Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect

Farag, Sherif; Fehniger, Todd A.; Ruggeri, Loredana; Velardi, Andrea; Caligiuri, Michael A.

doi:10.1182/blood-2002-02-0350

Cited by 455 publications

(383 citation statements)

References 136 publications

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“…results in cytolytic responses against the recipient tumor cells and reduced risk of relapse ('missing self'). 8,[28][29][30] A similar phenomenon can also be observed in HLA-matched SCT for AML, when the donor expresses a KIR for which the ligand is missing in the patient ('missing ligand'). 27 Although it is appealing to incorporate the receptor-ligand model into the criteria for donor selection in HLA-matched SCT, recent findings in the haploidentical setting showed that this model is more complex as not only inhibitory KIR, but also certain activating KIR have an important function in the process of tumor cell recognition and eradication.…”

Section: Discussionmentioning

confidence: 85%

CD3+/CD19+-depleted grafts in HLA-matched allogeneic peripheral blood stem cell transplantation lead to early NK cell cytolytic responses and reduced inhibitory activity of NKG2A

et al. 2009

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Natural killer (NK) cells have an important function in the antitumor response early after stem cell transplantation (SCT). As part of a prospective randomized phase III study, directly comparing the use of CD3 þ /CD19 þ -depleted peripheral blood stem cell (PBSC) harvests with CD34 þ -selected PBSC harvests in allogeneic human leukocyte antigen-matched SCT, we here show that the use of CD3 þ /CD19 þ -depleted PBSC grafts leads to early NK cell repopulation and reconstitution of the CD56 dim and CD56 bright NK cell subsets, with concomitant high cytolytic capacity. In the CD34 group, this process took significantly longer. Moreover, in the CD3/19 group after reconstitution, a higher percentage of killer immunoglobulin-like receptor-positive NK cells was found. Although similar percentages of CD94-positive NK cells were found in both groups, in the CD34 group, almost all expressed the inhibitory CD94:NKG2A complex, whereas in the CD3/19 group, the inhibitory CD94:NKG2A and the activating CD94:NKG2C complex were equally distributed. This preferential development of NKG2C-expressing NK cells in the CD3/19 group was paralleled by a loss of NKG2A-mediated inhibition of NK cell degranulation. These results show that the use of CD3 þ /CD19 þ -depleted grafts facilitates strong NK cell cytolytic responses directly after SCT, and the rapid emergence of an NK cell receptor phenotype that is more prone to activation.

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Section: Discussionmentioning

confidence: 85%

CD3+/CD19+-depleted grafts in HLA-matched allogeneic peripheral blood stem cell transplantation lead to early NK cell cytolytic responses and reduced inhibitory activity of NKG2A

et al. 2009

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“…NK cells (CD56 ϩ ) are innate immune lymphocytes critical to host defense against invading infectious pathogens and malignant transformation through elaboration of cytokines and cytolytic activity (48). The role of NK cells in allograft rejection is uncertain.…”

Section: Discussionmentioning

confidence: 99%

GM-CSF Restores Innate, But Not Adaptive, Immune Responses in Glucocorticoid-Immunosuppressed Human Blood In Vitro

Lucas

Schuchmann³

et al. 2003

The Journal of Immunology

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Infection remains the major complication of immunosuppressive therapy in organ transplantation. Therefore, reconstitution of the innate immunity against infections, without activation of the adaptive immune responses, to prevent graft rejection is a clinically desirable status in transplant recipients. We found that GM-CSF restored TNF mRNA and protein expression without inducing IL-2 production and T cell proliferation in glucocorticoid-immunosuppressed blood from either healthy donors or liver transplant patients. Gene array experiments indicated that GM-CSF selectively restored a variety of dexamethasone-suppressed, LPS-inducible genes relevant for innate immunity. A possible explanation for the lack of GM-CSF to restore T cell proliferation is its enhancement of the release of IL-1βR antagonist, rather than of IL-1β itself, since exogenously added IL-1β induced an IL-2-independent Con A-stimulated proliferation of glucocorticoid-immunosuppressed lymphocytes. Finally, to test the in vivo relevance of our findings, we showed that GM-CSF restored the survival of dexamethasone- or cyclosporine A-immunosuppressed mice from an otherwise lethal infection with Salmonella typhimurium. In addition to this increased resistance to infection, GM-CSF did not induce graft rejection of a skin allotransplant in cyclosporine A-immunosuppressed mice. The selective restoration potential of GM-CSF suggests its therapeutic use in improving the resistance against infections upon organ transplantation.

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“…11, 67, 68; for review, see Refs. 3,62,69). Donor NK cells attack host hemopoietic cells but not other tissues.…”

Section: Nk Cell-based Immunotherapeutic Strategies Against Cancermentioning

confidence: 99%

“…N atural killer cells have been initially identified as a lymphoid population representing the 10 -20% of PBMC, able to lyse MHC class I (MHC-I) 3 -negative tumor and virus-infected cells and to orchestrate innate immunity of the organism. The majority of NK cells is localized in peripheral blood, lymph nodes, spleen, and bone marrow (1) but can be induced to migrate toward inflammation sites by different chemoattractants (2).…”

mentioning

confidence: 99%

NK Cells and Cancer

Zamai

Ponti

Mirandola

et al. 2007

The Journal of Immunology

261

199

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In this review, we overview the main features and functions of NK cells, focusing on their role in cell-mediated immune response to tumor cells. In parallel, we discuss the information available in the field of NK cell receptors and offer a wide general overview of functional aspects of cell targeting and killing, focusing on the recent acknowledgments on the efficacy of NK cells after cytokine and mAb administration in cancer therapy. Since efficacy of NK cell-based immunotherapy has been proven in KIR-mismatch regimens or in TRAIL-dependent apoptosis, the ability to manipulate the balance of activating and inhibitory receptors on NK cells and of their cognate ligands, as well as the sensitivity of tumor cells to apoptosis, opens new perspectives for NK cell-based immunotherapy.

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Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect

Cited by 455 publications

References 136 publications

CD3+/CD19+-depleted grafts in HLA-matched allogeneic peripheral blood stem cell transplantation lead to early NK cell cytolytic responses and reduced inhibitory activity of NKG2A

CD3+/CD19+-depleted grafts in HLA-matched allogeneic peripheral blood stem cell transplantation lead to early NK cell cytolytic responses and reduced inhibitory activity of NKG2A

GM-CSF Restores Innate, But Not Adaptive, Immune Responses in Glucocorticoid-Immunosuppressed Human Blood In Vitro

NK Cells and Cancer

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