The long-term immunosuppressive effects of disulfide-linked HLA-G dimer in mice with collagen-induced arthritis

Kuroki, Kazuhiko; Hirose, Kaoru; Okabe, Yuki; Fukunaga, Yuko; Takahashi, Ami; Shiroishi, Mitsunori; Kajikawa, Mizuho; Tabata, Satoshi; Nakamura, Seiko; Takai, Toshiyuki; Koyanagi, Satoru; Ohdo, Shigehiro; Maenaka, Katsumi

doi:10.1016/j.humimm.2012.11.060

Cited by 35 publications

(33 citation statements)

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“…Mutagenesis studies of the free cysteines suggested that the HLA-G dimer more efficiently inhibits NK killing than the monomer and increases the efficiency of ILT2 signaling [32, 42, 43, 48]. Experimental data from several groups, including our laboratory, suggest that HLA-G dimer has increased avidity and proper structural orientation to induce efficient inhibitory signaling during ligation with human ILT2 and ILT4, and murine PIR-B-inhibitory receptors [32, 44, 45]. This makes HLA-G dimer as the most powerful ligand form for modulation of inflammatory and alloimmune responses in several pathological conditions, including the prolongation of kidney allograft survival or graft acceptance.…”

Section: Discussionmentioning

confidence: 99%

“…Recently published data by Kuroki et al [45] demonstrating that in an animal model of collagen-induced arthritis, HLA-G dimer interacting through a murine ILT homologue, the PIR-B receptor exhibited significantly more anti-inflammatory effects compared to monomer. To date, no data is available on studies of the anti-inflammatory effect of sHLA-G dimers in clinical applications.…”

Section: Discussionmentioning

confidence: 99%

“…In most studies plasma/serum levels of HLA-G was determined by ELISA. However, HLA-G-specific ELISA has limitations and does not discriminate the presence of monomer or dimer isoforms of HLA-G. New data has revealed that disulfide-linked dimeric complexes of HLA-G have high preferential binding to immune inhibitory receptors, induce efficient immune inhibitory receptor signaling, and have strong functional activities [32, 42–45]. Limited data are available on the role of HLA-G dimers in clinical pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

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HLA-G Dimers in the Prolongation of Kidney Allograft Survival

Ezeakile

Portik-Dobos

et al. 2014

Journal of Immunology Research

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Human leukocyte antigen-G (HLA-G) contributes to acceptance of allografts in solid organ/tissue transplantation. Most studies have determined that soluble HLA-G isoforms are systematically detected in serum/plasma of transplanted patients with significantly fewer episodes of acute and/or chronic rejection of allogeneic tissue/organ. Current models of the interactions of HLA-G and its specific receptors explain it as functioning in a monomeric form. However, in recent years, new data has revealed the ability of HLA-G to form disulfide-linked dimeric complexes with high preferential binding and functional activities. Limited data are available on the role of soluble HLA-G dimers in clinical pathological conditions. We describe here the presence of soluble HLA-G dimers in kidney transplant patients. Our study showed that a high level of HLA-G dimers in plasma and increased expression of the membrane-bound form of HLA-G on monocytes are associated with prolongation of kidney allograft survival. We also determined that the presence of soluble HLA-G dimers links to the lower levels of proinflammatory cytokines, suggesting a potential role of HLA-G dimers in controlling the accompanying inflammatory state.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HLA-G Dimers in the Prolongation of Kidney Allograft Survival

Ezeakile

Portik-Dobos

et al. 2014

Journal of Immunology Research

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“…In line with this, focus has been drawn to HLA-G dimers and synthetic dimer HLA-G molecules for possible therapeutic use (104). In mice, recombinant sHLA-G and synthetic HLA-G molecules have been shown to inhibit the early stages of arthritis in a rheumatoid arthritis disease model and to significantly prolong the acceptance of skin grafts (104, 105). It can be speculated that synthetic sHLA-G analogs might find a place in the treatment of certain pregnancy-related disorders, such as pre-eclampsia and assisted reproduction.…”

Section: Future Aspects and Conclusionmentioning

confidence: 99%

Controlling the Immunological Crosstalk during Conception and Pregnancy: HLA-G in Reproduction

