SHORT COMMUNICATION: CD3− CD56+ CD16+ Natural Killer Cells and Improvement of Pregnancy Outcome in IVF/ICSI Failure After Additional IVIG‐Treatment

Heilmann, L.; Schorsch, Martin; Hahn, Thomas von

doi:10.1111/j.1600-0897.2009.00790.x

Cited by 47 publications

(44 citation statements)

References 13 publications

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“…However, many clinical studies where IVIG were given to women suffering from recurrent spontaneous abortions, a noninflammatory condition, reported the opposite results, ie, decreased NK cell cytolytic activity and/or decreased number or percentage of circulating NK cells in treated women [35][36][37][38][39][41][42][43][44]. These discrepancies could be explained by the various conditions in which IVIG are used and, particularly, the existence or not of an inflammatory state.…”

Section: Discussionmentioning

confidence: 80%

“…Until recently, the possible role of NK cells in mediating the immunomodulatory effect of IVIG had never been mentioned. On the contrary, it was suggested that for preventing miscarriage, IVIG could act by inhibiting NK cells [35][36][37][38][39][40][41][42][43][44]. However, very recently, Chong et al [45] elegantly demonstrated that NK cells are necessary for the prevention of experimental autoimmune encephalomyelitis (EAE) by IVIG treatment.…”

Section: Discussionmentioning

confidence: 92%

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Role of Natural Killer Cells in Intravenous Immunoglobulin–Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg−/− (NSG) Mice

Gregoire-Gauthier

Fontaine

Benchimol

et al. 2015

Biology of Blood and Marrow Transplantation

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Although clinical studies have yet to demonstrate clearly the use of intravenous immunoglobulin (IVIG) for prevention of graft-versus-host disease (GVHD), their effective use in a xenogeneic mouse model has been demonstrated. We aimed to determine the mechanism of action by which IVIG contributes to GVHD prevention in a xenogeneic mouse model. NOD/LtSz-scidIL2rg(-/-) (NSG) mice were used for our xenogeneic mouse model of GVHD. Sublethally irradiated NSG mice were injected with human peripheral blood mononuclear cells (huPBMCs) and treated weekly with PBS or 50 mg IVIG. Incidence of GVHD and survival were noted, along with analysis of cell subsets proliferation in the peripheral blood. Weekly IVIG treatment resulted in a robust and consistent proliferation of human natural killer cells that were activated, as demonstrated by their cytotoxicity against K562 target cells. IVIG treatment did not inhibit GVHD when huPBMCs were depleted in natural killer (NK) cells, strongly suggesting that this NK cell expansion was required for the IVIG-mediated prevention of GVHD in our mouse model. Moreover, inhibition of T cell activation by either cyclosporine A (CsA) or monoclonal antihuman CD3 antibodies abolished the IVIG-induced NK cell expansion. In conclusion, IVIG treatment induces NK cell proliferation, which is essential for IVIG-mediated protection of GVHD in our mouse model. Furthermore, activated T cells are mandatory for effective IVIG-induced NK cell proliferation. These results shed light on a new mechanism of action of IVIG and could explain why the efficacy of IVIG in preventing GVHD in a clinical setting, where patients receive CsA, has never been undoubtedly demonstrated.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 92%

Role of Natural Killer Cells in Intravenous Immunoglobulin–Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg−/− (NSG) Mice

Gregoire-Gauthier

Fontaine

Benchimol

et al. 2015

Biology of Blood and Marrow Transplantation

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“…Total 42% of IVIGpatient or 34.9% ⁄ embryo transfer had a live born baby, and the live born rate per embryo was 16.6%. 81 High levels of pNK cells were found to predict biochemical pregnancy and spontaneous abortions with normal karyotype in the next pregnancy. Elevated CD56 + cells in pregnant women predict loss of karyotypically normal conceptus: a specificity of 87% and positive predictive value of 78%.…”

