Humoral immunity is the dominant barrier for allogeneic bone marrow engraftment in sensitized recipients.

We evaluated the relative contribution of the humoral and cellular arms of the immune response to bone marrow cells transplanted into sensitized recipients. We report here for the first time that humoral immunity contributes predominantly to allosensitization. Although the major role for nonmyeloablative conditioning is to control alloreactive host T cells in nonsensitized recipients, strikingly, none of the strategies directed primarily at T-cell alloreactivity enhanced engraftment in sensitized mice. In evaluating the mechanism behind this barrier, we found that humoral immunity plays a critical role in the rejection of allogeneic marrow in sensitized recipients. Adoptive transfer of as little as 25 microL serum from sensitized mice abrogated engraftment in secondary naive recipients. With the use of microMT mice as recipients, we found that T-cell-mediated immunity plays a secondary but still significant role in allorejection. Targeting of T cells in sensitized B-cell-deficient microMT mice enhanced alloengraftment. Moreover, both T- and B-cell tolerance were achieved in sensitized recipients when allochimerism was established, as evidenced by the acceptance of second donor skin grafts and loss of circulating donor-specific Abs. These findings have important implications for the management of sensitized transplant recipients and for xenotransplantation in which B-cell reactivity is a predominant barrier.