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Evidence for nonimmune mechanisms in the loss of hematopoietic chimerism in rat→mouse mixed xenogeneic chimeras
Author(s) -
Lee Lorri A.,
Sergio Justin J.,
Sykes Megan
Publication year - 1995
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/j.1399-3089.1995.tb00068.x
Subject(s) - bone marrow , haematopoiesis , immunology , chimera (genetics) , biology , clonal deletion , transplantation , transplantation chimera , myeloid , repopulation , cytotoxic t cell , immune system , t cell , cancer research , stem cell , medicine , hematopoietic cell , microbiology and biotechnology , biochemistry , t cell receptor , in vitro , gene
We have recently described a relatively nontoxic, nonmyeloablative conditioning regimen allowing engraftment of T cell‐depleted (TCD) rat bone marrow in mice, leading to a state of mixed xenogeneic chimerism and donor‐specific skin graft tolerance, apparently by a deletional mechanism. The conditioning regimen involves depletion of host T and NK cells with mAbs, followed by administration of 7 Gy thymic irradiation (TI) and 3 Gy whole body irradiation (WBI) prior to transplantation of TCD F344 rat bone marrow cells (BMC). Although the percentage of rat cells gradually declines over time post‐BMT in these animals, they demonstrate prolonged survival of donor‐specific rat skin grafts and an absence of anti‐rat antibody responses long after this decline is underway. We therefore hypothesized that the loss of rat hematopoietic repopulation may not be due to a loss of tolerance at the T cell or B cell level. We have now evaluated the effect of a repeat, late, donor marrow infusion on chimerism and tolerance. Treatment with 3 Gy WBI followed by TCD rat marrow infusion at 22 weeks following the original BMT led to a marked increase in rat cell repopulation of both myeloid and lymphoid lineages and prolonged the period of complete central and peripheral deletion of Vp5 + and Vβ11 + host T cells, which recognize endogenous (presumably mouse) superantigens presented by rat hematopoietic cells. Furthermore, the second marrow infusion did not induce a cytotoxic antibody response to rat marrow. Since these results suggested that the decline in rat chimerism in our model was not associated with a loss of T cell or B cell tolerance to the donor, we evaluated the possibility that a failure of NK cell tolerance led to the decline by comparing chimerism in animals receiving chronically NK cell‐depleting mAb and controls. Chronic NK depletion did not markedly enhance the level of rat repopulation in any lineage. Together, our results are most consistent with the interpretation that the gradual decline in rat repopulation in our chimeras reflects a competitive advantage of host hematopoietic cells over xenogeneic cells rather than immune‐mediated rejection, possibly due to species selectivity of cytokines and adhesion molecule interactions of hematopoietic progenitors and the marrow microenvironment. This host hematopoietic advantage might be counteracted by repeat donor‐specific marrow infusions.