Transplantation and innate immunity: the lesson of natural killer cells

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is largely employed for treating paediatric patients affected by many haematological conditions of both malignant and non-malignant origin, as well as by several hereditary disorders of the immune system and metabolism [1,2]. More than 40 years have elapsed since the first successful allo-HSCT, then performed using bone marrow (BM) cells [3,4], and through this procedure thousands of children have been cured of their original disease [1,2].All this long history has taught that the success of allo-HSCT is strictly dependent on the balance between the detrimental, sometimes fatal, attack of donor immune cells against recipient tissues (i.e. graft-versus-host disease, GVHD) and the favourable reaction of donor lymphocytes towards malignant cells (i.e. graft-versus-tumor, GVT, effect) and/or pathogens capable of causing life-threatening infections during the period of profound neutropenia and lymphopenia which follows the conditioning regimen. While in the context of classical allo-HSCT from an HLA-identical sibling large part of the GVT effect is related to the attack of donor T lymphocytes against non-shared minor histocompatibility antigens expressed on tumor cells, there is clear evidence that also a selective effect of donor innate immunity (i.e. not dependent from previous encounter with the antigen) can contribute to the eradication of the malignant clone [5]. The role played by the donor innate immunity has attracted the interest of the scientific community only in recent years, when significant advances in the use of allo-HSCT have occurred. In particular, while for many years an HLA-matched sibling was the only type of donor routinely employed, in the last decade, matched unrelated volunteers and unrelated umbilical cord blood (UCB) units are being largely utilized to transplant patients lacking an HLA-identical relative [6]. The most recent, and advanced, frontier of allo-HSCT is represented by t