![Clinical immunotherapies and alternative approaches to eliminate or circumvent antibodies against coagulation factors formed in patients with bleeding disorders. These concepts are illustrated using inhibitor formation in the treatment of hemophilia as an example. Alternative strategies include [1] immune tolerance induction (ITI) by frequent IV administration of antigen; [2] transient immune suppression therapy (IST); and [3] restoration of hemostasis using nonfactor therapeutics, thus avoiding the use of the target antigen. Center: Inhibitory antibodies are produced by B cells upon their T helper cell-dependent activation. T follicular helper cells promote the organization of germinal centers and the production of antibodies. B cells may differentiate into memory B cells (BM) or plasma cells (PCs), which produce antibodies long-term. Ultimately, inhibitors prevent blood clot formation by reducing/eliminating the activation of factor X. This reaction is a critical component of the coagulation cascade and normally occurs through the cooperation of activated FVIII (FVIIIa) and factor IX (FIXa). Left: Although little is known about the mechanisms by which ITI reverses inhibitor production upon frequent IV factor administration, evidence supports that high antigen doses can directly inhibit BM. IST may use small molecule drugs such as cyclophosphamide, a DNA alkylating agent that eliminates proliferating cells such as activated B and T cells. Rituximab (anti-CD20 antibody) depletes mature B cells (but not BM or PCs). Regulatory T cells (Tregs) are able to suppress inhibitor formation. Therefore, experimental approaches use inhibition of the mTOR pathway with rapamycin/sirolimus (which aids in deletion of effector T cells, suppresses germinal center formation, and promotes Treg induction); oral antigen administration or hepatic gene transfer to induce Tregs, or Treg cell therapy, among other approaches. Right: Alternatively, nonfactor therapies bypass the effect of inhibitors by using a bispecific antibody that partially mimics the function of FVIII but is not recognized by FVIII inhibitors (a treatment that, however, only applies to HA) or promotes coagulation by elimination/neutralization of critical components of anticoagulant pathways (such as AT or TFPI) through small interfering RNA or monoclonal antibody therapy. AT, antithrombin III; TFPI, tissue factor pathway inhibitor.](https://ash.silverchair-cdn.com/ash/content_public/journal/blood/140/10/10.1182_blood.2022016530/3/bloodbld2022016530cf1.png?Expires=1722684995&Signature=nH-QneRga3jqgEaHUKG0fYBPcYNVKT~EIwo3HaEzwROt5g9Fr8YDG6jJ0UnBQcJeBJye5ERKBQm~5p66pnTzssj7Uur2Evj~8JcRQostApuOYl5XoC8NUYSrOn3QM2fFmq1ZNQwHzjl~a-vSuDAUrMAFhAW4eh~Dh3WZNgGJ5Dfxtssx8-NWBUPi1PdiD-UEJy9xFzBxw~9FcQwSr0vMGgJpt1gdov-JJp6Z6vpLw4SNHKe9PZq72pUZ05siVzwaPGGL623k~cwQvE9B01pNMhQmW4h6UgyPPdYPv803jlVig-1BEu8g9i1mvQLwi8G8Z46TrUJkSX4h5N~O9nvNLw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Clinical immunotherapies and alternative approaches to eliminate or circumvent antibodies against coagulation factors formed in patients with bleeding disorders. These concepts are illustrated using inhibitor formation in the treatment of hemophilia as an example. Alternative strategies include [1] immune tolerance induction (ITI) by frequent IV administration of antigen; [2] transient immune suppression therapy (IST); and [3] restoration of hemostasis using nonfactor therapeutics, thus avoiding the use of the target antigen. Center: Inhibitory antibodies are produced by B cells upon their T helper cell-dependent activation. T follicular helper cells promote the organization of germinal centers and the production of antibodies. B cells may differentiate into memory B cells (BM) or plasma cells (PCs), which produce antibodies long-term. Ultimately, inhibitors prevent blood clot formation by reducing/eliminating the activation of factor X. This reaction is a critical component of the coagulation cascade and normally occurs through the cooperation of activated FVIII (FVIIIa) and factor IX (FIXa). Left: Although little is known about the mechanisms by which ITI reverses inhibitor production upon frequent IV factor administration, evidence supports that high antigen doses can directly inhibit BM. IST may use small molecule drugs such as cyclophosphamide, a DNA alkylating agent that eliminates proliferating cells such as activated B and T cells. Rituximab (anti-CD20 antibody) depletes mature B cells (but not BM or PCs). Regulatory T cells (Tregs) are able to suppress inhibitor formation. Therefore, experimental approaches use inhibition of the mTOR pathway with rapamycin/sirolimus (which aids in deletion of effector T cells, suppresses germinal center formation, and promotes Treg induction); oral antigen administration or hepatic gene transfer to induce Tregs, or Treg cell therapy, among other approaches. Right: Alternatively, nonfactor therapies bypass the effect of inhibitors by using a bispecific antibody that partially mimics the function of FVIII but is not recognized by FVIII inhibitors (a treatment that, however, only applies to HA) or promotes coagulation by elimination/neutralization of critical components of anticoagulant pathways (such as AT or TFPI) through small interfering RNA or monoclonal antibody therapy. AT, antithrombin III; TFPI, tissue factor pathway inhibitor.