Transplantation tolerance in nonhuman primates and humans

Area of Science:

• Immunology
• Transplantation immunology
• Regulatory T cell biology

Background:

• Nonmyeloablative bone marrow transplantation is explored for inducing organ allograft tolerance.
• Clinical studies focus on HLA-mismatched haploidentical renal allograft tolerance.
• Mechanisms involve regulatory T cells and deletion of donor-reactive T cells.

Purpose of the Study:

• To investigate mechanisms of organ allograft tolerance induced by nonmyeloablative bone marrow transplantation.
• To identify and track alloreactive T cell receptors (TCRs) and regulatory T cell (Treg) repertoires.
• To assess the efficacy of this protocol in nonhuman primates and patients.

Main Methods:

• Utilized high-throughput sequencing to identify and track alloreactive TCRs.
• Adapted sequencing methods to identify the donor-specific Treg repertoire.
• Analyzed T cell responses in patients and nonhuman primates undergoing transplantation.

Main Results:

• Transient chimerism and no graft-versus-host disease (GVHD) were observed in clinical studies.
• Early induction of donor-specific regulatory T cells and subsequent deletion of donor-reactive T cells were identified.
• Expansion of donor-specific Tregs correlated with tolerance induction in kidney transplant patients.
• Other organs (heart, lungs, liver) were less readily tolerated in nonhuman primates.

Conclusions:

• Nonmyeloablative bone marrow transplantation can induce renal allograft tolerance, with a key role for Tregs and T cell deletion.
• Transient chimerism alone is insufficient for tolerance of all organs.
• Adding recipient Tregs to protocols may enhance chimerism and reduce GVHD risk for broader organ tolerance.