Impact of vaccine therapy using nuclear histone H1 on allograft survival in experimental organ transplantation

Nakano, Toshiaki; Goto, Shigeru; Lai, Chia-Yun; Hsu, Li-Wen; Ono, Kazuhisa; Kawamoto, Seiji; Lin, Yu‐Chun; Kao, Ying-Hsien; Chiang, Kun‐Chun; Ohmori, Naoya; Goto, Takeshi; Sato, Shuji; Tu, Chieh-Hsien; Jawan, Bruno; Cheng, Yu‐Fan; Chen, Chao‐Long

doi:10.1016/j.trim.2007.01.003

Cited by 10 publications

(11 citation statements)

References 34 publications

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“…The therapeutic potential of antihistone H1 polyclonal antibody for overcoming rejection and liver inflammation was also confirmed by our group [19, 40]. We also confirmed the great potential of histone H1 vaccination in transplant recipients for tolerance induction [80, 81]. To further explore the roles of histone H1 and its future clinical application, we have generated antihistone H1 monoclonal antibodies (clone: 16G9, IgM), which possess immunosuppressive activity in vitro [82].…”

Section: Nuclear Antigens As a Therapeutic Targetsupporting

confidence: 56%

“…In addition, our previous study strongly suggested the binding of antihistone H1 Abregs to histone H1-like molecules, which may be transiently expressed on the cell membrane of splenocytes [19]. We have also demonstrated that antihistone H1 Abregs may selectively suppress the MAPK, NF- κ B, and calcineurin-NFAT signaling pathways during T-cell activation [40], coordinate the Th1/Th2 balance [81], and induce CD4 + CD25 + T cells [65]. Recent evidence suggests that antihistone H1 Abregs negatively regulate the harmful T-cell response, in part through collaboration with Tregs [93].…”

Section: Summary and Future Directionsmentioning

confidence: 99%

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Nuclear Antigens and Auto/Alloantibody Responses: Friend or Foe in Transplant Immunology

Nakano

Chen

Goto

2013

Clinical and Developmental Immunology

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In addition to cellular immune responses, humoral immune responses, mediated by natural antibodies, autoantibodies, and alloantibodies, have increasingly been recognized as causes of organ transplant rejection. In our previous studies, we have demonstrated the induction of antinuclear antibodies against histone H1 and high-mobility group box 1 (HMGB1), in both experimental and clinical liver transplant tolerance. The active induction of antinuclear antibodies is usually an undesirable phenomenon, but it is often observed after liver transplantation. However, the release of nuclear antigens and its suppression by neutralizing antibodies are proposed to be important in the initiation and regulation of immune responses. In this review article, we summarize the current understanding of nuclear antigens and corresponding antinuclear regulatory antibodies (Abregs) on infection, injury, inflammation, transplant rejection, and tolerance induction and discuss the significance of nuclear antigens as diagnostic and therapeutic targets.

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Section: Nuclear Antigens As a Therapeutic Targetsupporting

confidence: 56%

Section: Summary and Future Directionsmentioning

confidence: 99%

Nuclear Antigens and Auto/Alloantibody Responses: Friend or Foe in Transplant Immunology

Nakano

Chen

Goto

2013

Clinical and Developmental Immunology

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“…In this study, we demonstrated the upregulation of γδ T cells in liver allografts compared with naïve DA livers. In our previous studies, we demonstrated that the autoimmune response against nuclear antigens such as histone H1 might be an important phenomenon in overcoming rejection and in subsequent tolerance induction in a rat tolerogenic OLT model [51], [52], [53], [54]. The significance of autoimmunity against nuclear antigens such as histones and high-mobility group box 1 in immune regulation has been demonstrated [55], [56].…”

