CD56 ^bright natural killer regulatory cells in filgrastim primed donor blood or marrow products regulate chronic graft- versus -host disease: the Canadian Blood and Marrow Transplant Group randomized 0601 study results

Abstract

Randomized trials have conclusively shown higher rates of chronic graft-versus-host disease with filgrastim-stimulated apheresis peripheral blood as a donor source than unstimulated bone marrow. The Canadian Blood and Marrow Transplant Group conducted a phase 3 study of adults who received either filgrastim-stimulated apheresis peripheral blood or filgrastim-stimulated bone marrow from human leukocyte antigen-identical sibling donors. Because all donors received the identical filgrastim dosing schedule, this study allowed for a controlled evaluation of the impact of stem cell source on development of chronic graft-versus-host disease. One hundred and twenty-one evaluable filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow patient donor products were immunologically characterized by flow cytometry and tested for their association with acute and chronic graft-versus-host disease within 2 years of transplantation. The immune populations evaluated included, regulatory T cells, central memory and effector T cells, interferon γ positive producing T cells, invariate natural killer T cells, regulatory natural killer cells, dendritic cell populations, macrophages, and activated B cells and memory B cells. When both filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow were grouped together, a higher chronic graft-versus-host disease frequency was associated with lower proportions of CD56bright natural killer regulatory cells and interferon γ-producing T helper cells in the donor product. Lower CD56bright natural killer regulatory cells displayed differential impacts on the development of extensive chronic graft-versus-host disease between filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow. In summary, while controlling for the potential impact of filgrastim on marrow, our studies demonstrated that CD56bright natural killer regulatory cells had a much stronger impact on filgrastim-stimulated apheresis peripheral blood than on filgrastim-stimulated bone marrow. This supports the conclusion that a lower proportion of CD56bright natural killer regulatory cells results in the high rate of chronic graft-versus-host disease seen in filgrastim-stimulated apheresis peripheral blood. clinicaltrials.gov Identifier: 00438958.

An early increase of CD56bright natural killer subset as dominant effect and predictor of response to extracorporeal photopheresis for graft‐versus‐host disease

“…13 Recently, a controlled study was undertaken evaluating the impact of stem cell source on the development of GVHD by assessing an array of immune subsets in filgrastimprimed donor products. 7 It was reported that lower levels of CD56 bright NK cells and interferon γ-producing CD4 cells resulted in a higher rate of cGVHD. Moreover, only one of these two immune subsets, a low level of CD56 bright NK cells, was also associated with the development of aGVHD.…”

“…A total of 32 patients referred for ECP were enrolled and treated for a median of 7 months (interquartile range [IQR] [4][5][6][7][8][9][10][11][12][13][14]. Eleven patients with aGVHD (3 late-onset cases) and 21 with cGVHD (including 5 overlap syndrome cases) were recruited.…”

“…1,5,6 In addition, at present no studies have analyzed whether ECP induces or promotes the proliferation of CD56 bright natural killer (NK) cells, a subset of cells that potentially has an impact on the rate of cGVHD development following alloHSCT. 7 We hypothesized that CD56 bright NK cells, a population whose reduction is associated with cGVHD, could increase in those individuals responding to ECP, and that their longitudinal dynamics may correlate with the grade of response. To test this hypothesis, we prospectively and closely evaluated patient immune peripheral blood subsets during the ECP treatment and correlated their behavior with clinical outcomes.…”

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

“…Various subsets of NK cells play speci ic functions in the development and manipulation of GVHD. Examples include: (1) NKG2A + NK cells play a crucial role during early stages of GVHD following HSCT; (2) NKG2Cexpressing NK cells have a direct role in the early control of CMV reactivation after allogeneic HSCT; (3) c-Kit -CD 27 -CD11b + NK cell population is capable of signi icantly dimishing GVHD in the setting of fully mismatched allogeneic HSCT by supporting GVL effects whilst providing protection against the development of GVHD; (4) CD56 bright NK regulatory cells have been shown to have a much stronger impact on ilgrastimstimulated PB apheresis products than on ilgrastimstimulated BM products as lower proportions of CD56 bright NK regulatory cells result in higher rate of chronic GVHD seen in ilgrastim-stimulated PB apheresis; (5) iNK cell dose in allogeneic grafts is associated with signi icant improvement in GVHD and GVHD-free progression-free survival; (6) failure to reconstitute iNK cells following allogeneic HSCT is associated with higher risk of primary disease relapse; (7) low doses of adoptively transferred donor CD4 + iNK cells protect from GVHD while preserving GVT effects as these cells inhibit proliferation of alloreactive T cells and promote robust expansion of donor T regs; and (8) higher doses of CD4 -iNKT cells in PB stem cell allografts are associated with protection from acute GVHD [21,22,121,[124][125][126][127].…”

The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease

“…Four studies associated a decrease in CD58bright NK cells with the development of cGVHD [41,72–74]. In one of the studies, CXCR3 + CD56 bright NK cells inversely correlated with CXCL10 as a significant biomarker panel for the diagnosis of cGVHD [41].…”