Immune tolerance induction by nonmyeloablative haploidentical HSCT combining T-cell depletion and posttransplant cyclophosphamide

Abstract

Key Points• This study lays the foundation for the use of nonmyeloablative GVHD-free haploidentical HSCT.• This approach offers treatment of hematological diseases and a safe potential platform for cell therapy and organ transplantation.

Multi-lineage Lung Regeneration by Stem Cell Transplantation across Major Genetic Barriers

“…Clearly, there are two distinct barriers to these unique transplants. On one hand, rejection by the host must be overcome, which can be achieved in mice according to our protocol using 2 Gy TBI, plus post-transplantation Cy, and by 3 Gy TBI plus Cy in humans (Aversa et al, 2017). However, to make space in the lung niche so as to overcome stem cell competition with endogenous lung progenitors, irrespective of the immune rejection barrier, we need, as explained above, to combine NA with subsequent 6 Gy TBI 2 days later.…”

“…The protocol used was based on our recent work in haploidentical HSC transplantation (HSCT), which showed that a combination of T cell-depleted ''megadose'' HSCT with Cy administration following allogeneic BMT leads to marked chimerism upon treatment with a relatively safe non-myeloablative conditioning (Aversa et al, 2017). This approach was based on early studies by the John Hopkins group (Luznik et al, 2012) which showed that Cy is nontoxic to HSCs because of their high expression of the detoxifying enzyme aldehyde dehydrogenase, whereas activated alloreactive T cells are sensitive to deletion by this agent.…”

“…Notably, this approach for tolerance induction has been used in clinical transplantation of haploidentical HSCs in humans in elderly patients with multiple myeloma and Hodgkin's lymphoma, who cannot tolerate harsh conditioning protocols (Aversa et al, 2017). As such a mild protocol could be very attractive for induction of tolerance as part of lung progenitor transplantation, we attempted in the present study to use it as a platform for transplantation of allogeneic fetal lung progenitors in mice.…”

“…As described above, the immune debulking component of our conditioning protocol has already been used in the clinic to allow engraftment of T cell-depleted haploidentical HSCs (HSCT) in elderly patients with multiple myeloma or Hodgkin's lymphoma, who cannot tolerate harsh myeloablative conditioning (Aversa et al, 2017). This relatively mild and safe platform combining the power of megadose T cell-depleted HSCT with post-transplantation Cy treatment was shown to allow effective engraftment in these patients following conditioning with 3 Gy TBI without any risk for GvHD, while retaining sufficient host immunity to combat cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections during the early post-transplantation period.…”

“…Alternatively, a more attractive strategy could be offered if it were possible to induce durable immune tolerance toward donor antigens so as to avoid the need for chronic immune suppression, as was recently proposed for kidney transplantation in humans (Kawai et al, 2008(Kawai et al, , 2013Scandling et al, 2008;Sykes, 2018). Very recently, we described a relatively safe protocol for the induction of immune tolerance in patients with hematological malignancies on the basis of the use of T cell-depleted ''megadose'' hematopoietic progenitors in conjunction with high-dose posttransplantation cyclophosphamide (Cy) (Aversa et al, 2017). Recent reports in the literature indicating the presence of a significant level of hematopoietic progenitors in fetal lungs at embryonic day (E) 17.5 (Summer et al, 2005), and in the adult lung (Lefranç ais et al, 2017), indicated that these cells could potentially enable immune tolerance induction even in the absence of BM as a source for hematopoietic chimerism.…”