Induction of transplantation tolerance in haploidenical transplantation under reduced intensity conditioning: The role of ex-vivo generated donor CD8+ T cells with central memory phenotype

Haploidentical hematopoietic stem cell transplantation (HSCT) offers the advantage of readily available family member donors for nearly all patients. A ‘megadose’ of purified CD34+ hematopoietic stem cells is used to overcome the host’s residual immunity surviving the myeloablative conditioning, while avoiding severe GVHD. However, the number of CD34+ cells that can be harvested is insufficient for overcoming the large numbers of host T cells remaining after reduced intensity conditioning (RIC). Therefore, combining a ‘megadose’ of CD34+ HSCT with other tolerizing cells could potentially support and promote successful engraftment of haploidentical purified stem cell transplantation under a safer RIC. One approach to address this challenge could be afforded by using Donor CD8 T cells directed against 3rd-party stimulators, bearing an ex-vivo induced central memory phenotype (Tcm). These Tcm cells,depleted of GVH reactivity, were shown to be highly efficient in overcoming host T cells mediated rejection and in promoting fully mismatched bone-marrow (BM) engraftment, in HSCT murine models. This is likely due to the marked lymph node homing of the Tcm, their strong proliferative capacity and prolonged persistence in BM transplant recipients. Thus, combining anti 3rd-party Tcm cell therapy with a ‘megadose’ of purified CD34+ stem cells, could offer a safer RIC protocol for attaining hematopoietic chimerism in patients with hematological diseases and as a platform for organ transplantation or cell therapy in cancer patients.

► The role of ‘mega dose’ stem cell transplants in tolerance induction and the mechanisms underlining deletion of anti-donor CTLp by CD34 cells or progeny of these cells at the early time period post transplant.
► The potential synergy of donor anti-3rd party CTLs with ‘mega dose’ stem cell transplants in tolerance induction, and the role of Fas-FasL and perforin-dependent mechanisms.
► The advantage in tolerance induction for anti-3rd party CTLs with central memory phenotypes, including evaluation of lymph node homing, post transplant expansion and long-term survival.
► The double benefit of anti-3rd party CTLs with central memory phenotype exhibiting not only marked enhancement of Hematopoietic stem cell allografting but also GVL reactivity against a variety of B cell malignancies in the absence of GVHD.