Favorable impact of natural killer cell reconstitution on chronic graft-versus-host disease and cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation

Kheav, Vissal David; Busson, Marc; Scieux, Catherine; Latour, Régis Peffault de; Maki, Guitta; Haas, Philippe; Mazeron, Marie‐Christine; Carmagnat, Maryvonnick; Masson, Emeline; Xhaard, Aliénor; Robin, Marie; Ribaud, Patricia; Dulphy, Nicolas; Loiseau, Pascale; Charron, Dominique; Socié, Gèrard; Toubert, Antoine; Moins‐Teisserenc, Hélène

doi:10.3324/haematol.2014.108407

Cited by 51 publications

(47 citation statements)

References 48 publications

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“…[33][34][35] The ability of donor T cells to enhance early NK-cell functional maturation in the clinic is unclear, but may be related to the provision of relevant cytokines such as IL-2, IL-12, or IL-18 from numerous sources. 36 This is in contrast to the impact of GVHD on NK-cell numbers, where a clear deficiency exists 37,38 and indeed NK-cell deficiency has been suggested as a biomarker for GVHD, 39 although mechanisms are hitherto unknown. Our data show that during GVHD, competition between alloreactive T cells and NK cells for IL-15 results in impaired reconstitution of donor NK cells, with most remaining being early immature NK cells that are known to survive at low levels of IL-15.…”

Section: Discussionmentioning

confidence: 58%

GVHD prevents NK-cell–dependent leukemia and virus-specific innate immunity

Bunting

Varelias

Souza-Fonseca-Guimarães

et al. 2017

Blood

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Key Points• Donor T cells compete for IL-15 with NK cells during GVHD, resulting in profound defects in NK-cell reconstitution.• GVHD impairs NK-celldependent leukemia and pathogen-specific immunity.Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graftversus-host disease (GVHD) and opportunistic infections. Natural killer (NK) cells mediate important innate immunity that provides a temporal bridge until the reconstruction of adaptive immunity. Here, we show that the development of GVHD after allo-BMT prevented NK-cell reconstitution, particularly within the maturing M1 and M2 NK-cell subsets in association with exaggerated activation, apoptosis, and autophagy. Donor T cells were critical in this process by limiting the availability of interleukin 15 (IL-15), and administration of IL-15/IL-15Ra or immune suppression with rapamycin could restore NK-cell reconstitution. Importantly, the NK-cell defect induced by GVHD resulted in the failure of NK-cell-dependent in vivo cytotoxicity and graft-versus-leukemia effects.Control of cytomegalovirus infection after allo-BMT was also impaired during GVHD. Thus, during GVHD, donor T cells compete with NK cells for IL-15 thereby inducing profound defects in NK-cell reconstitution that compromise both leukemia and pathogen-specific immunity. (Blood. 2017;129(5):630-642)

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Section: Discussionmentioning

confidence: 58%

GVHD prevents NK-cell–dependent leukemia and virus-specific innate immunity

Bunting

Varelias

Souza-Fonseca-Guimarães

et al. 2017

Blood

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“…22 Kheav et al demonstrated that a high NK cell count at month 3 was associated with a lower incidence of cGVHD. 23 Functional analysis further demonstrated that expanded CD56 bri NK cells retained IFNg production, which is known to promote antimicrobial immunity through the maturation of dendritic cells and the induction of Th1 responses. 24,25 Our previous study also found that rapid reconstitution of CD56 bri NK cells was associated with a lower TRM post-transplantation.…”

Section: Discussionmentioning

confidence: 99%

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

Zhao

Wang

et al. 2016

OncoImmunology

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Leukemia relapse and chronic graft-versus-host disease (cGVHD) are still major obstacles of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The numbers and activity of natural killer (NK) and Tregulatory cells can be increased post-transplantation by exposure to interleukin-2 (IL-2). We tested whether administering low-dose IL-2 would decrease leukemia relapse while reducing cGVHD after allotransplantation. This controlled, open-label randomized trial included 90 recipients of allotransplants. Subjects were randomized in a 1:1 ratio to either receive or not receive low-dose IL-2 during the early post-transplantation period. Patients in the IL-2 arm received a subcutaneous injection of low-dose IL-2 (1£10 6 U/d) on day 60 after allo-HSCT. IL-2 was administered daily for 14 d followed by a 14-d hiatus. The primary endpoint was the cumulative incidence of leukemia relapse (CIR). Three-year CIRs for the IL-2 arm and control arm were 23% (range 16-30%) and 11% (range 6-15%; p D 0.20), respectively. Minimal residual disease-positive (MRDC) tests were more common in the IL-2 arm compared to the control arm (36% [range 29-44%] vs. 15% [range 10-20%], p D 0.03). The cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) was lower in the IL-2 arm compared to the control arm (33% [range 26-39%] vs. 57% [range 49-64%), p D 0.02). Therefore, the 3-y GVHD-free and GVHD progression-free survival (GPFS) rates were significantly higher in the IL-2 arm compared to the control arm (47% [range 39-55%] vs. 31% [range 25-38%], p D 0.048). Blood Tregs, NK cells, and NK-cell cytotoxicity were increased in subjects in the IL-2 arm between 3 mo and 6 mo post-transplantation. Administration of low-dose IL-2 during the immediate post-transplantation period was associated with a higher GPFS but did not decrease the CIR.

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“…38 In the setting of HSCT, several studies have addressed the role of CMV on immune recovery. 35,[39][40][41][42] However, none of these have provided multivariate evidence of the dominant role of CMV in shaping immune reconstitution, compared to pre-transplant characteristics, and to occurrence of GvHD. Further studies on a larger set of healthy controls are required to compare this pattern to that associated to CMV seropositivity in immunocompetent hosts.…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation

et al. 2014

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Immune reconstitution after allogeneic stem cell transplantation is a dynamic and complex process depending on the recipient and donor characteristics, on the modalities of transplantation, and on the occurrence of graft-versushost disease. Multivariate methods widely used for gene expression profiling can simultaneously analyze the patterns of a great number of biological variables on a heterogeneous set of patients. Here we use these methods on flow cytometry assessment of up to 25 lymphocyte populations to analyze the global pattern of long-term immune reconstitution after transplantation. Immune patterns were most distinct from healthy controls at six months, and had not yet fully recovered as long as two years after transplant. The two principal determinants of variability were linked to the balance of B and CD8 + T cells and of natural killer and B cells, respectively. Recipient's cytomegalovirus serostatus, cytomegalovirus replication, and chronic graft-versus-host disease were the main factors shaping the immune pattern one year after transplant. We identified a complex signature of underand over-representation of immune populations dictated by recipient's cytomegalovirus seropositivity. Finally, we identified dimensions of variance in immune patterns as significant predictors of long-term non-relapse mortality, independently of chronic graft-versus-host disease.

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Favorable impact of natural killer cell reconstitution on chronic graft-versus-host disease and cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation

Cited by 51 publications

References 48 publications

GVHD prevents NK-cell–dependent leukemia and virus-specific innate immunity

GVHD prevents NK-cell–dependent leukemia and virus-specific innate immunity

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation

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