Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • The rapidity of this specific immunosuppressive therapy

    2024-05-15

    The rapidity of this specific immunosuppressive therapy suggests that it inhibits or apoptoses plasma cells. Most serum autoantibodies to AChR are produced by long-lived plasma cells residing in spleen and bone marrow. These terminally differentiated cells are resistant to most non-specific immunosuppressive drugs, resulting in a delay of up to 18 months after initiation of general immunosuppressive therapy before MG patients improve [23], [24]. Apoptosis of plasma cells can be induced by crosslinking FcγRIIB on the plasma cells by immune complexes [101]. Specific immunosuppressive therapy may induce apoptosis in plasma cells through a similar antibody-mediated feedback mechanism. This process does not involve the B-cell receptor because it is not expressed on plasma cells. Therapeutic Cy3 azide can form immune complexes in vivo with AChR in fragments of postsynaptic membrane shed during complement mediated focal lysis, and these immune complexes may be important for the therapeutic effects. We found that therapeutic effects of passive transfer of antibodies to AChR cytoplasmic domains are not so extensive as is achieved by active immunization with the therapeutic vaccine (J. Luo, unpublished observation). This may be explained by limited availability of AChR released in the immune assault. High doses of the therapeutic vaccine are more effective at suppressing EAMG than are low doses, even though high doses elicit an immune response to AChR cytoplasmic domains similar to that induced by low doses [94]. Repeated weekly doses are more effective than the same amount of the vaccine in fewer doses over the same period of time. Sustained therapeutic antigen may be required for forming immune complexes with therapeutic antibodies to effectively inhibit antibody-producing cells. After re-immunization with Torpedo AChR, resistance of successfully treated rats to re-induction of EAMG is accompanied by a rapid increase of antibodies to the MIR, but antibody level to AChR cytoplasmic domains remains unchanged. This suggests that a different mechanism may be responsible for the long-term effect of therapy. Administering the therapeutic vaccine in IFA, which promotes Th2 responses, is more effective than in TiterMax that promotes inflammatory Th1 responses. The isotype switching after specific immunosuppressive therapy, together with preference for a Th2-promoting adjuvant, suggests that therapy may involve a shift from Th1 to Th2 response specific to extracellular epitopes. Th1 cells induce synthesis of complement-fixing antibodies that disrupt the postsynaptic membrane [102], [103]. In MG patients, the predominant isotypes of anti-AChR antibodies are IgG1 and IgG3 that fix complement [104]. When re-immunized with Torpedo AChR, unlike untreated EAMG rats that develop a pathogenic Th1 response, successfully treated rats develop a Th2-regulated antibody response that does not fix complement effectively and thus exhibits little pathogenicity. Passive transfer of antibodies to AChR cytoplasmic domains does not change the isotype profile of antibodies to the MIR in response to re-immunization with Torpedo AChR (J Luo, unpublished observation). This indicates that the polarized Th2 response specific to pathological extracellular epitopes is not antibody-mediated. CD4+CD25+FoxP3+ regulatory T cells have a key role in controlling autoimmunity and maintaining immunologic self-tolerance [105]. Recent studies have reported functional defects of CD4+CD25+ regulatory T cells from thymuses of MG patients and reduction in peripheral regulatory T cell population in untreated MG patients [106], [107], [108], [109], [110], [111], [112]. Impairment of suppressive activity of regulatory T cells and reduction in frequency of regulatory T cells in the spleen and peripheral blood were also demonstrated in EAMG rats [113], [114]. This indicates that numerical and functional deficiencies of regulatory T cells is associated, at least in part, with the specific autoimmune response to AChR [114]. This also suggests that EAMG in rats is a suitable experimental model for assessing the capability of the antigen-specific immunosuppressive therapy to reconstitute the suppressive activity of regulatory T cells. Regulatory T cells are usually proposed to mediate specific immunosuppression of EAMG [71], [72], [74], [75], [113]. Increase in Foxp3 expression in EAMG rats following oral administration of human α1 extracellular domain suggests that the therapy generated Foxp3+ regulatory T cells [75]. Administration of antigen to compartments rich in regulatory T cells results in specific suppression of the autoimmune response [115]. Foxp3+ regulatory T cells induce apoptosis of plasma cells [116]. Antigen-specific regulatory T cells suppress protective Th1 responses in infectious diseases [117], [118]. Contributions of regulatory T cells to antigen-specific immunosuppressive therapy with AChR cytoplasmic domains remain to be determined.