Rapamycin and MPA, But Not CsA, Impair Human NK Cell Cytotoxicity Due to Differential Effects on NK Cell Phenotype

Eissens, D. N.; Meer, Arnold van der; Cranenbroek, Bram van; Preijers, Frank; Joosten, Irma

doi:10.1111/j.1600-6143.2010.03242.x

Cited by 62 publications

(54 citation statements)

References 33 publications

(11 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hence, it is known that immature CD56 bright and NKG2A þ CD56 dim NK cells have a higher propensity to produce cytokines upon exogenous cytokine stimulation compared with more mature NK cells [1,7,10,[12][13][14]20,25,27]. Alternatively, cyclosporine A is also known to reduce target celleinduced IFN-g production and enhance cytokineinduced IFN-g production by human NK cells [32]. However, the latter conclusion remains controversial because another study showed that cyclosporine A did not alter cytokine production by NK cells [33].…”

Section: Discussionmentioning

confidence: 96%

Reconstitution of Natural Killer Cells in HLA-Matched HSCT after Reduced-Intensity Conditioning: Impact on Clinical Outcome

Pical-Izard

Crocchiolo

Granjeaud

et al. 2015

Biology of Blood and Marrow Transplantation

View full text Add to dashboard Cite

Recent advances in the development of reduced-intensity conditioning (RIC) have allowed a broader range of patients to access allogeneic hematopoietic stem cell transplantation (HSCT). Reconstitution of an effective immune system post-transplant, including natural killer (NK) cells, is critical for both tumor control and infectious disease control or prevention. The development and functions of NK cells in such settings remain elusive. Here we analyzed NK cell development in HLA-matched HSCT from related or unrelated donors, after RIC that included antithymocyte globulin (N = 45 patients). Our data reveal that NK cells quickly recover after RIC-HSCT, irrespective of donor type. Rapidly re-emerging NK cells, however, remain immature for more than 6 months. Effector functions resemble that of immature NK cells because they poorly produce IFN-γ and TNF-α in response to target cell stimulation, despite a rapid acquisition of degranulation ability and MIP-1β production. Strikingly, rapid reconstitution of cytokine production correlates with a lower relapse incidence (P = .01) and a better survival rate (P < .0001) at 1 year post-transplant, whereas degranulation capacity was associated with less relapse (P = .05). Our study demonstrates rapid quantitative reconstitution of the NK cell compartment despite administration of potent immune suppressive drugs as part of the conditioning regimen and after transplantation. However, there is a prolonged persistence of functional defects, the correction of which positively correlates with clinical outcome.

show abstract

Section: Discussionmentioning

confidence: 96%

Reconstitution of Natural Killer Cells in HLA-Matched HSCT after Reduced-Intensity Conditioning: Impact on Clinical Outcome

Pical-Izard

Crocchiolo

Granjeaud

et al. 2015

Biology of Blood and Marrow Transplantation

View full text Add to dashboard Cite

show abstract

“…Indeed, CsA pharmacodynamic effect on NK cells is distinct and allows NK cell cytotoxicity, 41 whereas it is impaired by MMF [42][43][44] or MTX. [45][46][47] Moreover, calcineurin inhibitors are the only immunosuppressive agents exerting their action by inhibiting interleukin-2 production.…”

