Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival

Malard, Florent; Labopin, Myriam; Chevallier, Patrice; Guillaume, Thierry; Duquesne, Alix; Rialland, Fanny; Derenne, Sophie; Péterlin, Pierre; Leaute, A.G. Chartois; Brissot, Éolia; Grégoire, Marc; Moreau, Philippe; Saas, Philippe; Gaugler, Béatrice; Mohty, Mohamad

doi:10.1182/blood-2015-12-688739

Cited by 47 publications

(38 citation statements)

References 37 publications

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“…It is noteworthy that the number of invariant natural killer T cells within the graft has also been shown to be associated with improved progression free survival. 24 The mechanisms that might underlie this association are unclear at the current time. The most straightforward explanation is that donor NK cells have a direct lytic activity against residual tumor cells within the patient.…”

Section: Discussionmentioning

confidence: 97%

The number of CD56dim NK cells in the graft has a major impact on risk of disease relapse following allo-HSCT

et al. 2017

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Key Points• A stem cell graft NK cell dose below 6.3 3 10 6 cells per kg associates with risk of disease relapse following T-cell-depleted allo-HSCT.• Clinical outcomes of patients undergoing allo-HSCT may be improved by setting an NK cell threshold within donor stem cell grafts.The graft-versus-leukemia (GVL) effect of allogeneic hemopoietic stem cell transplantation (allo-HSCT) is mediated by the donor immune system and acts to decrease the rate of disease relapse. Although studies of posttransplant immune reconstitution have identified correlates of clinical outcome, the number and profile of mature immune cells infused with the stem cell graft is also likely to be an important determinant and has been relatively poorly studied.We characterized immune cells within the stem cell graft of 107 patients who underwent T-cell-depleted allo-HSCT and related this to clinical outcome. The number of natural killer (NK) cells and T cells that were infused varied markedly between patients, but T-cell dosewas not an important factor in subsequent outcome. In contrast, the number of NK cells was a powerful determinant of the risk of disease relapse. Patients who received an NK cell dose below the median level of 6.3 3 10 6 cells per kg had a relapse rate of 40% at 2 years posttransplant compared with only 6% for those whose stem cell graft contained a dose above this value. Analysis of NK subsets showed that this effect was mediated primarily by the CD56 dim population of mature effector cells and that high-level expression of the activatory protein DNAM on donor NK cells was also strongly protective. These observations offer important insights into the mechanism of GVL and suggest that optimization studies of the number of NK cells within the stem cell graft should be considered as a means to reduce disease relapse.

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Section: Discussionmentioning

confidence: 97%

The number of CD56dim NK cells in the graft has a major impact on risk of disease relapse following allo-HSCT

et al. 2017

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“…[11][12][13] Donor graft iNKTs content and their capacity to expand have been associated with GVHD risk. [14][15][16] Total lymphoid irradiation and antithymocyte globulin conditioning in allo-HSCT patients result in an increase in the ratio of host iNKTs to conventional CD4 1 /CD8 1 T cells, which can reduce aGVHD in murine models and patients. 17,18 Here, we used a murine model of cGVHD induced by GC reaction that results in antibody production, deposition, and triggering of monocytes/macrophages to cause systemic fibrosis to evaluate the role of iNKT in preventing and treating cGVHD.…”

