Natural killer cell alloreactivity 10 years later

This article reviews the impact of natural killer (NK) cell alloreactivity on hematopoietic cell transplantation since it was first observed in haploidentical transplant recipients 10 years ago.

Research has established 'missing self-recognition' as the mechanism underlying NK cell-mediated graft-versus-leukemia effects in T-cell-depleted haploidentical hematopoietic cell transplantation and has clarified optimal transplantation protocols to harness NK cell alloreactivity.

In the past decade, clinical studies have shown that the benefits of donor-versus-recipient NK cell alloreactivity in haploidentical transplantation are triggered by specific human leukocyte antigen (HLA) class I mismatches. Donor HLA is crucial for driving NK cell education so that reconstituting NK cells mature as donor-tolerant and recipient-alloreactive. Transplantation of large doses of extensively T-cell-depleted hematopoietic grafts with no posttransplant immune suppression was found to be essential for development of NK cell alloreactivity. Clinical trials demonstrated that donor-versus-recipient NK cell alloreactivity is a key therapeutic element in haploidentical transplants for acute myeloblastic leukemia in adults and acute lymphoblastic leukemia in children. Moreover, in pilot studies, mature haploidentical NK cells were transiently transferred into lymphoablated patients with acute leukemia in remission. The results showed NK cell therapy may be a promising strategy for consolidating leukemia remission. In line with the notion that NK cell function is regulated by a balance between activating and inhibitory receptors, in the matched transplant setting, transplantation from donors possessing certain activating NK receptors (activating killer cell immunoglobulin-like receptors) appeared to protect from relapse and improved survival.