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Engraftment of rat bone marrow and its role in negative selection of murine T cells in mice conditioned with a modified nonmyeloablative regimen
Author(s) -
Tomita Yukihiro,
Lee Lorri A.,
Sykes Megan
Publication year - 1994
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.1399-3089.1994.tb00056.x
Subject(s) - bone marrow , clonal deletion , cd8 , immunology , immune tolerance , biology , negative selection , t cell , cancer research , immune system , t cell receptor , biochemistry , genome , gene
We have recently demonstrated that xenogeneic (rat) bone marrow engraftment and donor‐specific tolerance can be induced in mice conditioned with a nonmyeloablative regimen consisting of administration of anti‐CD4, ‐CD8, ‐Thy‐1.2, and ‐NK1.1 mAbs on days ‐6 and ‐1, 3 Gy whole body irradiation (WBI) on day 0, and 7 Gy thymic irradiation on day 0, followed by injection of T cell‐depleted (TCD) F344 BMC. We have now investigated the mechanism of tolerance in these mixed xenogeneic chimeras by evaluating the capacity of rat bone marrow‐derived cells to induce clonal deletion of mouse T cell subsets. Both Vβ5 + and Vβ11 + murine T cell subsets were markedly depleted in peripheral blood of chimeras but not of normal B1O mice. These results demonstrate that rat molecules contribute to the ligand for negative selection of these Vβ families of mouse T cells, and that rat bone marrow‐derived cells participate in negative selection of the murine T cell repertoire, suggesting that clonal deletion is probably a major mechanism of tolerance induction in this model. In addition, based on results in a similar allogeneic BMT model, we hypothesized that, if sufficient quantities of mAbs were administered, thymic irradiation could be eliminated from this regimen without compromising the ability to induce mixed xenogeneic chimerism and tolerance. We now demonstrate induction of comparable multilineage mixed xenogeneic chimerism in animals receiving this conditioning regimen with or without 7 Gy thymic irradiation. Thus, if a similar approach were applied clinically, the potential toxicity of this regimen might be reduced further by the elimination of thymic irradiation.