Development of a two‐step chromatography procedure that allows the purification of a high‐purity anti‐histone H1 monoclonal immunoglobulin M antibody with immunosuppressant activity

Shimada, Yoshihisa; Goto, Takeshi; Kawamoto, Seiji; Kiso, Takashi; Katayama, Akiko; Yamanaka, Yasushi; Aki, Tsunehiro; Chiang, Kun‐Chun; Nakano, Toshiaki; Goto, Shigeru; Chen, Chao‐Long; Ohmori, Naoya; Ono, Kazuhisa; Sato, Shuji

doi:10.1002/bmc.887

Cited by 9 publications

(7 citation statements)

References 18 publications

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“…Although this study has revealed novel mechanisms for immune modulation, much work remains for understanding the immunological aspects of anti‐histone H1 autoantibody in inflamed liver and liver allograft tolerance. Specifically, future work will focus on the in vitro and in vivo function of anti‐histone H1 mAb, which possesses mixed lymphocyte reaction–inhibitory activity 40 and on the characterization of cell‐surface histone H1(‐like) antigens that are transiently expressed during T‐cell activation 7 and also DC maturation 19 …”

Section: Discussionmentioning

confidence: 99%

Immunological aspects and therapeutic significance of an autoantibody against histone H1 in a rat model of concanavalin A‐induced hepatitis

Nakano

Goto

Lai³

et al. 2010

Immunology

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SummaryWe previously demonstrated the immunosuppressive activity of anti-histone H1 autoantibody induced in experimental and clinical liver allograft tolerance. This study aimed to explore the immunological aspects of anti-histone H1 autoantibody in liver injury induced by concanavalin A (Con A). To establish a Con A-hepatitis model, 20 mg/kg Con A was intravenously injected into rats, after which liver function and histopathological analyses were performed. In this model, anti-histone H1 autoantibody was transiently induced in the sera during the natural recovery stage, 3-7 days after Con A injection. To evaluate the therapeutic significance of anti-histone H1 autoantibody, a polyclonal antibody against histone H1 was intraperitoneally injected immediately after Con A injection. We found that injection of antihistone H1 antibody could reduce Con A-induced liver damage. Further mechanical analyses revealed that anti-histone H1 antibody altered the intracellular activation of mitogen-activated protein kinase, nuclear factor-jB and calcineurin via T-cell receptor signalling, suggesting that anti-histone H1 antibody may protect the liver from Con A-induced injury by inhibiting activation of effector T cells. These findings suggest that anti-histone H1 autoantibody may be a natural immune regulatory factor that protects inflamed livers suffering from autoimmune hepatitis and may lead to T-cell unresponsiveness through the selective regulation of mitogen-activated protein kinase/ nuclear factor-jB and calcineurin signalling.

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Section: Discussionmentioning

confidence: 99%

Immunological aspects and therapeutic significance of an autoantibody against histone H1 in a rat model of concanavalin A‐induced hepatitis

Nakano

Goto

Lai³

et al. 2010

Immunology

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“…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]. In addition, we have identified the functional epitope (SSVLYGGPPSAA) responsible for the immunosuppressive activity of 16G9 and have confirmed the diagnostic and therapeutic potential of histone H1 peptide [83].…”

Section: Nuclear Antigens As a Therapeutic Targetmentioning

confidence: 70%

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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“…16G9 mAb was generated as a tool to elucidate the mechanism of immunological tolerance in liver transplantation (19) and was found to have MLR-inhibitory activity (data not shown). Here, we used phage display to identify peptides from a large library that bind to Ab-binding sites, thereby mimicking the conformational features of both linear and conformational epitopes.…”

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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Development of a two‐step chromatography procedure that allows the purification of a high‐purity anti‐histone H1 monoclonal immunoglobulin M antibody with immunosuppressant activity

Cited by 9 publications

References 18 publications

Immunological aspects and therapeutic significance of an autoantibody against histone H1 in a rat model of concanavalin A‐induced hepatitis

Immunological aspects and therapeutic significance of an autoantibody against histone H1 in a rat model of concanavalin A‐induced hepatitis

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

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

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