T Cell-Mediated Rejection of Human CD34+ Cells Is Prevented by Costimulatory Blockade in a Xenograft Model

Abstract

A xenograft model of stem cell rejection was developed by co-transplantating human CD34⁺ and allogeneic CD3⁺ T cells into NOD-scid ɣ-chain^null mice. T cells caused graft failure when transplanted at any CD34/CD3 ratio between 1:50 and 1:.1. Kinetics experiments showed that 2 weeks after transplantation CD34⁺ cells engrafted the marrow and T cells expanded in the spleen. Then, at 4 weeks only memory T cells populated both sites and rejected CD34⁺ cells. Blockade of T cell costimulation was tested by injecting the mice with abatacept (CTLA4-IgG1) from day -1 to +27 (group A), from day -1 to +13 (group B), or from day +14 to +28 (group C). On day +56 groups B and C had rejected the graft, whereas in group A graft failure was completely prevented, although with lower stem cell engraftment than in controls (P = .03). Retransplantation of group A mice with same CD34⁺ cells obtained a complete reconstitution of human myeloid and B cell lineages and excluded latent alloreactivity. In this first xenograft model of stem cell rejection we showed that transplantation of HLA mismatched CD34⁺ cells may be facilitated by treatment with abatacept and late stem cell boost.

Keywords: Abatacept; CD34; Rejection; Stem cell transplantation; T cell.