Transfer of Recipient MHC Proteins to Donor Cells (trogocytosis) During Xenograft Bone Marrow Transplantation

Hematopoietic cell transplantation (HCT) is a common procedure for eradicating blood cancers and other diseases that involves reconstitution of the bone marrow and regeneration of the immune system after full or partial myeloablative therapy. Despite the widespread use of HCTs, no studies have investigated the extent of cell fusion or trogocytosis between blood cells of the donor and recipient in the transplant setting despite the many reports of fusion between blood cells and non-blood cells in the stem cell literature. The potential transfer of mismatched Class 1 MHC proteins and other surface molecules between cells by trogocytosis as identified in our study, has implications for outcome after allogeneic hematopoietic cell transplantation, specifically with reduced intensity conditioning regimens. A complete understanding of the cellular and molecular mechanisms of trogocytosis and its effect on the graft-versus–tumor effect, graft-versus-host disease (GVHD) and graft rejection will provide new insights that are likely to improve results of allotransplantation.

Using human donor HSCs to engraft NOD/SCID mice resulted in 100% of surviving donor cells with recipient (mouse) MHC class 1 on their surface in high concentrations. We also report on the transfer of CD45, CD56, CD14, CD41 and class 2 MHC proteins. Furthermore we could also demonstrate that radiation pre-conditioning increases the rate of trogocytosis between blood cells. Mouse chimeras were generated between MHC mismatched strains allowing us to investigate trogocytosis between blood cells in a none radiation setting as well as potential trogocytosis between blood cells and organs.

Trogocytosis has been described as a method of antigen presentation during a normal immune reaction. The paradox we have encountered and explore in our study is the fact that the trogocytosis we observe in the transplantation setting occurs in ‘reverse’ to what is expected. It is expected that during HCT the donor cells would be targeted for destruction by either recipient NK cells or T-cells. Even in the xenograft transplant model using NOD/SCID mice the residual NK cells are known to cause graft rejection. The literature regarding standard blood cell rejection indicates that the recipient NK, T cells and APCs acquire donor MHC through direct mechanisms (intact allo-MHC on APCs) or indirect mechanisms (processed donor (allo) antigen + self-MHC) resulting in the rejection of the donor cells. What we actually observe is the reverse. All donor cells acquire recipient MHC class 1. This novel observation of unidirectional transfer of MHC implies that trogocytosis could protect against graft rejection while not reducing graft-versus-tumor activity, thereby creating an opportunity for increasing patient survival rates. Despite the extensive use of experimental and clinical allotransplantation, fusion or trogocytosis between blood cells has not been well documented. Moreover, trogocytosis has not been considered in the stem cell field mainly because its mechanism is unknown and its significance has been limited to antigen presentation and to T-cells involved in immune reactions.

Rogers:Insception Biosciences: Consultancy.