Protective role of bone marrow cells in controlling alloreactivity (2003)

In their article, Mathew and colleagues (1) provided evidence that regulation of alloimmune responses in the direction of graft-versus-host (GVH) reactivity after inoculation of donor bone marrow cells in an attempt to induce donor-specific unresponsiveness may be controlled by autologous donor-cell preparations. The authors have ignored numerous observations that could support their conclusions, derived from studies involving the induction of transplantation tolerance in mixed chimeras induced with nonmyeloablative conditioning. Starting in the 1970s, numerous articles documented that after nonmyeloablative total lymphoid irradiation, recipients can accept fully mismatched bone marrow allografts, thus resulting in permanent and donor-specific transplantation tolerance yet avoiding GVH disease (D) (2). In subsequent studies, it was shown that bone marrow cells can exert suppression of the in vitro mixed lymphocyte reaction (3). However, induction of tolerance in mixed chimeras was mediated primarily by antigen-dependent clonal deletion (4). However, this veto-like activity, also shown to be mediated by purified stem cells, is mediated primarily by CD8+ T lymphocytes, which can abrogate GVHD after bone marrow transplantation without abrogating chimerism (5). Taken together, suppression of alloreactivity by hematopoietic cells, predominantly CD8+ lymphocytes, and to a lesser extent other cell subsets such as stem cells, is probably the basic mechanism behind the tolerance process that is typical for mixed chimeras. Indeed, most likely, most recipients with undetectable or minimal proportions of circulating donor cells were not tolerant thus necessitating continuous treatment with immunosuppressive agents. In contrast to Miami’s nontolerant “micro-chimeras”, overtly mixed chimeras with higher proportions of donor hematopoietic cells after deletion of alloreactive cells are fully tolerant and can accept any donor-derived allograft indefinitely, skin graft included, using no posttransplant immunosuppression (2,4,6). Furthermore, we have previously documented that the induction of transplantation tolerance is not an all-or-none phenomenon. Whereas chimeras across the major histocompatibility complex with less than 20% donor-type hematopoietic cells with stable mixed chimerism and no GVHD may accept weakly immunogenic organs, such as stromal cells capable of creating donor-derived hematopoietic microenvironment and bone, such chimeras consistently reject full thickness skin allograft from the same donor (6). In contrast, mixed chimeras with >20% circulating donor hematopoietic cells accept consistently full thickness donor skin allografts indefinitely (6). In view of the above, attention of the Miami team should be drawn to the fact that although suppressive capacity of lymphocytes may be documented in vitro, establishment of in vivo transplantation tolerance to organ allografts may require much more effective methods for induction of more visible mixed chimerism because mere documentation of in vitro-specific immunosuppression may be an epiphenomenon that may suggest relative hyporesponsiveness but not predict true in vivo tolerance to organ allografts. Until a better method will be used for the induction of significant chimerism or alloantigen-specific clonal deletion, durable and consistent induction of transplantation tolerance is unlikely to be accomplished in clinical practice. Shimon Slavin, M.D.