In experimental models, monoclonal antibodies against other targets have also had some success in preventing graft rejection, including nondepleting antibodies that bind the CD4 co-receptor or the co-stimulatory receptor CD28 on lymphocytes. Similarly, abatacept, a soluble recombinant CTLA-4–Ig fusion protein which binds to the co-stimulatory B7 molecules on antigen-presenting cells and prevents their interaction with CD28 on T cells, is approved for the treatment of rheumatoid arthritis.
16-7 Depletion of autoreactive lymphocytes can treat autoimmune disease.
In addition to their use in preventing transplantation rejection, monoclonal antibodies can be used to treat certain autoimmune diseases, and the different immune mechanisms targeted are discussed in the next few sections. We start by discussing the use of depleting and nondepleting antibodies to remove lymphocytes nonspecifically. The anti-CD20 monoclonal antibody rituximab was originally developed to treat B-cell lymphomas, but has also been tried in treating certain autoimmune diseases. By ligating CD20, rituximab (Rituxan, MabThera) transduces a signal that induces lymphocyte apoptosis and depletes B cells for several months. Certain autoimmune diseases are believed to involve autoantibody-mediated pathogenesis. There is evidence for the efficacy of rituximab in some patients with autoimmune hemolytic anemia, SLE, rheumatoid arthritis, or type II mixed cryoglobulinemia, all of which have autoantibodies as a part of their clinical presentation. Although CD20 is not expressed on antibody-producing plasma cells, their B-cell precursors are targeted by anti-CD20, resulting in a substantial reduction in the short-lived, but not the long-lived, plasma-cell population.
Alemtuzumab, discussed above for its use in treating leukemia and in transplant rejection, has shown some beneficial effect in studies of small numbers of patients with multiple sclerosis. However, immediately after its infusion, most multiple sclerosis patients suffered a frightening, although fortunately brief, flare-up of their illness, illustrating another potential complication of antibody therapy. Alemtuzumab was acting as intended, killing cells by complementand Fc-dependent mechanisms. However, it also stimulated the release of cytokines, including TNF-α, interferon (IFN)-γ, and IL-6, which transiently block nerve conduction in nerve fibers previously affected by demyelination. This caused the transient but dramatic exacerbation of symptoms. Nevertheless, alemtuzumab may be useful at early stages of the disease, when the inflammatory response is maximal, but this has yet to be determined.
Fig. 16.9 Anti-inflammatory effects of anti-TNF-α therapy and objective parameters of disease activity (as measured by pain in rheumatoid arthritis. The clinical course of 24 patients was score and swollen-joint count, respectively) and in the systemic followed for 4 weeks after treatment with either a placebo or a inflammatory acute-phase response, measured as a fall in the monoclonal antibody against TNF-α at a dose of 10 mg • kg–1. The concentration of the acute-phase C-reactive protein. Data courtesy antibody therapy was associated with a reduction in both subjective of R.N. Maini.