The role of donor-derived veto cells in nonmyeloablative haploidentical HSCT

Abstract

Allogeneic HSCT offers a route for achieving immune tolerance via mixed chimerism and remains the sole curative option for many nonmalignant, autoimmune and metabolic diseases. Present-day improvements of nonmyeloablative protocols are increasing the safety of HSCT, thereby widening the target population and resurrecting the interest of HSCT application as a platform for tolerance induction in organ transplantation. Using high cell doses of T-cell-depleted (TCD) grafts has been shown to circumvent graft-vs-host disease, leaving graft rejection as the main hindrance due to the robust host immunity that remains after mild conditioning. In this review we highlight the advantages of utilizing unique non-alloreactive 'veto' cells, such as anti-third party central memory CD8 T cells (Tcm), to enable induction of mixed chimerism after megadose HSCT under nonmyeloablative conditioning. Co-administration of HSCT with veto Tcm allows for induction of mixed chimerism that was successfully translated into immune tolerance, as demonstrated by engraftment of donor-type skin grafts. These veto Tcm cells have been shown to specifically eradicate anti-donor host T cells, through lymph-node sequestration and deletion, thus sparing host immunity and circumventing the need for life-long immunosuppression. Hence, data indicate that this treatment modality of combined TCD HSCT and adoptive transfer of Tcm veto cells under nonmyeloablative conditions may serve as a valuable tool for treatment of patients with a wide array of disorders such as hemoglobinopathies, autoimmune diseases and as a prelude for organ tolerance.

Donor bone marrow cells are essential for iNKT cell‐mediated Foxp3+ Treg cell expansion in a murine model of transplantation tolerance

“…Since Or‐Geva et al. reported that large numbers of hematopoietic stem cells (HSCs) or additional veto cells are required to overcome graft rejection after BMT in a model of reduced‐intensity conditions , a greater number of SPCs may be required to prevent rejection in our model.…”

iNKT cell activation plus T-cell transfer establishes complete chimerism in a murine sublethal bone marrow transplant model

“…Indeed, very strong veto activity was demonstrated for allogeneic T cells, particularly CD8 + T cell lines or clones; however, the utility of allogeneic CD8 + T cells for tolerance induction is limited owing to marked graft‐versus‐host reactivity. It was demonstrated that pre‐incubation of CD8 + T cells with CD3/CD28 particles or third‐party antigens in cytokine‐containing medium before infusion could attenuate the risk of graft‐versus‐host disease (GvHD), although these strategies have not yet been translated into human subjects.…”