Medium-dose intravenous immunoglobulin therapy for women with six or more recurrent miscarriages

Yamada, Hideto; Deguchi, Masashi; Maesawa, Yoko; Nakajima, Yuki; Nishino, Yukari; Tanimura, Kenji; Ebina, Yasuhiko

doi:10.1016/j.jri.2015.01.008

Cited by 10 publications

(8 citation statements)

References 10 publications

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“…These results suggested that IVIg specifically affects the uterus at the early phase and a high dose is required for it to be effective in this model. In agreement with our findings, Yamada et al reported a high live birth rate among uRPL patients who underwent high-dose IVIg therapy at the early phase of pregnancy (400 mg/kg for 5 days at gestational weeks 4-7) [6,56], but not in patients who received medium-dose IVIg therapy (20 g/day for 3 days from gestational sac detection) [57]. Thus, it highly recommended that IVIg is administered to uRPL patients as early and as highly dosed as possible.…”

Section: Discussionsupporting

confidence: 93%

Intravenous Immunoglobulin Suppresses Abortion Relates to an Increase in the CD44bright NK Subset in Recurrent Pregnancy Loss Model Mice

Tanaka¹,

Kitashoji²,

Fukunaga³

et al. 2016

Biology of Reproduction

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Recurrent pregnancy loss (RPL), which mostly is of unknown etiology (unexplained RPL, uRPL), is defined as three or more consecutive spontaneous abortions. Some women with uRPL display a higher fraction and cytotoxicity of natural killer (NK) cells in the periphery and endometrium. Therefore, some uRPL cases have been explained by autoimmune abnormalities. The efficacy of intravenous immunoglobulin (IVIg) for uRPL has been confirmed in several clinical trials; however, its mechanism remains unknown, mainly because the abortion mechanism remains to be elucidated. In the present study, we analyzed the mechanisms of both abortion and IVIg action using a uRPL mouse model in which abortion was induced by lipopolysaccharide injection. IVIg attenuated the abortion rate in the uRPL model mice. The suppressive effect of IVIg was maximized by high dose administration early after lipopolysaccharide injection. Specifically, we discovered the presence of two distinct uterine NK (uNK) subsets: CD44(bright) and CD44(mid) In uRPL model mice, we observed an increase in the number of CD44(bright) uNK cells, while the CD44(mid) uNK subset remained unchanged. Furthermore, when abortion was reduced by IVIg administration, the cell number of the CD44(bright) uNK subset did not increase, which might allow differentiating pathological from normal uNK cells based on CD44 expression. Based on these results, we propose not only an effective administration protocol of IVIg to the uRPL model mice, but also a novel mechanism of abortion related to the increase in the CD44(bright) subset and of IVIg, which suppresses the increase of the CD44(bright) subset.

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Section: Discussionsupporting

confidence: 93%

Intravenous Immunoglobulin Suppresses Abortion Relates to an Increase in the CD44bright NK Subset in Recurrent Pregnancy Loss Model Mice

Tanaka¹,

Kitashoji²,

Fukunaga³

et al. 2016

Biology of Reproduction

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“…Across multiple studies with various conditions, the general consensus is that IVIG inhibits NK cell cytotoxicity. This was shown in vitro using IVIG-treated PBMCs from normal donors ( 12 , 13 , 40 , 41 ), and in PBMCs after IVIG infusion of women with recurrent miscarriages ( 10 , 14 , 15 , 25 , 42 ), patients with immune thrombocytopenia ( 11 ) and CIDP ( 27 ). Our findings in KD patients agree with these reports ( Figure 2 ).…”

Section: Discussionmentioning

confidence: 87%

“…IVIG modulation of NK cells has been demonstrated in both in vivo and in vitro studies showing that IVIG can affect NK cell frequency and phenotype in the blood, and can also alter NK cell cytokine production, proliferation and cytotoxicity (10)(11)(12)(13)(14)(15). However, there is a lack of consensus on whether IVIG activates or inhibits NK cells.…”

