Takao Kanai

Human leukocyte antigen-G-expressing cells differently modulate the release of cytokines from mononuclear cells present in the decidua versus peripheral blood

PROBLEM: To better understand the role of human leukocyte antigen (HLA)‐G in regulating the T helper (Th)1/Th2 cytokine balance, one of key conditions in determining the fate of pregnancy, we asked whether the presence of HLA‐G protein altered the release of cytokines from both decidual mononuclear cells and peripheral blood mononuclear cells (PBMCs).
 METHOD OF STUDY: The amounts of cytokines released from decidual mononuclear cells and PBMCs were compared in the presence or absence of HLA‐G‐expressing cells.
 RESULTS: When cocultured with HLA‐G‐expressing cells, the amounts of tumor necrosis factor‐α and interferon‐γ released from decidual mononuclear cells and PBMCs were decreased, while the amounts of interleukin (IL)‐4 from PBMCs was increased, with IL‐4 release from decidual mononuclear cells being unchanged.
 CONCLUSIONS: Upon contact with HLA‐G, decidual mononuclear cells, and PBMCs as well, modulate their ability to release cytokines in a way that may shift the Th1/Th2 balance towards relative Th2 dominance, suggesting a role for HLA‐G in maintaining pregnancy.

CORNEAL FINDINGS IN A FOETUS WITH FABRY'S DISEASE

The cornea of a 22‐week foetus with Fabrys disease was examined biochemically and histopathologically. The α‐galactosidase activity in the cornea was very low compared with that of the normal control. Histopathologic examination revealed that intracytoplasmic: lamellar bodies surrounded by a single membrane were present in the epithelial cells. The lamellar bodies were thought to result from the abnormal accumulation of ceramide trihexoside. We conclude that ceramide trihexoside already has begun to accumulate progressively in the epithelial cells in the mid‐trimester of gestation.

Polymorphism of human leukocyte antigen-E gene in the Japanese population with or without recurrent abortion

PROBLEM: The aim of this study was to investigate the gene frequencies and shared alleles of human leukocyte antigen (HLA)‐E gene in Japanese couples with or without recurrent abortion.
 METHOD OF STUDY: Polymerase chain reaction (PCR)‐single strand conformation polymorphism (SSCP) analysis was carried out to detect polymorphism in exon 3 of the HLA‐E gene in 30 Japanese couples with recurrent abortion and 38 normal Japanese couples with proven fertility.
 RESULTS: No point mutation was detected in exon 3 of HLA‐E in both recurrent aborters and normal controls. HLA‐EG and HLA‐ER alleles were detected with frequencies of 66.7% and 33.3% in couples with recurrent abortion and 69.2% and 30.8% in normal couples, respectively. The gene frequency of HLA‐EG was higher than that of HLA‐ER, which is contrary to that found in Caucasian, African–American and Hispanic people but similar to Chinese people. The frequency of each allele was not significantly different between recurrent aborters and normal controls. The number of shared alleles between each couple with recurrent abortion is not significantly different from that with normal controls.
 CONCLUSION: Allele frequencies of HLA‐E were suggested to be different in Asian people from those in other ethnic people. In light of no specific distribution pattern in recurrent aborters, HLA‐E polymorphism does not seem to play a role in the pathogenesis of recurrent abortion.

Theoretical Basis for Herbal Medicines, Tokishakuyaku-San and Sairei-To, in the Treatment of Autoimmunity-Related Recurrent Abortion by Correcting T Helper-1/T Helper-2 Balance

PROBLEM AND METHOD OF STUDY: To get insight into the basis for the empirical usage of herbal medicines in the treatment of recurrent abortion, we examined whether Tokishakuyaku‐san (Toki) and Sairei‐to (Sai) modulate T helper‐1 (Th1) and T helper‐2 (Th2) cytokine release from peripheral blood mononuclear cells (PBMCs). The effects of these medicines were investigated as related to human leukocyte antigen (HLA)‐G, a non‐classical HLA class I antigen expressed on trophoblasts and a putative crucial player involved in fetomaternal immune interplay.
 RESULTS: Toki and Sai increased the release of Th1 group cytokines, tumor necrosis factor (TNF)‐α and interferon (IFN)‐γ while preserving the inhibitory effect of HLA‐G on the release of these cytokines. As for Th2 group cytokine release, Toki was without effect in modulating interleukin (IL)‐4 release, regardless of the presence of HLA‐G, whereas Sai nullified the effect of the presence of HLA‐G to stimulate the release of IL‐4 without affecting its release in the absence of HLA‐G.
 CONCLUSION: Toki and Sai may have therapeutic potential, particularly in autoimmunity‐related recurrent abortion where Th2 response is pathologically enhanced, but not in recurrent abortion involving alloimmune fetomaternal derangement, a condition of, rather, an enhanced Th1 response.

