Prenatal Tolerance Induction: Relationship between Cell Dose, Marrow T-Cells, Chimerism, and Tolerance

Abstract

It was reported that the dose of self-antigens can determine the consequence of deletional tolerance and donor T cells are critical for tolerance induction in mixed chimeras. This study aimed at assessing the effect of cell doses and marrow T cells on engraftment and tolerance induction after prenatal bone marrow transplantation. Intraperitoneal cell transplantation was performed in FVB/N (H-2K q ) mice at gestational day 14 with escalating doses of adult C57BL/6 (H-2K b ) marrows. Peripheral chimerism was examined postnatally by flow cytometry and tolerance was tested by skin transplantation. Transplantation of light-density marrow cells showed a dose response. High-level chimerism emerged with a threshold dose of 5.0 × 10 6 and host leukocytes could be nearly replaced at a dose of 7.5-10.0 × 10 6 . High-dose transplants conferred a steady long-lasting donor-specific tolerance but were accompanied by >50% incidence of graft-versus-host disease. Depletion of marrow T cells lessened graft-versus-host disease to the detriment of engraftment. With low-level chimerism, tolerance was a graded phenomenon dependent upon the level of chimerism. Durable chimerism within 6 months required a threshold of ≥ 2% chimerism at 1 month of age and predicted a 50% chance of long-term tolerance, whereas transient chimerism (<2%) only caused hyporesponsiveness to the donor. Tolerance induction did not succeed without peripheral chimerism even if a large amount of injected donor cells persisted in the peritoneum. Neither did an increase in cell doses or donor T-cell contents benefit skin graft survivals unless it had substantially improved peripheral chimerism. Thus, peripheral chimerism level can be a simple and straightforward test to predict the degree of prenatal immune tolerance.

Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice

“…In the mouse, this period exists prior to E17 (25). In the murine model of allogeneic IUHCT, when transplants have been performed at E14-E15, numerous studies have reported failure of engraftment or of only microchimerism (26-34), inconsistent or absent tolerance induction (26,31,35), or immunization to alloantigen after IUHCT (30,33). Similarly, studies of organ transplantation after IUHCT with minimal levels of chimerism in large animal studies have shown an absence of tolerance (36), incomplete tolerance (37), or donor-specific tolerance (38).…”

Characterization of Tolerance Induction through Prenatal Marrow Transplantation: The Requirement for a Threshold Level of Chimerism to Establish Rather than Maintain Postnatal Skin Tolerance

“…Our results support commonplace following IUT (7-9). It reduces donorspecific alloreactivity of host lymphocytes in MLR, but that the failure of primary skin acceptance after spontaneous or experimental depletion of peripheral chimerism only minimally prolongs survivals of donor skin grafts (6). Although tolerant mice could have a trace of donor was not attributable to the loss of tolerance but rather to the incapability of establishing sufficient tolerance at cells in the thymus at 7-8 months old (6), longer term follow-up in this study did not reveal detectable donor lower or undetectable chimerism levels.…”

Transplantation NK'Oed in the first trimester

“…Likewise, Chen et al recently observed a threshold of 2% chimerism at 1 month of age that was predictive of longterm blood chimerism and an even chance at donor-specific tolerance for allogeneic skin grafts. 4 These findings underscore the importance of chimerism levels in the development of tolerance and the importance of the makeup and size of the initial graft in the eventual establishment of stable chimerism.…”