Submitted April 17, 2006
Accepted April 25, 2006
Humoral immunity is the dominant barrier for allogeneic
bone marrow engraftment in sensitized recipients
Hong Xu, Paula M Chilton, Michael K Tanner, Yiming Huang, Carrie L Schanie, Mariano Dy-Liacco, Jun Yan, and Suzanne T Ildstad*
Institute for Cellular Therapeutics, University of Louisville, Kentucky, USA
James Graham Brown Cancer Center, University of Louisville, Kentucky, USA
* Corresponding author; email: stilds01{at}louisville.edu.
We have evaluated the relative contribution of the humoral and cellular arms of the immune response to bone marrow cells transplanted in 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 unsensitized 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 µl of serum from sensitized mice abrogated engraftment in secondary naive recipients. We found that T-cell-mediated immunity plays a secondary but still significant role in allorejection in sensitized recipients using µMT mice as recipients. Targeting of T-cells in sensitized B-cell-deficient µMT mice enhanced alloengraftment. Moreover, both T- and B-cell tolerance were achieved in sensitized recipients when allochimerism was established, evidenced by acceptance of second donor skin grafts and loss of the circulating donor-specific Abs. These findings have important implications for management of sensitized transplant recipients as well as for xenotransplantation in which B-cell reactivity is a predominant barrier.
