Resistance of fetal PVG rats to induction of allograft tolerance

Abstract

Artificially induced immunological tolerance is often envisaged as experimental mimicry of events which occur naturally during the acquisition of self tolerance. Thus, it has been inferred that similar circumstances will facilitate the induction of both types of unresponsiveness. Since tolerance to most self determinants appears to have been established by the time of birth and allograft tolerance can be experimentally induced more readily, if not exclusively, in very young animals, it is commonly assumed that susceptibility to induction of tolerance to foreign antigens will continue to increase as progressively younger animals are tested. The experiments reported in this study extend the range of circumstances under which younger animals may be found to be less susceptible, or even completely resistant, to tolerance induction. While neonatal PVG rats were highly susceptible to the induction of tolerance to (PVG x DA)F1 hybrid determinants, fetal PVG rats were only partially susceptible at 19 days and were completely resistant at 17 and 18 days of gestation. Furthermore, only 39% of neonatal PVG rats that had been inoculated with F1 hybrid bone marrow cells at 18 days of gestation could be rendered tolerant by procedures which were effective in 100% of previously untreated neonates. These observations were interpreted to indicate that a certain stage of maturity must be attained before fetal rats become susceptible to tolerance induction. Asymmetry in susceptibility to tolerance induction in response to the inoculation of F1 hybrid bone marrow cells was observed when PVG and DA fetuses, but not neonates, were compared. This difference in the response of the two strains recalls the divergence in immune reactivity of offspring, previously reported when PVG and DA embryos were transferred to surrogate mothers of the other strain. It is also in agreement with earlier reports of substantial differences in the ease of tolerance induction between different strain combinations. The asymmetry between PVG and DA rats in the present experiments is speculatively attributed to differences in rates of immunological maturation of the two strains.

Mechanisms and models of peripheral CD4 T cell self-tolerance

“…It could be argued, however, that the response induced by injecting the same dose of virus into a young versus an old mouse is not a valid comparison (21). In addition, a number of studies have shown that a graft given before the development of the immune system still leads to rejection of that tissue (22)(23)(24)(25)(26)(27)(28). This is even true for grafts mismatched for as little as one minor histocompatibility (minor-H) antigen (29), and argues strongly against a tolerance window early in life.…”

Effect of in utero Infusion Route on Lymphocyte Distribution in Fetal Rat Tissues

“…results], determinations after injection via intravenous and intraperitoneal routes were performed after 1, 6, and 96 h; the intraperitoneal route takes more than 6 and less than 96 h to 'stabilize' in fetuses. Furthermore, McCullagh [6] noticed that the success of tolerance induction in fetal rats depends on the infusion route and that the intraperitoneal route of cell administration in fetal rats was found to be less efficient than the intravenous route, even 2 weeks after injection. Immunological tolerance was induced in rat fetuses before 19 days [6,7].…”

“…Furthermore, McCullagh [6] noticed that the success of tolerance induction in fetal rats depends on the infusion route and that the intraperitoneal route of cell administration in fetal rats was found to be less efficient than the intravenous route, even 2 weeks after injection. Immunological tolerance was induced in rat fetuses before 19 days [6,7]. Immunological maturation in the rat begins at 14-16 weeks of gestation [27] when the fetuses are developed enough to resist in utero injections.…”