Obiltoxaximab and raxibacumab are FDA-approved Mabs for treatment of patients after inhalation exposure to Bacillus anthracis spores. Both Mabs block the binding of B anthracis “protective antigen” to its cellular receptor, preventing entry of anthrax lethal and edema factors into cells. They are approved for the treatment or prophylaxis of adults and children with inhalational anthrax in combination with appropriate antibacterial drugs. Interestingly, these Mabs were not tested in humans because exposing a control cohort to inhalational anthrax is unethical and there are too few naturally infected persons to conduct a proper clinical trial.
Immunosuppressive agents are commonly used in two clinical circumstances: transplantation and autoimmune disorders. The agents used differ somewhat for the specific disorders treated (see specific agents and Table 55–1), as do administration schedules.
Because autoimmune disorders are very complex, optimal treatment schedules have yet to be established in many of them.
In organ transplantation, tissue typing—based on donor and recipient histocompatibility matching with the human leukocyte antigen (HLA) haplotype system—is required. Close histocompatibility matching reduces the likelihood of graft rejection and may also reduce the requirements for intensive immunosuppressive therapy. Prior to transplant, patients may receive an immunosuppressive regimen, including antithymocyte globulin, daclizumab, or basiliximab. Four types of rejection can occur in a solid organ transplant recipient: hyperacute, accelerated, acute, and chronic. Hyperacute rejection is due to preformed antibodies against the donor organ, such as anti– blood group antibodies. Hyperacute rejection occurs within hours of the transplant and cannot be stopped with immunosuppressive drugs. It results in rapid necrosis and failure of the transplanted organ. Accelerated rejection is mediated by both antibodies and T cells, and it also cannot be stopped by immunosuppressive drugs. Acute rejection of an organ occurs within days to months and involves mainly cellular immunity. Reversal of acute rejection is usually possible with general immunosuppressive drugs such as azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, glucocorticoids, cyclophosphamide, methotrexate, and sirolimus. Recently, biologic agents such as anti-CD3 monoclonal antibodies have been used to stem acute rejection. Chronic rejection usually occurs months or even years after transplantation. It is characterized by thickening and fibrosis of the vasculature of the transplanted organ, involving both cellular and humoral immunity. Chronic rejection is treated with the same drugs as those used for acute rejection.
Allogeneic hematopoietic stem cell transplantation is a well-established treatment for many malignant and nonmalignant diseases. An HLA-matched donor, usually a family member, is located, patients are conditioned with high-dose chemotherapy and/or radiation therapy, and then donor stem cells are infused. The conditioning regimen is used not only to kill cancer cells in the case of malignant disease, but also to totally suppress the immune system so that the patient does not reject the donor stem cells. As patients’ blood counts recover (after reduction by the conditioning regimen) they develop a new immune system that is created from the donor stem cells. Rejection of donor stem cells is uncommon and can only be treated by infusion of more stem cells from the donor.