Post transplant persistence of host cells augments the intensity of acute graft-versus-host disease and level of donor chimerism, an explanation for graft-versus-host disease and rapid displacement of host cells seen following non-myeloablative stem cell transplantation?

Abstract

Although the use of non-myeloablative stem cell transplantation (NST) reduces the severity of graft-versus-host disease (GVHD), GVHD remains a major complication following allogeneic transplantation. Since following NST in comparison with myeloablative conditioning, higher proportions of host immunohematopoietic cells may persist while donor-derived alloreactive lymphocytes are being infused, thus possibly serving as host antigen presentation for continuous stimulation of donor T cells, we speculated that GVHD may be similarly amplified by conditioning followed by intentional administration of host cells. This hypothesis was tested in a preclinical animal model. Increased incidence of GVHD, higher mortality and increased levels of chimerism were observed in recipients reconstituted with host cells, particularly with non-irradiated spleen cells. Graft-versus-leukemia effect was not impaired by post transplant cell administration. These results suggest that GVHD may be amplified by recipient cell infusion using either irradiated or viable stimulatory host cells, thus possibly explaining in part higher than anticipated incidence of GVHD and rapid displacement of host cells and conversion to 100% donor type cells following NST. Administration of irradiated host antigen-presenting cells post transplantation may thus represent a potential approach for amplification of the alloreactive capacity of donor lymphocytes following stem cell transplantation.

Prophylaxis of acute GVHD: manipulate the graft or the environment?

“…39 Indeed, the persistence of host APCs may exacerbate GVHD after RIC transplants, 40 and overall the contribution of the regimen intensity to GVHD risk is only one of many factors. 41 …”

Measurement of antigen specific immune responses: 2006 update

“…The curative potential of allogeneic hematopoietic stem cell transplantation (SCT) for malignancies is not only due to direct antitumor effect of chemo(radio)therapy administered prior to transplantation, but also to elimination of residual malignant cells by alloreactive donor T cells in the transplant. This principle has been pioneered by Slavin (Jerusalem, IL) who highlighted the novel therapeutic options created by this insight (42). The main challenge is to retain this graft‐versus‐leukemia (GVL) reactivity whilst avoiding graft‐versus‐host reactivity which is a major cause of morbidity and mortality.…”