Section: Introductionmentioning

confidence: 99%

Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells

Paz²,

Thangavelu³

et al. 2017

Blood

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• Low doses of donor iNKT infusion prevent and reverse murine cGVHD.• iNKT efficacy in treating established cGVHD is dependent on donor Treg expansion.Chronic graft-versus-host-disease (cGVHD) can cause multiorgan system disease, typically with autoimmune-like features, resulting in high mortality and morbidity caused by treatment limitations. Invariant natural killer T cells (iNKTs), a small population characterized by expression of a semi-invariant T-cell receptor, rapidly produce copious amounts of diverse cytokines on activation that exert potent immune regulatory function.Here, we show that iNKTs are significantly reduced in a cGVHD murine model that recapitulates several aspects of autoimmunity and organ fibrosis observed in patients with cGVHD. Low iNKT infused doses effectively prevented and, importantly, reversed established cGVHD, as did third-party iNKTs. iNKTs suppressed the autoimmune response by reducing the germinal center (GC) reaction, which was associated with an increase in total Tregs and follicular Tregs (Tfr) that control the GC reaction, along with pathogenic antibody production. Treg depletion during iNKT infusions completely abolished iNKT efficacy in treating cGVHD. iNKT cell interleukin 4 production and GC migration were critical to cGVHD reversal. In vivo stimulation of iNKT cells by a-galactosyl-ceramide was effective in both preventing and treating cGVHD. Together, this study demonstrates iNKT deficiency in cGVHD mice and highlights the key role of iNKTs in regulating cGVHD pathogenesis and as a potentially novel prophylactic and therapeutic option for patients with cGVHD. (Blood. 2017;129(23):3121-3125)

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“…These grafts are generally prepared by administration of granulocyte colony-stimulating factor (G-CSF) to healthy donors which mobilizes hematopoietic stem cells (HSCs) into the blood before cells are harvested by leukapheresis. The clinical advantage of using PBSCs compared to bone marrow grafts includes accelerated neutrophil engraftment, which increases the likelihood to engraft, and in addition PBSC allografts contain a much larger number of T-cells compared to bone marrow grafts, which has been correlated with better outcome (Malard et al 2016; Pabst et al 2007; Rezvani et al 2006). …”

Section: Introductionmentioning

confidence: 99%

Granulocyte colony-stimulating factor alters the systemic metabolomic profile in healthy donors

2016

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IntroductionPeripheral blood stem cells mobilized by granulocyte colony-stimulating factor (G-CSF) from healthy donors are commonly used for allogeneic stem cell transplantation. The effect of G-CSF administration on global serum metabolite profiles has not been investigated before.ObjectivesThis study aims to examine the systemic metabolomic profiles prior to and following administration of G-CSF in healthy adults.MethodsBlood samples were collected from 15 healthy stem cell donors prior to and after administration of G-CSF 10 µg/kg/day for 4 days. Using a non-targeted metabolomics approach, metabolite levels in serum were determined using ultrahigh performance liquid chromatography-tandem mass spectrometry and gas chromatography/mass spectrometry.ResultsComparison of the metabolite profiles of donors before and after G-CSF treatment revealed 239 metabolites that were significantly altered. The major changes of the metabolite profiles following G-CSF administration included alteration of several fatty acids, including increased levels of several medium and long-chain fatty acids, as well as polyunsaturated fatty acids; while there were lower levels of other lipid metabolites such as phospholipids, lysolipids, sphingolipids. Furthermore, there were significantly lower levels of several amino acids and/or their metabolites, including several amino acids with known immunoregulatory functions (methionine, tryptophan, valine). Lastly, the levels of several nucleotides and nucleotide metabolites (guanosine, adenosine, inosine) were also decreased after G-CSF administration, while methylated products were increased. Some of these altered products/metabolites may potentially have angioregulatory effects whereas others may suggest altered intracellular epigenetic regulation.ConclusionOur results show that G-CSF treatment alters biochemical serum profiles, in particular amino acid, lipid and nucleotide metabolism. Additional studies are needed to further evaluate the relevance of these changes in healthy donors.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-016-1139-x) contains supplementary material, which is available to authorized users.

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Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival

Cited by 47 publications

References 37 publications

The number of CD56dim NK cells in the graft has a major impact on risk of disease relapse following allo-HSCT

The number of CD56dim NK cells in the graft has a major impact on risk of disease relapse following allo-HSCT

Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells

Granulocyte colony-stimulating factor alters the systemic metabolomic profile in healthy donors

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