Crucial role of FLT3 ligand in immune reconstitution after bone marrow transplantation and high-dose chemotherapy

Abstract

IntroductionThe period of immune deficiency after high-dose chemotherapy and bone marrow (BM) transplantation (BMT) results in significant morbidity and mortality. 1 Whereas early recovery of innate immunity (granulocytes, monocytes/macrophages and natural killer [NK] cells) results in reconstitution of protective immunity against many bacterial pathogens, the levels of functional lymphocytes (components of adaptive immunity) frequently remain abnormal for many months or years. 2 Low levels of B cells and immunoglobulins, as well as reduced CD4 T cells, predispose transplant recipients to severe bacterial (such as Streptococcus pneumoniae or Haemophilus influenzae) and opportunistic viral infections (such as cytomegalovirus, EpsteinBarr virus, and herpes). 1,[3][4][5][6] Consequently, significant efforts have been pursued to develop more efficient means of accelerating immune recovery after BMT. Whereas the identification of granulocyte colony-stimulating factor and granulocyte/monocyte colony-stimulating factor has been used to successfully promote clinical granulocyte recovery, 7 no cytokine treatment has been developed to accelerate B-and T-cell reconstitution after myeloablation and BMT.The fms-like tyrosine kinase 3 (FLT3, also called Flk2) receptor and its ligand (FL) have been shown to play an important role in Tand particular B-cell development. [8][9][10][11] However, despite having extensively reduced B-cell progenitors, mature B cells are reduced to a much less extent in adult FL Ϫ/Ϫ 11 and Flk2 Ϫ/Ϫ 8 mice, suggesting a redundant role of FL in peripheral B-cell homeostasis. The role of FL in sustaining mature B cells in older mice when B-cell progenitors in the BM normally are reduced 12,13 has not, however, been investigated.Notably, patients undergoing chemotherapy-induced myeloablation and BMT have increased serum levels of FL, 14,15 initially thought to reflect an important role of FL in hematopoietic stem cell reconstitution after BMT. However, more recent studies in FL Ϫ/Ϫ mice suggest that FL is not important in regulation of hematopoietic stem cell numbers or function, but rather in early lymphoid development. 10,16 Thus, in the present study we explored whether FL might play an important role in B-and T-cell reconstitution after BMT and chemotherapy-induced myeloablation. Herein, we provide compelling evidence for a fundamental role of FL in regeneration of the B-cell compartment after myeloablation of adult recipients, and in line with this, an age-progressive loss of B-cell progenitors in adult FL Ϫ/Ϫ mice, ultimately resulting in depletion of conventional B cells. In contrast, the peripheral pool of B1 and marginal zone (MZ) B cells, derived from progenitors existing predominantly during fetal and early postnatal development, are sustained and expanded in a FL-independent manner. Materials and methods AnimalsMice deficient in FL expression on a pure C57BL/6 (CD45.2) background were generated as previously described. 9 FL Ϫ/Ϫ CD45.1 mice were obtained by cross breeding of FL Ϫ/Ϫ CD45.2 mice...

FLT3 receptor and ligand are dispensable for maintenance and posttransplantation expansion of mouse hematopoietic stem cells

“…13,38,39 Notably, compared with WT mice a reduction was observed in total PB reconstitution in Fl Ϫ/Ϫ mice at 16 weeks after transplantation (3.6-fold; Figure 2B). This was almost entirely due to a failure to regenerate primarily B cells and partially T cells in the absence of FL, in agreement with recent studies, 19,40 whereas myeloid reconstitution, representing the best measure of HSC activity because of the short half-life of the myeloid lineage, was not significantly reduced in peripheral blood ( Figure 2B) or in BM ( Figure 2C) of Fl Ϫ/Ϫ recipients. Furthermore, the regeneration of donor-derived LSKCD150 ϩ HSC compartment was not different in Fl Ϫ/Ϫ and WT recipients ( Figure 2D).…”

Macrophage colony-stimulating factor receptor marks and regulates a fetal myeloid-primed B-cell progenitor in mice

“…Previous studies have demonstrated that Flt3-Ligand-deficient mice have a reduction in B-cell progenitors in the E14.5 FL. 35 Here we reproduced this finding in Flt3 receptor-deficient (Flk2 2/2 ) mice, and found that although the FL cellularity was not affected (Figure 5B), the frequency of ProB cells was further and dramatically reduced in the E14.5 FL of Flk2 2/2 Csf1r 2/2 double-deficient embryos, when compared with Csf1r 2/2 and Flk2 2/2 single-deficient embryos ( Figure 5C). This finding supports that CSF1R and FLT3 have complementary and critical roles in regulation of the emergence of fetal B-cell progenitors.…”

Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development

“…This, however, does not rule out a more crucial role of FL in the GM lineage. In the case of B lymphopoiesis, FL has been shown to have a critical role in B-cell generation after BM transplantation, 42 becomes increasingly important with age, and-most notably IL-7-independent B lymphopoiesis-is strictly FL dependent. 10 Thus, further studies might better reveal conditions in which FL is critically involved in generation and regeneration of cells of the GM lineage.…”