Abstract
In the context of hematopoietic stem cell (HSC) transplantation, conditioning with myelo- and immune-ablative agents is used to eradicate the patient’s diseased cells, generate space in the marrow and suppress immune reactions prior to the infusion of donor HSCs. While conditioning is required for effective and long-lasting HSC engraftment, currently used regimens are also associated with short and long-term side effects on extramedullary tissues and even mortality. Particularly in patients with severe combined immunodeficiency (SCID), who are generally less than 1-year old at the time of transplantation and often suffer from existing comorbidities. There is a pressing need for development of alternative, less toxic conditioning regimens. Hence, we here aimed to improve efficacy of currently used myeloablative protocols by combining busulfan with stem-cell niche-directed therapeutic agents (G-CSF or plerixafor) that are approved for clinical use in stem cell mobilization. T, B and myeloid cell recovery was analyzed in humanized NSG mice after different conditioning regimens. Increasing levels of human leukocyte chimerism were observed in a busulfan dose-dependent manner, showing comparable immune recovery as with total body irradiation in CD34-transplanted NSG mice. Notably, a better T cell reconstitution compared to TBI was observed after busulfan conditioning not only in NSG mice but also in SCID mouse models. Direct effects of reducing the stem cell compartment in the bone marrow were observed after G-CSF and plerixafor administration, as well as in combination with low doses of busulfan. Unfortunately, these direct effects on the stem population in the bone marrow were not reflected in increased human chimerism or immune recovery after CD34 transplantation in NSG mice. These results indicate moderate potential of reduced conditioning regimens for clinical use relevant for all allogeneic transplants.
Highlights
Allogeneic and gene-corrected autologous hematopoietic stem cell (HSC) transplantation may result in limited engraftment of progenitors without a preceding conditioning regimen due to the occupation of bone marrow (BM) and thymic niches by host cells, which results in incomplete graft function, immune reconstitution and cure [1]
The standard preconditioning method in mice for hematopoietic stem cell (HSC) transplantation is total body irradiation (TBI), varying the irradiation dose depending on the mouse strain
T-cell development in the thymus including all development stages was comparable between busulfan- and TBI-conditioned mice (Figure 1D), the T-cell output in Peripheral blood (PB) at 20 weeks after transplantation was higher for busulfan-conditioned mice (Figure 1E)
Summary
Allogeneic and gene-corrected autologous hematopoietic stem cell (HSC) transplantation may result in limited engraftment of progenitors without a preceding conditioning regimen due to the occupation of bone marrow (BM) and thymic niches by host cells, which results in incomplete graft function, immune reconstitution and cure [1]. Conditioning contributes to an improved HSC transplantation outcome by increasing HSC engraftment, immune chimerism and immune function and by reducing the risk of graft rejection, it may have a negative impact on patient well-being due to short-term and long-term treatment-related morbidity and mortality [2,3]. Busulfan is used as a conditioning agent prior to HSC transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells (HSPCs) [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
