Year: 2010
Type: article
Abstract: Impaired thymopoiesis contributes to immune deficiency following HSCT. Clinical data suggest that thymic insufficiency may contribute to graft-versus-host disease and infectious clearance. We have previously shown that androgen withdrawal enhances thymus renewal by thymic epithelial cell (TEC) proliferation, increased entry of thymic progenitors and accelerated thymocyte development. We now demonstrate that FMS-like tyrosine kinase 3 (Flt-3) enhances thymopoiesis in conjunction with androgen blockade. Flt-3 increases stem cell number (LSK, Lineage- Sca-1+ cKit+), B cell precursors (Lineage- Sca-1+IL-7ra+), and T cell directed stem cells (Lineage- Sca-1+ cKit+ CCR9+) in the marrow of older mice without altering thymic function. Immature granulocyte and dendritic cell precursors were also enriched in the marrow. In contrast, in young mice, Flt-3 increased the emigration of stem cells without altering the distribution of marrow cell populations. To test the effect of the Flt-3-treated marrow on thymic reconstitution, aged mice were pre-treated with lupron or saline and conditioned with 900 cGy radiation. One million congenic T-cell depleted marrow cells were adoptively transferred from Flt-3 treated or saline treated donors. Flt-3-treated marrow in combination with lupron led to the most rapid thymic reconstitution, nearly doubling total congenic thymocytes by 5 weeks post-transplant. Thymic subsets were increased including: CD4 single positive (2.67x), CD8 single positive (2.69 x), double positive (1.92x), and double negative subsets (1.59x) compared to saline-treated marrow and recipient controls. Thymocyte subsets and total numbers were significantly greater in lupron-treated hosts receiving Flt-3-treated marrow than in lupron-treated hosts receiving saline-treated marrow. In contrast, Flt-3-treated marrow transferred in the absence of lupron did not increase thymopoiesis. These data suggest that: T cell directed precursor number and precursor entry may be critical points of thymic regulation post-HSCT. By enhancing TEC proliferation, T precursor emigration, and thymocyte maturation via androgen withdrawal with lupron, it appears that precursor number becomes limiting. Flt-3 increases T directed precursors in the marrow thereby further enhancing thymic recovery. These data may present a clinical opportunity to improve thymic renewal following stem cell transplantation by Flt-3 treatment of donors and androgen withdrawal in hosts.
Authors: K.M. Williams, A.R. Moore, R.E. Gress
Institutions: National Institutes of Health, National Cancer Institute
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2071557541