined by flow cytometry using available reagents. Results: An engraftment window was identified after day 52 gestation lasting until day 71 (term gestation: 145 days). This period was associated with the expression of the leukocyte common antigen CD45 on all cells in the thymus. Double-positive and single-positive CD4 and CD8 cells began appearing in the thymus just prior (day 45 gestation) to the beginning of the engraftment window, while single-positive CD4 or CD8 cells do not begin appearing in peripheral organs until late in the engraftment period, suggesting deletional mechanisms may be operative. In concert, surface IgM-positive cells express CD45 in the thymus at day 45, with a comparable delay in the appearance of IgM/CD45 cells in the periphery until late in the engraftment window. Conclusions: These findings support a central role for the thymus in multilineage immune cell maturation during the period of fetal transplantation receptivity. Further, they suggest that fetal engraftment receptivity is due to gestational age-dependent deletional tolerance.

A Long-term Follow-up Study on the Engraftment of Human Hematopoietic Stem Cells in Sheep

“…Another possibility is the gestational day of injection. zanjani et al [27] injected cells at days 51-71 of gestation, whereas we injected cells at days 45-49 of gestation. However, according to our previous studies [1,2,24,28], the gestational day of fetal sheep for performing the cell injection (45-79 gestational days) did not affect the engraftment efficiency, either.…”

Boosting Hematopoietic Engraftment after in Utero Transplantation through Vascular Niche Manipulation

“…In contrast, CD146 ++− cells enhanced BM hematopoietic engraftment whether they were administered 3 days prior to the HSC graft or concomitantly with it. The ability of CD146 ++− , but not CD146 +++ , cells to enhance hematopoietic engraftment when transplanted simultaneously with the HSC, suggests that the effect of CD146 ++− cells could be mediated, at least in part, by their ability to alter the innate and adaptive immune responses ( Domev et al., 2014 , English et al., 2010 , Le Blanc and Davies, 2015 , Le Blanc et al., 2007 ), perhaps protecting the transplanted HSC from the rudimentary immune elements present within the fetus at this stage of gestation ( Skopal-Chase et al., 2009 ).…”

Potential of Mesenchymal Stem Cells for Liver Regeneration

“…In addition to the unique characteristics of the fetus itself as a recipient, there are several additional advantages of selecting sheep as an animal model: 1) sheep are fairly close in size to humans during development and throughout life, which should greatly facilitate, or even eliminate the need for, scale-up of the protocol for clinical human therapies once promising results have been obtained in the fetal sheep model, 2) the physiology and developmental processes are similar and therefore, sheep have been for decades the model to study normal fetal growth and fetal abnormalities [182][183][184][185], 3) in contrast to mice and rats, sheep are outbred, and thus present a diverse genetic background, just like humans, 4) the development of sheep immune system has been extensively studied and it closely parallels that of humans [186][187][188][189][190][191][192][193][194], 5) the long lifespan and large size allows the study of cellular fate in the same animal for several years after transplantation, which provides critical answers about long-term efficacy and safety of the therapy in question. Collectively, these properties make the fetal sheep an ideal model in which to test the therapeutic potential of MSC and obtain results that could readily be translated into clinical studies.…”