NK cells produce high levels of IL‐10 early after allogeneic stem cell transplantation and suppress development of acute GVHD

Abstract

Natural killer (NK) cells rapidly reconstitute following allogeneic stem cell transplantation (allo‐SCT), at the time when alloreactive T cell immunity is being established. We investigated very early NK cell reconstitution in 82 patients following T cell‐depleted allo‐SCT. NK cell number rapidly increased, exceeding T cell reconstitution such that the NK:T cell ratio was over 40 by day 14. NK cells at day 14 (NK‐14) were donor‐derived, intensely proliferating and expressed chemokine receptors targeted to lymphoid and peripheral tissue. Spontaneous production of the immunoregulatory cytokine IL‐10 was observed in over 70% of cells and transcription of cytokines and growth factors was augmented. NK‐14 cell number was inversely correlated with the incidence of grade II‐IV acute graft versus host disease (GVHD). These findings reveal that robust reconstitution of immunoregulatory NK cells by day 14 after allo‐SCT is an important determinant of the clinical outcome, suggesting that NK cells may suppress the development of the T cell‐mediated alloreactive immune response through production of IL‐10.

Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post-transplant

“…They produce interferon (IFN)-g, perforin and granzyme [1]. A robust reconstitution of immunoregulatory NK cells by day 14 after allogeneic stem cell transplantation is an important determinant of clinical outcome, and it has been suggested that NK cells may suppress the development of the T cell-mediated alloreactive immune response through production of IL-10 [4]. A robust reconstitution of immunoregulatory NK cells by day 14 after allogeneic stem cell transplantation is an important determinant of clinical outcome, and it has been suggested that NK cells may suppress the development of the T cell-mediated alloreactive immune response through production of IL-10 [4].…”

“…However, there is increasing evidence for immunoregulatory NK cells that might mediate immune responses by secretion of interleukin (IL)-10, IL-4 and transforming growth factor (TGF)-b and/or might be responsive to these particular cytokines [2][3][4][5]. A robust reconstitution of immunoregulatory NK cells by day 14 after allogeneic stem cell transplantation is an important determinant of clinical outcome, and it has been suggested that NK cells may suppress the development of the T cell-mediated alloreactive immune response through production of IL-10 [4]. In a co-culture system, the interaction between macrophages and endometrial stromal cells was shown to down-regulate cytotoxicity of NK cells, possibly by stimulating the secretion of IL-10 and TGF-b [6].…”

Natural killer cells in patients with hematologic malignancies, solid tumors and in recipients of hematopoietic stem cell transplantation

“…Examples of non-speci ic adoptive immunotherapies include: CD3/CD28-activated DLIs; lymphokine-activated killer cells; anti-CD3-activated killer cells; tumor-in iltrating lymphocytes; in vitro-generated or selected tumor cytotoxic T lymphocytes; γ/δ-T cells; and NK cells [26]. However, NK cells are attractive candidates for adoptive cellular therapy in patients with HMs and solid tumors, as well as in recipients of allogeneic HSCT as they enhance GVT/GVL effects without causing GVHD [1,26,97,[169][170][171][172][173][174].…”

“…NK cells in HSCT: Allogeneic HSCT has revolutionized the treatment of HMs, but the use of this potentially curative therapy is limited by: GVHD, infections and relapse of the primary disease [27,106,170,232]. Relapse of HM remains the leading cause of treatment failure of allogeneic HSCT [26,32].…”

“…Enhancement of GVL without increasing the incidence of GVHD can be achieved by adopting the following maneuvers: optimal donor selection, optimal conditioning therapy, administration of GVHD prophylaxis, and administration of T-cells and donor-derived NK cells which are amenable to ex vivo manipulation and clinical manufacture [106]. Studies have shown that: augmentation of T-cell alloreactivity may be in luenced by NK cells in recipients of T-cell deleted allografts, and while immunosuppression with sirolimus and expansion of T-regulatory cells may decrease the incidence of acute GVHD by suppressing the development of T-cell mediated alloreactivity [170,237,238].…”