B-cell-dependent memory T cells impede nonmyeloablative mixed chimerism induction in presensitized mice

Area of Science:

• Immunology
• Transplantation Biology
• Cellular Immunology

Background:

• Presensitization to human leukocyte antigen (HLA) antigens poses a significant barrier to successful organ transplantation.
• Donor-specific tolerance through mixed chimerism offers a potential strategy to overcome transplantation challenges in presensitized individuals.

Purpose of the Study:

• To investigate the role of T-cell memory versus alloantibody in the rejection of donor bone marrow (BM) in long-term presensitized mice.
• To evaluate nonmyeloablative bone marrow transplantation (BMT) regimens for achieving donor-specific tolerance in presensitized models.

Main Methods:

• Utilized B-cell-deficient μMT B6 mice and wild-type (WT) B6 mice, both presensitized to donor antigens.
• Administered nonmyeloablative BMT regimens.
• Assessed long-term multilineage chimerism, donor-specific skin tolerance, T-cell responses, and alloantibody levels.

Main Results:

• Successful chimerism and tolerance were achieved in presensitized μMT B6 mice.
• In long-term presensitized WT B6 mice, BMT failed to reliably establish chimerism and tolerance, despite low alloantibody levels.
• Strong anti-donor memory T-cell responses were observed in rejecting WT mice, while μMT mice showed diminished T-cell responses.

Conclusions:

• T-cell memory, rather than circulating alloantibody, is the primary factor responsible for the rejection of donor BM in long-term presensitized WT mice.
• These findings highlight T-cell memory as a critical target for improving transplantation outcomes in presensitized recipients.