Crucial role of FLT3 ligand in immune reconstitution after bone marrow transplantation and high-dose chemotherapy.
Almost 5 decades after the first clinical transplantations, delayed immune reconstitution remains a considerable hurdle in bone marrow transplantation, and the mechanisms regulating immune reconstitution after transplantation remain to be established. Whereas adult fms-like tyrosine kinase 3 ligand-deficient (FL(-/-)) mice have reduced numbers of early B- and T-cell progenitors, they sustain close to normal levels of mature B and T cells. Herein, we demonstrate that adult bone marrow cells fail to reconstitute B-cell progenitors and conventional B cells in lethally irradiated FL(-/-) recipients, which also display delayed kinetics of T-cell reconstitution. Similarly, FL is essential for B-cell regeneration after chemotherapy-induced myeloablation. In contrast, fetal progenitors reconstitute B lymphopoiesis in FL(-/-) mice, albeit at reduced levels. A critical role of FL in adult B lymphopoiesis is further substantiated by an age-progressive decline in peripheral conventional B cells in FL(-/-) mice, whereas fetally and early postnatally derived B1 and marginal zone B cells are sustained in a FL-independent manner. Thus, FL plays a crucial role in sustaining conventional B lymphopoiesis in adult mice and, as a consequence, our findings implicate a critical role of FL in promoting immune reconstitution after myeloablation and bone marrow transplantation.
Buza-Vidas
Natalija
N
Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
Cheng
Min
M
Duarte
Sara
S
Nozad
Hojjatollah
H
Jacobsen
Sten Eirik W
SE
Sitnicka
Ewa
E
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001402:B-Lymphocytes / Q000502:physiology; D016026:Bone Marrow Transplantation; D051799:Delayed Graft Function; D053686:Fetal Stem Cells; D007107:Immune System / Q000166:cytology / Q000502:physiology*; D038041:Lymphopoiesis; D008565:Membrane Proteins / Q000276:immunology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012038:Regeneration; D013601:T-Lymphocytes / Q000502:physiology
D000970:Antineoplastic Agents; D008565:Membrane Proteins; C084881:flt3 ligand protein