Section: Discussionmentioning

confidence: 96%

Immunological and Regenerative Aspects of Hepatic Mast Cells in Liver Allograft Rejection and Tolerance

et al. 2012

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The precise roles of mast cells in liver allograft rejection and tolerance are still unknown. This study aimed to explore the roles of mast cells in immune regulation and liver regeneration for tolerance induction by using rat models of orthotopic liver transplantation (OLT). Stem cell factor (SCF) and its receptor c-Kit, which are critical to the migration and development of not only stem cells but also mast cells, significantly increased in the tolerogenic livers as compared with rejected livers. The significant elevation of mast cell tryptase, high-affinity IgE receptor, and histamine suggested the activation of mast cells in liver allografts at the tolerogenic phase after OLT. Immunohistochemical analysis using confocal microscope clearly showed colocalization of mast cells, Foxp3+ Tregs, γδ T cells, and recipient-derived hepatic progenitor cells with higher expression of SCF, IL-9, IL-10, TGF-β1, and IL-17 related to immunoregulation and liver regeneration in the donor grafts of a tolerogenic OLT model. Cross-talk among mast cells and other cells was evaluated by in vitro studies demonstrating that syngeneic bone marrow−derived mast cells (BMMCs) co-cultured with naïve splenocytes or primary hepatocytes significantly increased the population of splenic γδ T cells by mitogen stimulation or by mast cell degranulation, and also significantly induced the hepatocyte proliferation, respectively. Our results suggested that mast cells in the donor grafts may play important roles in the induction/maintenance of immune tolerance and liver regeneration resulting in the replacement of hepatic cells from donor to recipient.

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“…Histone H1 vaccination of transplant recipients led to the production of immunosuppressive factors and the modification of cytokine/cellular profiles. Histone H1 vaccination has great potential as a tolerance therapy for prospective transplantation (26). Recently, we evaluated the immunosuppressive state of histone H1-immunized rats using MLR (27).…”

Section: Discussionmentioning

confidence: 99%

A Novel Peptide Mimotope Identified As a Potential Immunosuppressive Vaccine for Organ Transplantation

Chiang

Shimada²,

Nakano³

et al. 2009

The Journal of Immunology

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We reported that anti-histone H1 autoantibody is one of the main immunosuppressive factors in serum that is induced after orthotopic liver transplantation in a rat tolerogenic model. We generated a novel anti-histone H1 IgM mAb produced by hybridoma 16G9 (16G9 mAb) that shows MLR-inhibitory activity. Identification of a functional epitope responsible for the immunosuppressive activity of 16G9 mAb may lead to the establishment of a novel therapeutic strategy. We used a combinatorial phage display peptide library to screen for peptides that bind to 16G9 mAb. Consequently, two peptides that bind to 16G9 mAb, SSV and LPQ, were selected from the library. The binding of 16G9 mAb to histone H1 was inhibited by SSV. SSV was recognized by rat tolerogenic post-orthotopic liver transplantation serum and the binding to SSV was inhibited by histone H1. Mice were immunized with keyhole limpet hemocyanin-conjugated SSV and LPQ. Abs induced by SSV immunization inhibited Con A-stimulated splenocyte proliferation, and the inhibition was neutralized by preincubation with SSV. Splenocytes stimulated by anti-CD3 Ab were inhibited by SSV-induced Abs using CFSE labeling. SSV immunization in rats before heterotopic heart transplantation resulted in significant prolonged allograft survival. These findings suggested that SSV is a functional histone H1-binding epitope for 16G9 mAb. SSV is capable of determining serum immunoreactivity against histone H1 as an index marker for tolerance. The inhibitory activity of SSV-induced Abs on blast cell proliferation and the prolonged graft survival that results from SSV immunization imply a potential for the development of an immunosuppressive vaccine.

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Impact of vaccine therapy using nuclear histone H1 on allograft survival in experimental organ transplantation

Cited by 10 publications

References 34 publications

Nuclear Antigens and Auto/Alloantibody Responses: Friend or Foe in Transplant Immunology

Nuclear Antigens and Auto/Alloantibody Responses: Friend or Foe in Transplant Immunology

Immunological and Regenerative Aspects of Hepatic Mast Cells in Liver Allograft Rejection and Tolerance

A Novel Peptide Mimotope Identified As a Potential Immunosuppressive Vaccine for Organ Transplantation

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