The role of immunologic tests for subfertility in the clinical environment

Kwak‐Kim, Joanne; Alsubki, Lujain; Luu, Thanh; Ganieva, Umida; Thees, Amy; Dambaeva, Svetlana; Gilman‐Sachs, Alice

doi:10.1016/j.fertnstert.2022.04.009

Cited by 11 publications

(6 citation statements)

References 124 publications

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“…Immunotherapeutic approaches, including corticosteroids, calcineurin inhibitors, intravenous immunoglobulin, and anti-TNF agents, could be targeting the maternal immune system against early embryos or fetuses. [4][5][6] In this clinical study, the calcineurin inhibitor tacrolimus will be www.md-journal.com administered to Th1-dominant women with intractable infertility. Th1-dominant immune status is defined as a Th1/Th2 cell ratio ≥ 10.3 in the peripheral blood, which was previously determined by adding 1 standard deviation to the mean Th1/ Th2 cell ratio of 28 women with a history of normal delivery.…”

Section: Discussionmentioning

confidence: 99%

“…[3] While approximately 85% of infertile couples have any of these identified factors, [3] the remaining 15% suffer physically and emotionally from unexplained intractable infertility. In recent years, maternal-to-fetal immunological problems have been noted as a different mechanism from conventional factors contributing to infertility and pregnancy loss, [4][5][6] but there are no appropriate evidence-based measures in clinical practice for the diagnosis and treatment of infertility that involve immune factors. During pregnancy, the maternal immune system is dramatically altered to eliminate rejection and induce tolerance to a semi-allogeneic fetus.…”

Section: Introductionmentioning

confidence: 99%

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Multicenter, 2-dose single-group controlled trial of tacrolimus for the severe infertility patients

Hisano

Nakagawa²,

Ono

et al. 2023

Medicine

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Introduction: Infertility is estimated to affect 8% to 12% of reproductive-aged couples worldwide. While approximately 85% of infertile couples have an identified cause, the remaining 15% suffer physically and emotionally from unexplained intractable infertility. In recent years, maternal-to-fetal immunological abnormalities have attracted attention as mechanisms that differ from the conventional factors contributing to infertility and pregnancy loss. A T-helper 2 (Th2)-dominant immune state has been proposed as a maternal immune alteration to eliminate rejection and induce tolerance to a semi-allogeneic fetus. An imbalance in Th1 responses would not induce adequate maternal immune tolerance to the fetus or early embryos. Tacrolimus, widely used as an immunosuppressant agent in solid organ transplant recipients, is expected to suppress maternal rejection and promote tolerance to early embryos after assisted reproductive technology by modulating the immunological environment of the preimplantation endometrium. We planned an exploratory clinical trial to determine the efficacy, safety, and dosage of tacrolimus in women with intractable infertility. Methods and analysis: This is a multicenter, 2-dose, single-group controlled trial in infertile women who failed to achieve a chemical pregnancy despite multiple in vitro fertilization (IVF) and embryo transfer (ET) treatment cycles. The following 2 key selection criteria were set: no underlying factors of infertility despite appropriate evaluation and presence of Th1-dominant immune state, defined as a Th1/Th2 cell ratio ≥ 10.3 in the peripheral blood. A total of 26 eligible participants are randomly assigned (in a 2:1 ratio) to receive immunosuppressive therapy with oral tacrolimus at a daily dose of 2 mg or 4 mg. Tacrolimus is administered for 16 days starting from 2 days before ET. The primary endpoint is the presence of clinical pregnancy 3 weeks after IVF/ET treatment, and the secondary endpoint is the presence of biochemical pregnancy 2 weeks after IVF/ET treatment. Safety evaluation and biomarker discovery for tacrolimus treatment in infertile women will be conducted simultaneously. Trial registration number: Japan Registry of Clinical Trials (jRCT; jRCTs031220235).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multicenter, 2-dose single-group controlled trial of tacrolimus for the severe infertility patients

