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Transplantation and innate immunity: the lesson of natural killer cells.

Bertaina A, Locatelli F, Moretta L - Ital J Pediatr (2009)

Bottom Line: Natural killer cells have been demonstrated to play a major role in mediating an anti-leukemia effect in patients given a T-cell depleted allogeneic hematopoietic stem cell transplantation from an HLA-haploidentical family donor.A recent study on high-risk pediatric acute lymphoblastic leukemia refractory to chemotherapy further highlighted the importance of donors with alloreactive natural killer cells in haploidentical hematopoietic stem cell transplantation, as it demonstrated that these cells can emerge starting from the fourth-fifth month after the allograft and persist for many months.This study represents a major breakthrough in the cure of otherwise fatal leukemias, providing information on the best criteria for choosing the optimal donor.

View Article: PubMed Central - HTML - PubMed

Affiliation: Paediatric Haematology/Oncology, University of Pavia, Foundation IRCCS Policlinico San Matteo, Pavia, Italy.

ABSTRACT
Natural killer cells have been demonstrated to play a major role in mediating an anti-leukemia effect in patients given a T-cell depleted allogeneic hematopoietic stem cell transplantation from an HLA-haploidentical family donor. In particular, donor-derived natural killer cells, which are alloreactive (i.e. KIR/HLA mismatched) towards recipient cells, significantly contribute to the eradication of leukemia blasts escaping the preparative regimen to transplantation. A recent study on high-risk pediatric acute lymphoblastic leukemia refractory to chemotherapy further highlighted the importance of donors with alloreactive natural killer cells in haploidentical hematopoietic stem cell transplantation, as it demonstrated that these cells can emerge starting from the fourth-fifth month after the allograft and persist for many months. This study represents a major breakthrough in the cure of otherwise fatal leukemias, providing information on the best criteria for choosing the optimal donor.

No MeSH data available.


Related in: MedlinePlus

Donor-derived alloreactive NK cells are able to kill leukaemia targets (this preventing disease recurrence), dendritic cells (DC) of the recipient (this preventing graft-versus-host disease recurrence) and cytotoxic T-lymphocytes of the recipient (this preventing graft rejection). Modified from Ruggeri et al. Science 2002.
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Figure 2: Donor-derived alloreactive NK cells are able to kill leukaemia targets (this preventing disease recurrence), dendritic cells (DC) of the recipient (this preventing graft-versus-host disease recurrence) and cytotoxic T-lymphocytes of the recipient (this preventing graft rejection). Modified from Ruggeri et al. Science 2002.

Mentions: One of the most intriguing clinical questions related to donor NK alloreactivity involves the observation that this peculiar GVT effect is completely separated by the occurrence of GVHD, this indicating that NK cells are able to kill leukaemia targets, while sparing normal tissues. Clearly, the selectivity of the GVT effect displayed by NK cells cannot be attributed to an attack directed against antigens with a restricted expression on tumor cells, as the ligands of NK-cell KIR inhibitory receptors are, as mentioned above, determinants of HLA-class I molecules which are expressed on all nucleated cells of the body. Thus, the preferential lysis of tumor cells by NK lymphocytes can be interpreted only in view of the role played by activatory signals. Indeed, there is large experimental evidence that killing of allogeneic cells also depends on the surface density of activating receptors on NK cells and on the expression of their ligands on target cells [16,17]. It is currently accepted that leukaemia targets express on their cell surface ligands able to efficiently engage activatory KIR receptors [18]. Support to this interpretation is provided by the observation that, in the animal model, alloreactive NK cells not only lyse leukaemia blasts, but also kill recipient dendritic cells (DC) and T lymphocytes [10], all these targets belonging to cells deriving from the haematopoietic tissue, which, evidently, has a particular capacity to render NK cells efficiently active. This biological observation translates into other two relevant clinical advantages, namely prevention of GVHD, whose occurrence is certainly facilitated by the role played by recipient DC [19], and prevention of graft rejection, which is a complication mainly due to the effect of recipient cytotoxic T lymphocytes surviving the preparative regimen (see also Figure 2 for details).


