Cytotoxic Function of Umbilical Cord Blood Natural Killer Cells: Relevance to Adoptive Immunotherapy

Abstract

Decreased graft-versus-host disease (GVHD), ease of accessibility, and sustained engraftment encourage the use of umbilical cord blood (UCB) as an alternative source to bone marrow for immune reconstitution in children with leukemia. Natural killer (NK) cells rapidly expand after stem cell transplantation and are important for regulating GVHD and providing graft-versus-leukemia (GVL) effects. This review highlights the phenotypic and functional differences between UCB NK cells and adult peripheral blood (APB) NK cells, and discusses the possible therapeutic benefit of using UCB NK cells for adoptive immunotherapy in leukemia. Alloreactive NK cells show potent cytotoxic activities against human leukocyte antigen (HLA)-nonidentical leukemic cells and reduce leukemia relapses. The higher numbers of NK progenitors in UCB makes it a convenient source for ex vivo expansion of UCB NK cells for posttransplant treatment. UCB NK cells readily respond to interleukin-15, which may greatly enhance their antitumor effect. Activation and expansion protocols for UCB NK cells are currently being developed.

Umbilical Cord Blood Natural Killer Cells, Their Characteristics, and Potential Clinical Applications

“…This lower activity could be explained by the fact that UCB NK cells have decreased expression of certain adhesion molecules on their surface such as CD2, CD11a, CD18, and CD62L (15, 16), decreased expression of CD16 (15), decreased expression of perforin and granzyme B (14, 23), and lower killer-cell immunoglobulin-like receptors (KIRs) expression together with a higher expression of inhibitory molecules such as NKG2A when compared to PB NK cells indicating an immature phenotype (14, 23). However, activation with cytokines such as IL-2 or IL-15 or the combination of IL-15 with IL-2 or IL-18 was able to restore or enhance their cytotoxicity to the levels observed for PB NK cells (14, 16, 23, 25, 29). Moreover, although the frequencies of NK cells present in UCB is greater than PB (14), low numbers of UCB NK cells are obtained as a result of the limited volume of an UCB unit, which is a major obstacle in obtaining sufficient numbers of NK cells for clinical application.…”

A novel three-dimensional stromal-based model forin vitrochemotherapy sensitivity testing of leukemia cells

“…[9] The ability of leukemia cells to establish self-protective niches in bone marrow is regulated by interactions between the stromal-secreted chemokine, stromal-derived factor 1α (SDF-1α), also known as CXCL12, and the receptor C-X-C chemokine receptor type 4 (CXCR4). [10] This SDF-1a-CXCR4 interaction attracts the circulating leukemia cells to bone marrow niches [11] in the same way it is used for homing of hematopoietic cells. [12] Targeting the CXCL12-CXCR4 pathway, for example, provides a novel mechanism to disrupt the interaction between stroma-leukemia cells and disrupt the protective microenvironment of the leukemia cells using CXC4 antagonists.…”

Neonatal Natural Killer Cell Function: Relevance to Antiviral Immune Defense

“…NK cells can perform antibody-dependent cellular cytotoxicity (ADCC) through CD16 [9] or directly exert their cytotoxic ability by the release of perforin and granzyme B [1, 3, 10]. NK cells also kill tumor and virus-infected cells by apoptosis, mediating through TNF-related apoptosis-inducing ligand (TRAIL) and FasL [11].…”