IVIG induces apoptotic cell death in CD56dim NK cells resulting in inhibition of ADCC effector activity of human PBMC

Bunk, Sebastian; Ponnuswamy, Padmapriya; Trbic, A.; Mališauskas, Mantas; Anderle, Heinz; Weber, Alfred; Winkler, Anna M.; Butterweck, Harald Arno; Teschner, Wolfgang; Scheiflinger, Friedrich; Hermann, Corinna; Reipert, Birgit M.

doi:10.1016/j.clim.2018.10.018

Cited by 9 publications

(7 citation statements)

References 32 publications

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“…Indeed, several studies have shown that RPL women have measurable defects in peripheral T regulatory (T reg ) 47 ; women successfully treated with IVIg show increased peripheral T reg numbers as well as enhanced T reg activation status and suppressive function (Figure 2, 4). 48,49,50 While IVIg may improve regulatory adaptive responses through indirect effects such as pro-inflammatory cytokine 51 and complement neutralization (Figure 2, 5), 52 inhibition of antibody dependent cytotoxicity 45 and restoration of the anti-idiotype network, 53 other mechanisms implicating tolerogenic antigen-presenting cells (APC) have also recently been recently described. One proposed mechanism is through T regulatory cell epitopes (Tregitopes) which are highly conserved moieties contained within all IgG allotypes (Figure 2, 6).…”

Section: Methodsmentioning

confidence: 99%

“…IVIg mechanism of action. While human data suggests that IVIg treatment acts by neutralizing pathogenic anti‐HLA antibodies/autoantibodies 43 (Figure 1, 1), suppressing Th1 cytokine production and skewing towards a Th2 response 44 (Figure 2, 2), as well as by suppressing NK cell cytotoxicity (Figure 2, 3), 45,46 IVIg's ability to enhance adaptive regulatory responses has gained much interest in the last decade. Indeed, several studies have shown that RPL women have measurable defects in peripheral T regulatory (T reg ) 47 ; women successfully treated with IVIg show increased peripheral T reg numbers as well as enhanced T reg activation status and suppressive function (Figure 2, 4) 48,49,50 .…”

Section: Introductionmentioning

confidence: 99%

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Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss

Banjar

Kadour

Khoudja

et al. 2023

American J Rep Immunol

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Problem Recurrent pregnancy loss (RPL) affects up to 4% of couples attempting to conceive. RPL is unexplained in over 50% of cases and no effective treatments exist. Due to the immune system's pivotal role during implantation and pregnancy, immune‐mediated RPL may be suspected and immunomodulatory treatments like intravenous immunoglobulin (IVIg) have been administered but remain controversial. The goal of our study was to evaluate our center's 6 year‐outcomes and to develop a framework for IVIg use in RPL. Method of the study Retrospective, single‐center cohort study. All patients having received IVIg for unexplained RPL at the McGill Reproductive Immunology Clinic (MRIC) from January 2014 to December 2020 were included if maternal age was <42 years, body mass index (BMI) < 35 kg/m2, non‐smoker and having had ≥3 consecutive RPL despite previous treatment with aspirin and progesterone. IVIg 0.6–0.8 g/kg was given prior to conception and monthly during pregnancy until 16–20 weeks’ gestation. We compared IVIg treated patient's outcomes to a separate “natural history cohort”. This cohort was composed of patients consulting at the McGill recurrent pregnancy loss clinic and the MRIC over a 2‐year period (January 2020 to December 2021) with similar inclusion criteria as the treatment cohort but did not receive IVIg or other immunomodulatory treatments. The association of IVIg with outcomes (compared to no IVIg) was evaluated among the groups of patients with primary RPL and secondary RPL. The primary outcome was live birth rate (LBR), secondary outcomes included IVIg safety, obstetrical, and neonatal complications. Results Among 169 patients with unexplained RPL that were included in the study, 111 had primary RPL (38 exposed to IVIg and 83 controls) and 58 had secondary RPL (nine exposed to IVIG and 49 controls). Among patients with primary RPL (n = 111), the LBR was 64.3% (18/28) among patient exposed to IVIg compared to 43.4% (36/83) in controls (p = 0.079); regression analysis adjusting for BMI and number of previous miscarriages showed benefit favoring the use of IVIg (OR = 3.27, CI 95% (1.15–10.2), p = 0.03) when evaluating for live birth. In the subgroup of patients with ≥5 previous RPL and primary RPL (n = 31), IVIg was associated with higher LBR compared to control (10/15 (66.7%) vs. 3/16 (18.8%); p = 0.0113) but not the in the sub‐group of patients with <5 miscarriages and primary RPL (8/13 (61.5%) vs. 33/67 (49.3%); p = 0.548). IVIG treatment did not improve LBR in patients with secondary RPL in our study (3/9 (33.3%) vs. 23/49 (47%); p = 0.495). There were no serious adverse events in the IVIg treatment group, obstetrical/neonatal complications were similar between groups. Conclusion IVIg may be an effective treatment for patients with RPL if appropriately used in specific groups of patients. IVIg is a blood product and subject to shortages especially with unrestricted off‐label use. We propose considering IVIg in well‐selected patients with high order RPL who have failed standard medical therapy. ...

