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NK Cells in Transplantation

Adenugba, Akinbami PhD1

doi: 10.1097/TP.0000000000001914
In View: eResources

1 Department of Surgery, University Hospital Regensburg, Regensburg, Germany.

Received 8 August 2017. Revision received 9 August 2017.

Accepted 10 August 2017.

The author declares no funding or conflicts of interest.

Correspondence: Akinbami Adenugba, PhD, Department of Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee-11, 93053 Regensburg, Germany. (

Natural killer (NK) cells are a component of the innate immune system that use a combination of activating and inhibiting receptors specific for HLA class I molecules to differentiate between autologous and allogeneic cells, thereby controlling their activation in response to foreign tissues [A]. Once activated, NK cells produce cytotoxic effector molecules without the need for priming by antigen presenting cells. This process takes place before the engagement of adaptive immune system. Recent studies in mice have shown that NK cells can undergo clonal expansion to create innate memory, analogous to memory responses of the adaptive immune system1 [B]. NK cells are one of the first leucocyte populations to be reconstituted after hematopoietic stem cell transplantation (HSCT).2 More rapid reconstitution of NK cells in patients treated for hematological malignancies was associated with superior outcomes, because patients with more than 200 NK cells/μL by 1 month after autologous HSCT showed significant progression-free survival, although the overall survival rate did not change.3 Notably, these NK cells were later found to require a kind of education involving the interaction with recipient's HLA before they could attain full cytotoxic and cytokine production.4 The early transfer of unmodified NK cells from a haploidentical donor as a cell-based therapy5 was also correlated with a 37% improvement in a 2-year overall survival rate of high-risk acute myeloid leukemia patients.6 Coadministration of IL-2 with NK cell infusion or the prior activation of NK cells with IL-2 promoted the persistence of donor-versus-recipient NK cell alloreactivity.7,8





By comparison to HSCT, there are limited and conflicting mechanistic data on the role of NK cells in solid organ transplantation. Nevertheless, several lines of evidence point to a possible role of NK cells in determining outcomes after transplantation. Studies in liver transplant recipients comparing those requiring lifelong maintenance immunosuppression to patients developing tolerance revealed characteristic differences in their NK cells and δ1TCR+ T cell compartments.9 Similarly, donor NK cells isolated from the transplanted liver expressed markers that favor the migration to recipient’s lymph nodes, a finding with potential mechanistic relevance.10 NK cells may also contribute to the rejection of kidney and lung transplants.11 Infiltration of kidney allografts by cytotoxic CD56+ cells producing high amounts of granzyme A and B12 and interferon-gamma has been identified as a feature of acute rejections in kidney transplants.13 One mechanism by which interferon-gamma–producing NK cells may contribute to the rejection of liver allografts may operate through the initiation of inflammation that promotes T cell-mediated responses.14 Biopsies from lung transplant patients with obliterative bronchiolitis revealed an increase in the number of lung-resident NK cells, which was accompanied by a decrease in the number of NK cells present in peripheral blood. Hence, it is suggested that NK cells migrate from peripheral blood to the lung after activation, where they contribute to rejection.15 Nevertheless, the development of non-Hodgkin lymphoma, a well-recognized complication of immunosuppression, has been linked to a defect in NK cell maturation that reduces the production of perforin.16

Another critical issue concerning the role of NK cells in transplantation is whether donor NK cells will recognize HLA class I molecules17 via polymorphic inhibitory killer immunoglobulin (Ig)–like receptors (KIRs). A comprehensive list of human KIR genes can be found on the website of IMGT [C]. Recognition of HLA molecules as “nonself” by KIR receptors will trigger NK cell activation even if the difference is located on just 1 allele. Several studies into the role of KIR polymorphism in HSCT and solid organ transplantations have been conducted, producing conflicting results that have made it difficult to establish the role of KIRs in NK cell function in transplantation. Some, but not all, studies reported on a beneficial effect of matching KIR expression.18-21 HLA matching has been reported to contribute to ameliorated NK cell responses in patients with leukemia undergoing bone marrow transplantation,22,23 but not in those patients with a high-risk disease or those treated at later stages.24 Studies showing a benefit from HLA compatibility suggest that NK cells contribute to the prevention of rejection by dampening the activation of other immune cells.

Clearly, the role of NK cells during immune responses represents an emerging topic of clinical relevance. Future studies will need to define aspects of specificity, memory, and the communication of innate and adaptive immune cells.

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