A subclass of soluble HLA-G1 modulates the release of cytokines from mononuclear cells present in the decidua additively to membrane-bound HLA-G1

PROBLEM Our previous studies have demonstrated that a subclass of soluble human leukocyte antigen-G1 protein (sub-sHLA-G1), that has alpha1 to alpha3 extra-cellular portion but lacks C-terminus of authentic soluble HLA-G1 secreted by trophoblasts, fine-tunes the release of cytokines from peripheral blood mononuclear cells (PBMCs) chiefly by counterbalancing membrane-bound HLA-G1 (mHLA-G1), and thereby may play a role in maintaining pregnancy. In this study, we investigated whether the presence of sHLA-G1 protein altered the release of cytokines from decidual mononuclear cells (DMCs) which are localized at the interface of feto-maternal interaction and whose cell population is completely different from PBMCs. METHOD OF STUDY We cultured peripheral DMCs with either HLA-A and -B lacking B lymphoblast cell line (721.221 cells) or the cells transfected with mHLA-G1 (721.221-G1 cells) with or without sub-sHLA-G1. Cytokines concentrations in the culture media were determined by an enzyme-linked immunosorbent assay. RESULTS Regardless of the presence of mHLA-G1 expressing cells, the addition of the recombinant sub-sHLA-G1 protein in the DMC culture media decreased the amounts of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma, with the release of IL-4 from DMCs being unchanged. CONCLUSION The sub-sHLA-G1 protein modulates the release of cytokines from DMCs additively to mHLA-G1 expressing cells. In view of the distinct fetomaternal interaction during implantation, it appears that sHLA-G1 might play a role in the establishment of pregnancy by regulating cytokine release in concert with mHLA-G1.

Herbal medicines, Sairei-to and Tokishakuyaku-san, differently modulate the release of cytokines from decidual versus peripheral blood mononuclear cells.

PROBLEM AND METHOD OF STUDY: We have shown that Tokishakuyaku‐san (Toki) and Sairei‐to (Sai) enhance T helper‐1 (Th1) cytokine release from peripheral blood mononuclear cells (PBMCs); thereby, they could be a therapeutic means in the treatment of autoimmunity related recurrent abortion in which T helper‐2 (Th2) polarization is exaggerated, the condition purported to benefit from these herbal medicines. However, an open question is whether these medicines might enhance Th1 cytokine release in decidual tissues and thereby stimulate the killer activity, thus, working counterproductively by accelerating maternal alloimmune reactions toward fetal tissues. To address this, we examined the effects of these medicines on the release of cytokines from decidual mononuclear cells (DMCs) in comparison with PBMCs on the assumption that they might act differently on these cell types. The effects of these medicines were investigated as related to human leukocyte antigen (HLA)‐G, a nonclassical HLA class I antigen expressed on trophoblasts and a putative crucial player involved in fetomaternal immune interplay.
 RESULTS: Regarding Th1 cytokines, Toki marginally increased the release of tumor necrosis factor (TNF)‐α, but not interferon (IFN)‐γ from DMCs while Sai did not affect the release of both. Both Toki and Sai were without effect in modulating the release of interleukin (IL)‐4, a member of Th2 cytokines. Interestingly, the presence of HLA‐G reduced the release of Th1 cytokines from DMCs regardless of the addition of Toki, Sai or none. These findings are in sharp contrast with PBMCs on which these medicines seem to act so as to enhance Th1 polarization and attenuate Th2 polarization.
 CONCLUSION: Differential effects of Toki and Sai on the release of Th1/Th2 cytokines between DMCs and PBMCs may afford the rationale of these medicines in the treatment of autoimmunity‐related recurrent abortion.

Successful Treatment by Double Filtrate Plasmapheresis in a Pregnant Woman With the Rare P Blood Group and a History of Multiple Early Miscarriages

Abstract:  Individuals of P type, a rare blood group, have anti‐PP1Pk antibody in their serum, which causes spontaneous abortion in the early stages. We report a patient of p type suffering from multiple spontaneous abortions. We also review previously reported cases from published work. A 36‐year‐old woman (gravida 2, para 0) was referred to our hospital because of habitual abortion. At the third pregnancy, we started double filtration plasmapheresis (DFPP) from 7 weeks 3 days to remove the antibody. We attained rapid decline in the titer and normal fetal growth. Gradual tapering of the DFPP frequency caused neither a rebound of the titer nor growth retardation. During the course, she experienced only one episode of catheter infection as an adverse effect. At 37 weeks 3 days, after 57 DFPP repetitions, a 2496 g girl was delivered by cesarean section. The infant suffered neither from anemia nor from severe jaundice. A review of previous reports indicates that the titer of the pathogenic antibody should be kept as low as possible from the early gestational stage in P‐incompatible habitual abortion cases, otherwise the case typically comes to an unfavorable outcome. Plasma exchanges with fresh plasma potentially induce contamination by either known or unknown pathogens. Such risks are reduced using DFPP because the volume of albumin solution that replaces fresh plasma is less than that by plasma exchange. The present case, along with previous reports, shows that DFPP is an effective therapy for treating P‐incompatible pregnancy. 

Theoretical Basis for Herbal Medicines, Tokishakuyaku‐San and Sairei‐To, in the Treatment of Recurrent Abortion: Enhancing the Production of Granulocyte–Macrophage Colony‐Stimulating Factor in Decidual Stromal Cells

To get insight into the basis for the empirical usage of herbal medicines, such as Tokishakuyaku‐san (Toki) and Sairei‐to (Sai) in the treatment of recurrent abortion and intrauterine growth restriction, we examined whether these medicines modulate the production of granulocyte–macrophage colony‐stimulating factor (GM‐CSF), a cytokine working as an important mediator for intercellular communication in the embryonic development, in decidual stromal cells (DSCs).