Alloreactive Natural Killer Cells Initiate A Unique Cellular And Molecular Pathway That Greatly Accelerates Immune Reconstitution After Allogeneic Bone Marrow Transplantation

One outstanding issue in allogeneic hematopoietic transplantation is impaired immune reconstitution. As the primary site of T cell development, the thymus plays a key role in the generation of a strong yet self-tolerant adaptive immune response, essential in the face of the potential threat from pathogens or neoplasia. Allogeneic hematopoietic transplantation may acutely damage the thymus through the chemo or radiotherapy, antibody therapy of the conditioning regime, infections acquired by the immunosuppressed patient, and thymic graft versus host disease. To date, attempts to improve thymic reconstitution have been disappointing. Pre-clinical experiments and pilot clinical trials tried to assess the role of a variety of therapeutic approaches, such as transfer of lymphoid progenitor cells, thymic grafts, or enhancement of thymopoiesis by administration of hormonal or cytokine/growth factor-based therapies, such as sex-steroid blockade, and IL-7, IL-22, KGF, or Flt-3 ligand administration (reviewed in Chaudhry et al., Immunol Rev. 2016). In mouse MHC mismatched transplantation models (F1 H-2d/b→parent H-2b), we previously found that infusion of donor versus recipient alloreactive NK cells eradicated recipient-type lympho-hematopoietic lineage cells, thereby enhancing engraftment, protecting from GvHD and eradicating leukemia (Ruggeri et al., Science 2002). Here, in the same models we show that infusion of alloreactive NK cells greatly accelerates the post-hematopoietic transplant recovery of donor-type immune cells, i.e., dendritic cells (DCs) (p Disclosures No relevant conflicts of interest to declare.