Crucial Role of FLT3 Ligand in Immune Reconstitution Following Bone Marrow Transplantation and High Dose Chemotherapy.

Almost five decades after the first clinical transplantations, delayed immune reconstitution mechanisms regulating immune reconstitution post-transplantation remain to be established. While early recovery of innate immunity (myeloid and NK cells) results in reconstitution of protective immunity against bacterial pathogens, the levels of functional lymphocytes frequently remain abnormal for months or years. Low levels of B cells, immunoglobulins and CD4 T cells, predispose transplant recipients to severe bacterial and viral infections. Whereas the identification of granulocyte colony stimulating factor (G-CSF) and granulocyte/monocyte stimulating factor (GM-CSF) has been used to successfully promote clinical granulocyte recovery, no cytokine treatment has been developed to accelerate B and T cell reconstitution following myeloablation and BMT. While adult fms-like tyrosine kinase 3 (FLT3) ligand (FL) 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 (McKenna, H.J. et al. Blood 2000, Sitnicka, E. et al. Immunity 2002, Sitnicka, E. et al. J Exp Med 2003).

Herein, we demonstrate that adult BM 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 following 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 finding implicate a critical role of FL in promoting immune reconstitution following myeloablation and BM transplantation.