Section: Introductionmentioning

confidence: 99%

High Dose Intravenous IgG Therapy Modulates Multiple NK Cell and T Cell Functions in Patients With Immune Dysregulation

et al. 2021

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Intravenous immunoglobulin (IVIG) is an effective immunomodulatory treatment for immune dysregulation diseases. However, the mechanisms by which it reduces systemic inflammation are not well understood. NK cell cytotoxicity is decreased by IVIG in women with reduced fertility, but IVIG effects on NK cells in immune dysregulation are less clear. We hypothesized that IVIG modulation of lymphocyte function, especially in NK cells, is important for resolution of inflammation. Our aim was to identify IVIG-induced changes in a cohort of patients with Kawasaki disease (KD) and those that occur broadly in pediatric patients with various immune dysregulatory diseases. Peripheral blood mononuclear cells (PBMCs) of patients with KD or autoimmune/inflammatory diseases were phenotyped pre and post high dose IVIG treatment by flow cytometry. In KD patients, after IVIG infusion Treg cell frequency and the proportion of activated CD25+ immunoregulatory CD56bright NK cells was increased, and multiple lymphocyte subsets showed increased expression of the lymphoid tissue homing receptor CD62L. Importantly, IVIG treatment decreased the frequency of cells expressing the degranulation marker CD107a among cytotoxic CD56dim NK cells, which was reflected in a significant reduction in target cell killing and in decreased production of multiple pro-inflammatory mediators. Interestingly, the activating receptor CD336 was expressed on a higher proportion of CD56bright NK cells after IVIG in both KD and autoimmune/inflammatory patients while other NK receptors were increased differentially in each cohort. In autoimmune/inflammatory patients IVIG induced the proliferation marker CD71 on a higher percentage of CD56dim NK cells, and in contrast to KD patients, CD107a+ cells were increased in this subset. Furthermore, when PBMCs were stimulated ex vivo with IL-2 or Candida antigen in autologous plasma, more of the CD4+ T cells of KD patients expressed CD25 after IVIG therapy but fewer cytotoxic T cells were degranulated based on CD107a expression. In summary, IVIG treatment in patients with immune dysregulation has multiple effects, especially on NK cell subsets and CD4+ T cells, which are compatible with promoting resolution of inflammation. These novel findings provide insight into the immunomodulatory actions of IVIG in autoimmune and inflammatory conditions.

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“…Many studies have discovered that women with RM presented an abnormal activation of the immune system [134][135][136]; IVIG is currently introduced as a novel treatment for women with RM. Expectedly, the results are encouraging [59,[137][138][139][140][141] and show that IVIG can significantly increase reproductive success in women with a history of RM. For instance, Ahmadi et al [59] found that IVIG can dramatically regulate the Th1/Th2 ratio by decreasing Th1 (CD4 + IFN-γ + ) cells and increasing Th2 (CD4 + IL-4 + ) cells (p<0.0001).…”

Section: Intravenous Immunoglobulinmentioning

confidence: 83%

The exploration of Hashimoto's Thyroiditis related miscarriage for better treatment modalities

Min¹,

Wang²,

Chen³

et al. 2020

Int. J. Med. Sci.

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Hashimoto's thyroiditis (HT) is the most prevalent autoimmune thyroid disease (ATD) worldwide and is strongly associated with miscarriage and even recurrent miscarriage (RM). Moreover, with a deepening understanding, emerging evidence has shown that immune dysfunctions caused by HT conditions, including imbalanced subsets of CD4+ T-helper cells, B regulatory (Breg) cells, high expression levels of CD56dim natural killer (NK) cells, and cytokines, possibly play an important role in impairing maternal tolerance to the fetus. In recent years, unprecedented progress has been made in recognizing the specific changes in immune cells and molecules in patients with HT, which will be helpful in exploring the mechanism of HT-related miscarriage. Based on these findings, research investigating some potentially more effective treatments, such as selenium (Se), vitamin D3, and intravenous immunoglobulin (IVIG), has been well developed over the past few years. In this review, we highlight some of the latest advances in the possible immunological pathogenesis of HT-related miscarriage and focus on the efficacies of treatments that have been widely introduced to clinical trials or practice described in the most recent literature.

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Medium-dose intravenous immunoglobulin therapy for women with six or more recurrent miscarriages

Cited by 10 publications

References 10 publications

Intravenous Immunoglobulin Suppresses Abortion Relates to an Increase in the CD44bright NK Subset in Recurrent Pregnancy Loss Model Mice

Intravenous Immunoglobulin Suppresses Abortion Relates to an Increase in the CD44bright NK Subset in Recurrent Pregnancy Loss Model Mice

High Dose Intravenous IgG Therapy Modulates Multiple NK Cell and T Cell Functions in Patients With Immune Dysregulation

The exploration of Hashimoto's Thyroiditis related miscarriage for better treatment modalities

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