A Review of Cyclophosphamide-Induced Transplantation Tolerance in Mice and Its Relationship With the HLA-Haploidentical Bone Marrow Transplantation/Post-Transplantation Cyclophosphamide Platform.

Hisanori Mayumi

doi:10.3389/fimmu.2021.744430

Abstract

The bone marrow transplantation (BMT) between haplo-identical combinations (haploBMT) could cause unacceptable bone marrow graft rejection and graft-versus-host disease (GVHD). To cross such barriers, Johns Hopkins platform consisting of haploBMT followed by post-transplantation (PT) cyclophosphamide (Cy) has been used. Although the central mechanism of the Johns Hopkins regimen is Cy-induced tolerance with bone marrow cells (BMC) followed by Cy on days 3 and 4, the mechanisms of Cy-induced tolerance may not be well understood. Here, I review our studies in pursuing skin-tolerance from minor histocompatibility (H) antigen disparity to xenogeneic antigen disparity through fully allogeneic antigen disparity. To overcome fully allogeneic antigen barriers or xenogeneic barriers for skin grafting, pretreatment of the recipients with monoclonal antibodies (mAb) against T cells before cell injection was required. In the cells-followed-by-Cy system providing successful skin tolerance, five mechanisms were identified using the correlation between super-antigens and T-cell receptor (TCR) Vβ segments mainly in the H-2-identical murine combinations. Those consist of: 1) clonal destruction of antigen-stimulated-thus-proliferating mature T cells with Cy; 2) peripheral clonal deletion associated with immediate peripheral chimerism; 3) intrathymic clonal deletion associated with intrathymic chimerism; 4) delayed generation of suppressor T (Ts) cells; and 5) delayed generation of clonal anergy. These five mechanisms are insufficient to induce tolerance when the donor-recipient combinations are disparate in MHC antigens plus minor H antigens as is seen in haploBMT. Clonal destruction is incomplete when the antigenic disparity is too strong to establish intrathymic mixed chimerism. Although this incomplete clonal destruction leaves the less-proliferative, antigen-stimulated T cells behind, these cells may confer graft-versus-leukemia (GVL) effects after haploBMT/PTCy.

Highlights

The best results of human allogeneic BMT have been obtained when the donor is an HLA-matched sibling or an unrelated donor who is matched to the recipient at each of eight high-expression HLA molecules: both alleles at each of HLA-A, -B, -C and -DRB1
After we published the novel Cy-induced tolerance method, using a single bolus dosing of Cy, that can overcome skin allograft barriers in H-2 identical murine combinations [3], this method was re-evaluated in a mouse BMT model by Johns Hopkins Hospital group [4], and soon used for human BMT to cross HLA-haploidentical combinations [1, 2]
Mainly in H-2 identical strain combinations, the sequential five mechanisms of skin allograft tolerance consisting of: 1) the clonal destruction of antigen-stimulated-thusproliferating mature T cells with Cy; 2) the peripheral clonal deletion associated with immediate peripheral chimerism; 3) the intrathymic clonal deletion associated with intrathymic chimerism; 4) the delayed generation of Ts cells; and 5) the delayed generation of clonal anergy [8,9,10]

Summary

Introduction

The best results of human allogeneic BMT have been obtained when the donor is an HLA-matched sibling or an unrelated donor who is matched to the recipient at each of eight high-expression HLA molecules: both alleles at each of HLA-A, -B, -C and -DRB1. These results suggest that permanent tolerance to fully allogeneic skin grafts may be induced because mAb given before the stimulating cell injection reduces the number of reactive T cells in the recipient mice.

Results

Conclusion