2014

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In several years after its discovery in the placenta, the human leukocyte antigen (HLA) class Ib protein, HLA-G, was not given much attention, nor was it assigned great importance. As time has unraveled, HLA-G has proven to have distinctive functions and an unforeseen and possibly important role in reproduction. HLA-G is characterized mainly by its low polymorphism and restricted tissue distribution in non-pathological conditions. In fact, its expression pattern is primarily limited to extravillous cytotrophoblast cells at the maternal-fetal interface during pregnancy. Due to low polymorphism, almost the same protein is expressed by virtually all individuals. It is these unique features that make HLA-G differ from its highly polymorphic HLA class Ia counterparts, the HLA-A, -B, and -C molecules. Its function, seemingly diverse, is typically receptor-mediated, and involves interactions with a wide range of immune cells. As the expression of HLA-G primarily is limited to gestation, this has given rise to the hypothesis that HLA-G plays an important role in the immunological tolerance of the fetus by the mother. In keeping with this, it might not be surprising that polymorphisms in the HLA-G gene, and levels of HLA-G expression, have been linked to reproductive failure and pre-eclampsia. Based on recent studies, we speculate that HLA-G might be involved in mechanisms in reproductive immunology even before conception because HLA-G can be detected in the genital tract and in the blood of non-pregnant women, and is present in seminal fluid from men. In addition, HLA-G expression has been found in the pre-implanted embryo. Therefore, we propose that a combined contribution from the mother, the father, and the embryo/fetus is likely to be important. Furthermore, this review presents important aspects of HLA-G in relation to reproduction: from genetics to physiological effects, from pregnancy and pregnancy complications to a short discussion on future possible means of preventative measures and therapy.

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“…It was previously demonstrated that a disulfide‐linked HLA‐G dimer mediates an inhibitory signal through LILRB1 100 times more than that of HLA‐G monomer (35). Moreover, HLA‐G dimer provides much more efficient signals than HLA‐G monomer by binding both LILRB1 and LILRB2 at the same time (40). It is interesting that the membrane‐bound form of HLA‐G can also form a disulfide‐linked dimer on the cell surface of the human choriocarcinoma cell line Jeg3, which endoge‐nously expresses HLA‐G (41) as well as HLA‐G trans‐fectants (42, 43).…”

Section: Discussionmentioning

confidence: 99%

HLA‐G dimer targets Granzyme B pathway to prolong human renal allograft survival

et al. 2019

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Human leukocyte antigen G (HLA‐G), a nonclassic HLA class Ib molecule involved in the maintenance of maternal tolerance to semiallogeneic fetal tissues during pregnancy, has emerged as a potential therapeutic target to control allograft rejection. We demonstrate here that the level of soluble HLA‐G dimer was higher in a group of 90 patients with a functioning renal allograft compared with 40 patients who rejected (RJ) their transplants. The HLA‐G dimer level was not affected by demographic status. One of the potential mechanisms in tissue‐organ allograft rejection involves the induction of granzymes and perforin, which are the main effector molecules expressed by CD8+ cytotoxic T lymphocytes and function to destroy allogeneic transplants. Using genomics and molecular and cellular analyses of cells from T‐cell–mediated RJ and nonrejected kidney transplant patients, cells from leukocyte Ig‐like receptor B1 (LILRB1) transgenic mice, humanized mice, and genetically engineered HLA‐G dimer, we demonstrated a novel mechanism by which HLA‐G dimer inhibits activation and cytotoxic capabilities of human CD8+ T cells. This mechanism implicated the down‐regulation of Granzyme B expression and the essential involvement of LILRB1. Thus, HLA‐G dimer has the potential to be a specific and effective therapy for prevention of allograft rejection and prolongation of graft survival.—Ajith, A., Portik‐Dobos, V., Nguyen‐Lefebvre, A. T., Callaway, C., Horuzsko, D. D., Kapoor, R., Zayas, C., Maenaka, K., Mulloy, L. L., Horuzsko, A. HLA‐G dimer targets Granzyme B pathway to prolong human renal allograft survival. FASEB J. 33, 5220–5236 (2019). http://www.fasebj.org

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The long-term immunosuppressive effects of disulfide-linked HLA-G dimer in mice with collagen-induced arthritis

Cited by 35 publications

References 10 publications

HLA-G Dimers in the Prolongation of Kidney Allograft Survival

HLA-G Dimers in the Prolongation of Kidney Allograft Survival

Controlling the Immunological Crosstalk during Conception and Pregnancy: HLA-G in Reproduction

HLA‐G dimer targets Granzyme B pathway to prolong human renal allograft survival

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