Hisano

Nakagawa²,

Ono

et al. 2023

Medicine

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“…Although no consensus has been reached in the literature, high levels and increased cytotoxicity of uterine NK cells (NKu) seem to be associated with RM and RIF. [21][22][23] Other authors have also observed high levels of peripheral blood NK cells (NKp) in women with a history of RM. Elevated cytotoxic activity of NKp cells has also been linked…”

Section: Immune System and Rmmentioning

confidence: 98%

“…with an increased risk of RM and RIF. 21,24,25 Although NKu and NKp cells have different phenotypes, a correlation may exist between the systemic and uterine immune responses. 26 Macrophages are the second most abundant cell population at the maternal-embryo interface.…”

Section: Immune System and Rmmentioning

confidence: 99%

“…Studies in humans have shown that abnormalities in the innate immune response can increase the risk of reproductive failure. Although no consensus has been reached in the literature, high levels and increased cytotoxicity of uterine NK cells (NKu) seem to be associated with RM and RIF 21–23 . Other authors have also observed high levels of peripheral blood NK cells (NKp) in women with a history of RM.…”

Section: Immune System and Rmmentioning

confidence: 99%

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Obesity and recurrent miscarriage: The interconnections between adipose tissue and the immune system

Gonçalves,

Feitosa,

Cavalcante

et al. 2023

American J Rep Immunol

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Currently, obesity is considered a global public health problem. It is the main risk factor for noncommunicable diseases and reproductive complications, such as recurrent miscarriage (RM). RM affects approximately 1% of couples of reproductive age, and recent studies suggest that its prevalence is increasing. Immunological abnormalities may be responsible for a significant number of cases of unexplained RM. Obesity is recognized as a chronic low‐grade inflammatory condition. The accumulation of fat in obese adipose tissue promotes changes in the local and systemic immune response. Adipokines, exosomes, micro‐RNAs, lipids, and other factors released or secreted by adipose tissue are responsible for the interconnection between obesity and the immune system. Obesity‐induced dysregulation of the innate and acquired immune response is also involved in the immunopathology of pregnancy loss in patients with unexplained RM. Therefore, understanding the communication pathways between maternal adipose tissue and the immune response in women living with obesity and RM is an important objective. Thus, diagnostic tools and new immunomodulatory therapies may be proposed for the management of patients with concurrent obesity and RM.

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Inflammatory responses in early pregnancy: Physiological and pathological perspectives

Negishi,

Morita

2024

Reprod Medicine & Biology

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BackgroundSeveral conditions such as infertility, repeated implantation failure, and recurrent pregnancy loss can pose challenges in early pregnancy. These issues can be caused by the abnormal inflammatory response with various factors, including exogenous and endogenous agents, and pathogenic and nonpathogenic agents. In addition, they can be exacerbated by maternal immune response to the abovementioned factors.MethodsThis review aimed to assess the detrimental inflammatory effects of chronic endometritis, endometrial microbiota disturbance, and maternal immune system abnormalities on early pregnancy. Further, essential details such as ovulation, implantation, trophoblast invasion, and placental formation, were examined, thereby highlighting the beneficial roles of inflammation.Main FindingsExcessive inflammation was associated with various early pregnancy disorders. Meanwhile, a lack of appropriate inflammation could also contribute to the development of different early pregnancy complications.ConclusionExcessive inflammation and insufficient inflammation can possibly lead to abnormal conditions in early pregnancy, and appropriate inflammation is required for a successful pregnancy.

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The role of immunologic tests for subfertility in the clinical environment

Cited by 11 publications

References 124 publications

Multicenter, 2-dose single-group controlled trial of tacrolimus for the severe infertility patients

Multicenter, 2-dose single-group controlled trial of tacrolimus for the severe infertility patients

Obesity and recurrent miscarriage: The interconnections between adipose tissue and the immune system

Inflammatory responses in early pregnancy: Physiological and pathological perspectives

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