Histocompatibility studies in a closely bred colony of dogs. V. Mechanisms of cellular adaptation in long-term DL-A identical radiation chimeras.

Abstract

20 Cooperstown beagles of known DL-A genotypes (B" dogs) were exposed to supralethal total body irradiation and received a bone marrow allograft from a DL-A identical donor (A" dog); the resulting chimeras have survived uneventfully for 882, 1466 days, with no evidence of secondary disease, and have been tolerant to kidney and skin allografts obtained from the donor of marrow. Treatment of "A" dogs with serum obtained from their long-term "B" chimeras had no significant effect upon the ability of the recipients to reject "B" skin allografts...

Induction of Allogeneic Unresponsiveness in Adult Dogs

“…The individual pedigree origin of each DLA haplotype available for testing within this colony has been used as a marker for the assessment of the allogeneic activity of non-DLA products under conditions of donor-recipient identity for products of the DLA complex. As noted in earlier reports (1)(2)(3)(4)(5), bone marrow allografts performed in DLA-identical dogs bearing DLA haplotypes derived from the same pedigree sources have regularly resulted in stable long-term chimerism with no GVH complications. The results observed in dogs bearing the same DLA haplotypes (i.e., haplotypes which type alike but are derived from different pedigree sources) depended upon the particular pedigree origins of the DLA haplotypes involved.…”

“…The observation that the state of allogeneic unresponsiveness observed in long-term radiation chimeras may be due to an active inhibition of the clonal proliferation required to produce antigen-reactive lymphocytes (5), and recent reports of the ability of suppressor T cells to produce allogeneic unresponsiveness in other species (28)(29)(30)(31) point, however, to the possibility that the states of allogeneic unresponsiveness associated with irradiation and marrow transplantation may be related to the active production of populations of suppressor cells in the tolerant host.…”

“…In earlier studies of the induction of allogeneic unresponsiveness by supralethal total body irradiation and bone marrow transplantation, recipients were allotted a recovery period of 43-120 days after reconstitution with bone marrow, before challenge with a test kidney allograft obtained from the donor of marrow (2). The resulting state of immunological tolerance extended to all donor tissues, including kidney, skin, heart, lung, liver, and pancreas (5), but was limited to tissues obtained from the donor of marrow (3)(4)(5). Such individual-specificity, taken together with the hazards of GVH disease in non-DLAidentical donor-recipient combinations, appeared to constitute a serious obstacle to further progress in the application of irradiation and bone marrow transplantation techniques to the production of allogeneic unresponsiveness in large mammalian species.…”

“…Challenge of'the recipients with kidney (1), heart (6), lung (7), liver (8,9), pancreas (8,9), or skin (3) allografts obtained from the donor of marrow within [3][4][5][6] mo after irradiation and marrow reconstitution has demonstrated, in addition, that such chimeras are unresponsive to other allogeneic tissues obtained from that particular donor. The individual specificity of this state of tolerance was shown by the ability of the chimeras to reject skinl grafts from other DLA-identical and(or) DLA-incompatible sources at a rate siimilar to that docuimented in uintreated dogs (3).…”

“…The selectively bred lines of' beagles miainitainied at The Mary Imogene Bassett Hospital in Cooperstowni, N. Y., have provided an animal resouirce in which the transplantation of' bonie marrow from genotypically DLA-idenitical donors into irradiated littermate and(or) nonlittermate dogs bearing DLA haplotypes derived from the same pedigree origins can regularly produce long-term stable chimerism, with no evidence of a graftversus-host response at any time after transplantation (1)(2)(3)(4)(5). Challenge of'the recipients with kidney (1), heart (6), lung (7), liver (8,9), pancreas (8,9), or skin (3) allografts obtained from the donor of marrow within [3][4][5][6] mo after irradiation and marrow reconstitution has demonstrated, in addition, that such chimeras are unresponsive to other allogeneic tissues obtained from that particular donor.…”