Facilitation of Tolerance in Weanling Mice by Enhancing the Proliferation of Donor Lymphoreticular Cells

Abstract

Summary A latent period between injection of BALB/c spleen cells and grafting of BALB/c skin results in a substantially increased rate of graft acceptance by weanling DBA/2 recipients. Such a latent period does not facilitate tolerance induction when the donors are (C3H × A) F1 hybrids and recipients are weanlings of the C3H strain, a difference attributed to the lack of a stimulus to donor cell proliferation in this hybrid-to-parent combination. That stimuli to donor cell proliferation, other than the host antigens, also facilitate tolerance induction in weanling animals was also demonstrated. Five strong indifferent antigens were administered to donors 6 weeks before harvest of cells, and again to recipients following the cell transfer. A higher rate of tolerance induction was observed with BALB/c donors and weanling DBA/2 recipients, but the effect was much more evident with (C3H × A) F1 donors and weanling C3H recipients. Although females of the BALB/c and DBA/2 strains do not reject syngeneic male skin grafts, the graft-host interactions assay suggested that a histocompatibility difference associated with the Y chromosome does exist in these strains. Further support for such a difference was noted in the tolerance studies: When female cells were included in the BALB/c inoculum and the recipients were weanling DBA/2 males, the rate of tolerance induction was significantly increased over that observed when both donor and recipient were female. These studies suggest the following components in the mechanism of tolerance induction: a) proliferation of donor lymphoid cells which can be exaggerated by increasing graft vs host activity or by pretreatment with indifferent strong antigenic stimuli and b) a latent interval after cell transfer from donor to recipient and before attempted grafting during which it is proposed the donor cells proliferate in response to immune stimuli from the host. Observations presented here, and extended in the succeeding paper, suggest that it may be possible for immunologically competent cells to be committed to specific immune pathways to the exclusion of other pathways. The implications of these observations for transplantation theory and as a step toward development of immunologic tolerance in higher mammals are considered.