Section: Pro-inflammatory Cytokines Induce Coagulationmentioning

confidence: 99%

REVIEW ARTICLE: Immunological Modes of Pregnancy Loss

Kwak‐Kim

Park

Ahn

et al. 2010

American J Rep Immunol

108

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Citation Kwak‐Kim J, Park JC, Ahn HK, Kim JW, Gilman‐Sachs A. Immunological modes of pregnancy loss. Am J Reprod Immunol 2010During the implantation period, a significant portion of embryos are lost and eventually less than half of clinically established pregnancies end as full‐term pregnancies without obstetrical complications. A significant portion of these pregnancy losses is associated with immune etiologies, including autoimmune and cellular immune abnormalities. Although an autoimmune etiology such as anti‐phospholipid antibodies (APAs) has been reported to induce placental infarct and thrombosis at maternal–fetal interface, APAs induce inflammatory immune responses as well. Inflammatory immune responses, such as increased proportions of NK cells and Th1/Th2 cell ratios in peripheral blood are related to recurrent pregnancy losses and multiple implantation failures. Systemic and local inflammatory immune responses seem to be induced by activation of Toll‐like receptors with infectious agents, fetal cell debris, or gonadotropin‐releasing hormone agonist, etc. Cellular activation of T and NK cells leads to pro‐inflammatory cytokine storm and consequently, placental infarction and thrombosis. Potential application of anti‐inflammatory therapeutic agents for the prevention of pregnancy losses should be explored further.

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“…Studies have shown that pregnant and non-pregnant RM patients may have elevated levels of NK cells [17,18] + and CD16 + ) declined in women who gave birth after IVIg treatment [23]. In the future, identifying immune biomarkers that characterize RM patients who may benefit from IVIg therapy is worth investigating.…”

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confidence: 99%

Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics

Christiansen

2014

Clin Exp Immunol

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Recurrent miscarriage (RM) is the occurrence of three or more consecutive miscarriages before gestational week 20 and is a condition that affects 1-3% of women [1]. RM can be classified into two categories: primary RM (no prior live birth) or secondary RM (three or more consecutive miscarriages following a live birth). In addition to genetic and anatomical factors causing RM, many studies have suggested that signs of autoimmunity and dysregulation of natural killer (NK) cell immunity characterize women with RM.Approximately 25 years ago, the first pilot studies on the use of intravenous immunoglobulin (IVIg) for the treatment of RM were conducted and reported a live birth rate of 80-82% [2,3], which provided support to warrant further investigation in placebo-controlled trials. In 2006, a Cochrane review of IVIg treatment for RM in eight placebo-controlled trials with 303 RM patients was conducted, concluding that IVIg did not increase live birth rates when compared to placebo [odds ratio (OR) = 0·98; 95% confidence interval (CI) = 0·61-1·58] [4]. However, this review did not differentiate between primary and secondary RM patients. Separate analysis of these two subsets of RM patients may be necessary, as several studies have observed that secondary RM is a condition dominated by immunological risk factors when compared to primary RM, suggesting large heterogeneity between these two subgroups.Tumour necrosis factor (TNF)-α is a cytokine involved in the immune system's inflammatory response. Piosik et al. analysed peripheral blood samples of RM patients taken at gestational week 5, and found that TNF-α levels were increased significantly in secondary RM patients compared to primary RM patients (P = 0·042) [1]. This indicates that secondary RM is a condition with an increased proinflammatory response in early pregnancy.More evidence of the role of immunological factors in secondary RM has been reported in studies that have shown associations between secondary RM patients with specific maternal human leucocyte antigen (HLA) polymorphisms. Kruse et al. found that there was a significantly higher prevalence of the HLA-DRB1*03 allele in secondary RM patients compared with controls (OR = 1·8; 95% CI = 1·3-2·5) [5], whereas the allele was not increased in patients with primary RM. A previous pregnancy with a boy can be a risk factor for secondary RM. In general, maternal immune recognition of male-specific minor histocompatibility (HY) antigens expressed in male fetal and trophoblast cells is well tolerated, resulting in a live birth. However, pregnancy with a boy may prime the mother's HY immunity. Nielsen et al. found that maternal carriage of HLA class II alleles that restrict anti-HY antigen responses reduces the chances of a live birth in secondary RM patients with a firstborn boy compared with a firstborn girl (OR = 0·17; 95% CI = 0·1-0·4; P = 0·0001) [6]. In another study, the prevalence of a 14 base pair insertion in exon 8 of the HLA-G gene was found to be increased significantly in secondary RM patients, compa...

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SHORT COMMUNICATION: CD3⁻CD56⁺CD16⁺ Natural Killer Cells and Improvement of Pregnancy Outcome in IVF/ICSI Failure After Additional IVIG‐Treatment

Abstract: In a subgroup of RIF-patients with high level of CD56(+) CD16(+) NK-cells the additional application of IVIG leads to a favourable pregnancy outcome.

Cited by 47 publications

References 13 publications

Role of Natural Killer Cells in Intravenous Immunoglobulin–Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg−/− (NSG) Mice

Role of Natural Killer Cells in Intravenous Immunoglobulin–Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg−/− (NSG) Mice

REVIEW ARTICLE: Immunological Modes of Pregnancy Loss

Advances of intravenous immunoglobulin G in modulation of anti-fetal immunity in selected at-risk populations: science and therapeutics

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