Section: Discussionmentioning

confidence: 99%

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis

Bleyzac

Cuzzubbo

Rénard

et al. 2016

Bone Marrow Transplant

View full text Add to dashboard Cite

There is currently a major concern regarding the optimal immunosuppression therapy to be administered after hematopoietic stem cell transplantation (HSCT) to reduce both the toxicity of GvHD and the rate of relapse. We report the outcome of high-risk leukemia children transplanted with a new way of managing cyclosporine (CsA)-based GvHD prophylaxis. A total of 110 HSCT in 109 ALL or AML children who received CsA without mycophenolate or methotrexate in matched related as well as in matched or mismatched unrelated stem cell transplantation were included. CsA dosage regimens were individualized to obtain specific trough blood concentrations values. The incidences of grade I-II and III-IV acute GvHD were 69.1% and 1.8%, respectively, and 8.4% for chronic GvHD. GvHD was neither more frequent nor severe in unrelated than in related HSCT. GvHD occurred in 87% of patients with a mean CsA trough concentration ⩽ 120 ng/mL versus 43% with concentration 4120 ng/mL (Po 0.0001). Five-year disease-free survival (DFS) and overall survival were 78% and 83.6%, respectively. DFS was 76.9% for ALL and 80.4% for AML patients. There was no difference in DFS between matched siblings and matched unrelated or mismatched unrelated HSCT. DFS in patients with minimal residual disease (MRD) ⩾ 10 − 3 and in those with MRD o 10 − 3 before SCT was comparable. Our results indicate that a GvHD prophylaxis regimen based on CsA without mycophenolate or methotrexate is safe and effective whatever the donor compatibility is. These results suggest that GvL effect may be enhanced by this strategy of GvHD prophylaxis.

show abstract

“…In particular, TNF-a has been linked to increased replication of CMV (45). In vitro, TNF-a directly stimulates the CMV immediate-early promoter and can dramatically increase malignant transformations by triggering the NF-kB transcriptional activator, thus contributing to the immune failure seen in various malignancies (46). Our experimental evidence supports this possibility: intracellular cytokine production in NK cells differed quite notably between both OLT groups with de novo tumors, with NK cells of 2C + expressing mainly TNF-a and those of 2C 2 produced more IFN-g. Popivanova et al (47) showed that blocking TNF-a reduces carcinogenesis of this solid colorectal tumor, whereas IFN-g levels, as mediated by NK cells, predict long-term survival in patients with gastrointestinal stromal tumors after treatment with imatinib mesylate (48).…”

Section: Discussionmentioning

confidence: 99%

Expansion of CMV-Mediated NKG2C+ NK Cells Associates with the Development of Specific De Novo Malignancies in Liver-Transplanted Patients

Achour

Baychelier

Besson

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Solid cancers are a major adverse outcome of orthotopic liver transplantation (OLT). Although the use of chronic immunosuppression is known to play a role in T cell impairment, recent insights into the specificities of NK cells led us to reassess the potential modulation of this innate immune cell compartment after transplantation. Our extensive phenotypic and functional study reveals that the development of specific de novo noncutaneous tumors post-OLT is linked to unusual NK cell subsets with maturation defects and to uncommon cytokine production associated with the development of specific cancers. Remarkably, in CMV+ patients, the development de novo head/neck or colorectal tumors is linked to an aberrant expansion of NK cells expressing NKG2C and a high level of intracellular TNF-α, which impact on their polyfunctional capacities. In contrast, NK cells from patients diagnosed with genitourinary tumors possessed a standard immature signature, including high expression of NKG2A and a robust production of IFN-γ. Taken together, our results suggest that under an immunosuppressive environment, the interplay between the modulation of NK repertoire and CMV status may greatly hamper the spectrum of immune surveillance and thus favor outgrowth and the development of specific de novo tumors after OLT.

show abstract

Rapamycin and MPA, But Not CsA, Impair Human NK Cell Cytotoxicity Due to Differential Effects on NK Cell Phenotype

Cited by 62 publications

References 33 publications

Reconstitution of Natural Killer Cells in HLA-Matched HSCT after Reduced-Intensity Conditioning: Impact on Clinical Outcome

Reconstitution of Natural Killer Cells in HLA-Matched HSCT after Reduced-Intensity Conditioning: Impact on Clinical Outcome

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis

Expansion of CMV-Mediated NKG2C+ NK Cells Associates with the Development of Specific De Novo Malignancies in Liver-Transplanted Patients

Contact Info

Product

Resources

About