Selective allodepletion: have we finally found the holy grail?

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment option for patients with hematologic malignancies and nonmalignant disorders of hematopoiesis. Outcomes of allogeneic HSCT have improved steadily over the decades [1]. However, significant challenges remain. One of these challenges is the so-called Holy Grail of stem cell transplantation immunology: to preserve the beneficial effects of donor T cells against the tumor and against pathogenswhile avoidingallogeneic graft-versus-host disease (GVHD) [2]. To find the Holy Grail, we must develop methods or treatments that selectively deplete Tcells that react against host alloantigens, yet preserve tumor-specific and pathogenreactive T cells. Experiments published by Ross et al. in this issue of Biology of Blood and Marrow Transplantation [3] suggest that post-transplantation cyclophosphamide (PTC), a novel form of GVHD prophylaxis, may do just that. PTC is celebrating its golden anniversary. In October 1963, Berenbaum and Brown reported that cyclophosphamide (Cy) treatment of rats prolonged the survival of skin allografts, and that graft survival was longest when the drug was given 1 to 3 days after, rather than before, transplantation [4]. The road to the use of PTC in allogeneic HSCT is long, but significant credit must be given to Hisanori Mayumi et al. in the laboratory of Kikuo Nomoto [5]. These investigators developed a method for establishing hematopoietic microchimerism and robust tolerance to minor histocompatibility antigens in mice by i.v. infusion of allogeneic spleen cells followed in 2 or 3 days by intraperitoneal administration of high-dose Cy [6]. They showed that a high dose of cells was required for tolerance induction, and that the dose and timing of Cy were critical to the outcome [7]. For example, tolerance and chimerismwere induced if the drugwere given on day 2 or 3 after cell infusion, but not if the drugwere given on day 1 or on day 4. Interestingly, Cy-induced tolerance was blocked by peritransplantation treatment of the recipient with cyclosporine A [8]. Finally, they showed that tolerance of the microchimeric donor cells was mediated initially by Cy-induced destruction of alloreactive host T cells, then by intrathymic clonal deletion of donor-reactive host cells, and