B-Cell-Dependent Memory T Cells Impede Nonmyeloablative Mixed Chimerism Induction in Presensitized Mice

Abstract

Presensitization to HLA antigens limits the success of organ transplantation. The achievement of donor-specific tolerance via mixed chimerism could improve outcomes of transplantation in presensitized patients. In presensitized B-cell-deficient μMT B6 mice, we developed nonmyeloablative bone marrow transplantation (BMT) regimens that successfully tolerized presensitized T cells, achieving long-term (LT) multilineage chimerism and tolerance to donor-type skin. To apply these regimens in wild-type (WT) animals while avoiding antibody-mediated destruction of donor bone marrow cells, presensitized WT B6 mice were rested >2 years to allow alloantibody clearance. However, chimerism and tolerance were not reliably achieved in LT presensitized WT B6 mice in which alloantibody had declined to minimal or undetectable levels before BMT. Strong antidonor memory T-cell responses were detected in LT presensitized WT B6 mice after rejection of donor bone marrow (BM) occurred, whereas levels of alloantibody remained consistently low. In contrast, presensitized μMT B6 mice had diminished memory T-cell responses compared to WT B6 mice. These data implicate T-cell memory, but not alloantibody, in rejection of donor BM in LT presensitized WT mice.

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

“…This aspect does not seem to play a critical role in skin graft rejection, but it is generally considered a major problem for bone marrow transplantation in mice (34). For this reason we were not able to induce mixed chimerim in sensitized recipients with circulating donor-specific antibodies (not shown).…”

Desensitization for solid organ and hematopoietic stem cell transplantation

“…Evidence of the role of T-cell memory in rejection of bone marrow grafts was shown by Levesque et al . 169 in a murine model. Rejection of bone marrow grafts in allo-presensitized mice was reduced among B-cell-deficient mice, while no reduction in rejection was observed among wildtype mice whose alloantibody had cleared or decreased to minimal levels.…”

Non-Antibody Mediated Roles of B Cells in Allograft Survival

“…However, subsequent studies from our and other groups have shown that alloreactive T cell memory is impaired in B cell-deficient mice, suggesting a role for B cells beyond antibody production [35,53,54]. Alloreactive effector T cells developing in the absence of B cells contained fewer IL7Rα − expressing memory precursors, resulting in decreased memory T cell numbers and impaired memory recall [54].…”