Transplantation and innate immunity: the lesson of natural killer cells.

Bertaina A, Locatelli F, Moretta L - Ital J Pediatr (2009)

Donor-derived alloreactive NK cells are able to kill leukaemia targets (this preventing disease recurrence), dendritic cells (DC) of the recipient (this preventing graft-versus-host disease recurrence) and cytotoxic T-lymphocytes of the recipient (this preventing graft rejection). Modified from Ruggeri et al. Science 2002.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806872&req=5

Figure 2: Donor-derived alloreactive NK cells are able to kill leukaemia targets (this preventing disease recurrence), dendritic cells (DC) of the recipient (this preventing graft-versus-host disease recurrence) and cytotoxic T-lymphocytes of the recipient (this preventing graft rejection). Modified from Ruggeri et al. Science 2002.
Mentions: One of the most intriguing clinical questions related to donor NK alloreactivity involves the observation that this peculiar GVT effect is completely separated by the occurrence of GVHD, this indicating that NK cells are able to kill leukaemia targets, while sparing normal tissues. Clearly, the selectivity of the GVT effect displayed by NK cells cannot be attributed to an attack directed against antigens with a restricted expression on tumor cells, as the ligands of NK-cell KIR inhibitory receptors are, as mentioned above, determinants of HLA-class I molecules which are expressed on all nucleated cells of the body. Thus, the preferential lysis of tumor cells by NK lymphocytes can be interpreted only in view of the role played by activatory signals. Indeed, there is large experimental evidence that killing of allogeneic cells also depends on the surface density of activating receptors on NK cells and on the expression of their ligands on target cells [16,17]. It is currently accepted that leukaemia targets express on their cell surface ligands able to efficiently engage activatory KIR receptors [18]. Support to this interpretation is provided by the observation that, in the animal model, alloreactive NK cells not only lyse leukaemia blasts, but also kill recipient dendritic cells (DC) and T lymphocytes [10], all these targets belonging to cells deriving from the haematopoietic tissue, which, evidently, has a particular capacity to render NK cells efficiently active. This biological observation translates into other two relevant clinical advantages, namely prevention of GVHD, whose occurrence is certainly facilitated by the role played by recipient DC [19], and prevention of graft rejection, which is a complication mainly due to the effect of recipient cytotoxic T lymphocytes surviving the preparative regimen (see also Figure 2 for details).

Bottom Line: Natural killer cells have been demonstrated to play a major role in mediating an anti-leukemia effect in patients given a T-cell depleted allogeneic hematopoietic stem cell transplantation from an HLA-haploidentical family donor.A recent study on high-risk pediatric acute lymphoblastic leukemia refractory to chemotherapy further highlighted the importance of donors with alloreactive natural killer cells in haploidentical hematopoietic stem cell transplantation, as it demonstrated that these cells can emerge starting from the fourth-fifth month after the allograft and persist for many months.This study represents a major breakthrough in the cure of otherwise fatal leukemias, providing information on the best criteria for choosing the optimal donor.

View Article: PubMed Central - HTML - PubMed

Affiliation: Paediatric Haematology/Oncology, University of Pavia, Foundation IRCCS Policlinico San Matteo, Pavia, Italy.

ABSTRACT
Natural killer cells have been demonstrated to play a major role in mediating an anti-leukemia effect in patients given a T-cell depleted allogeneic hematopoietic stem cell transplantation from an HLA-haploidentical family donor. In particular, donor-derived natural killer cells, which are alloreactive (i.e. KIR/HLA mismatched) towards recipient cells, significantly contribute to the eradication of leukemia blasts escaping the preparative regimen to transplantation. A recent study on high-risk pediatric acute lymphoblastic leukemia refractory to chemotherapy further highlighted the importance of donors with alloreactive natural killer cells in haploidentical hematopoietic stem cell transplantation, as it demonstrated that these cells can emerge starting from the fourth-fifth month after the allograft and persist for many months. This study represents a major breakthrough in the cure of otherwise fatal leukemias, providing information on the best criteria for choosing the optimal donor.

No MeSH data available.


Related in: MedlinePlus