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss

Banjar

Kadour

Khoudja

et al. 2023

American J Rep Immunol

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“…A modification of an antibody‐dependent complement‐mediated cytotoxicity assay protocol developed for assessing endothelial cell injury induced by human serum . PIECs (2.5 × 10 5 ) were seeded into 6‐well plates and treated with pooled human serum or heat‐inactivated human serum (inactivated at 56°C for 30 minutes) for different periods of time and at different concentrations.…”

Section: Methodsmentioning

confidence: 99%

“…A modification of an antibody-dependent complement-mediated cytotoxicity assay protocol developed for assessing endothelial cell injury induced by human serum. 23 PIECs (2.5 × 10 5 ) were seeded into 6-well plates and treated with pooled human serum or heat-inactivated human serum (inactivated at 56°C for 30 minutes) for different periods of time and at different concentrations. Fresh non-anticoagulated human blood without any restriction of blood type was obtained from healthy volunteers, pooled human serum and heatinactivated human serum was from the same healthy volunteers (n = 15, including all ABO blood types), and the treated PIECs were collected for subsequent experiments.…”

Section: Antibody-dependent Complement-mediated Cytotoxicity (Adcc)mentioning

confidence: 99%

A potential role of TLR2 in xenograft rejection of porcine iliac endothelial cells: An in vitro study

Chen

Gao

Chen

et al. 2019

Xenotransplantation

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Background Porcine vascular endothelial cells are a major participant in xenograft rejection. The Toll‐like receptor 2 (TLR2) pathway plays an important role in both innate and adaptive immunity. The specific role of TLR2 in the response to a xenograft has not been reported. Whether the TLR2 pathway in pig vascular endothelial cells is involved in acute rejection needs to be investigated, and the mechanism is explored. Methods We used a modified antibody‐dependent complement‐mediated cytotoxicity (ADCC) assay to conduct in vitro experiments. In porcine iliac artery endothelial cells (PIECs), siRNA was used to knock down the expression of TLR2, CXCL8, and CCL2. The effect of human serum or inactivated human serum on the expression of TLR2 was analyzed by real‐time PCR and Western blotting, and transwell assays were used to assess the chemotactic efficiency of PIECs on human monocyte‐macrophages (THP‐1 cells) and human neutrophils. The downstream signaling pathways activated by human serum were detected by Western blotting, and the regulation of proinflammatory chemokines and cytokines by TLR2 signaling was assessed by real‐time PCR and ELISA. Results TLR2 was significantly upregulated in PIECs after exposure to human serum, and porcine proinflammatory chemokines, CXCL8 and CCL2, were induced, at least partially, in a TLR2‐dependent pattern; the upregulated chemokines participated in the chemotaxis of human neutrophils and THP‐1 cells across the species barrier. Conclusions (i) TLR2 is significantly upregulated in PIECs by human serum, (ii) the elevated TLR2 participates in the chemotaxis of inflammatory cells through the secretion of chemokine CCL2 and CXCL8, and (iii) blockade of TLR2 would be beneficial for xenograft survival.

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“…In particular, it has been demonstrated that removal of dimers from IVIg preparations abrogates therapeutic benefit in ITP mouse models [ 210 ]. However, some conflicting reports exist regarding the therapeutic impact of IgG dimers in IVIg [ 157 ], and to date, there is no definitive evidence for the hypothesis of FcγR blockade.…”

Section: The Signal-to-noise Problem In Igg Signallingmentioning

confidence: 99%

Serum immunoglobulin and the threshold of Fc receptor-mediated immune activation

Bauer-Smith,

Sudol,

Beers

et al. 2023

Biochimica et Biophysica Acta (BBA) - General Subjects

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IVIG induces apoptotic cell death in CD56dim NK cells resulting in inhibition of ADCC effector activity of human PBMC

Cited by 9 publications

References 32 publications

Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss

Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss

A potential role of TLR2 in xenograft rejection of porcine iliac endothelial cells: An in vitro study

Serum immunoglobulin and the threshold of Fc receptor-mediated immune activation

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