Journal
CELLS
Volume 10, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/cells10051077
Keywords
conditioning; busulfan; G-CSF; plerixafor; HSC transplantation; immune reconstitution
Categories
Funding
- European Union's Horizon 2020 research and innovation programme [666908]
- Dutch Rare Diseases Foundation (ZZF, Zeldzame Ziekten Fonds)
- H2020 Societal Challenges Programme [666908] Funding Source: H2020 Societal Challenges Programme
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In the context of HSC transplantation, current conditioning regimens have severe side effects on bone marrow and the immune system, especially for SCID patients. Research aimed to improve the efficacy of conditioning by combining established therapeutic agents with busulfan, showing moderate potential in reducing toxicity and enhancing immune recovery.
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.
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