In animal models, antibodies targeting an individual cytokine have been used to inhibit that cytokine’s function during an otherwise intact immune response. Experiments of this type provided some of the first evidence that the cytokine IL-12 provides an important signal in polarizing CD4+ T cells into the TH1 lineage following infection with an intracellular protozoan. This approach has also been used with great success in humans. One of the most common treatments for the inflammatory autoimmune disease rheumatoid arthritis (see Chapter 16) is the administration of an antibody that binds to the cytokine TNF-α; in this case, the inhibition of TNF-α activity provides patients with relief from the symptoms of joint inflammation. The great utility of this antibody therapy has led to the development of related strategies for inhibiting cytokine actions in vivo. One successful approach has been to create a hybrid protein that has the ligand-binding domain of the cytokine’s receptor fused to the constant-region domains (Fc) of an antibody heavy chain (Fig. A.42). This Fc-fusion protein acquires the stability and long half-life of an antibody, but has the binding properties of the cytokine receptor. When given in vivo, the Fc-fusion protein binds to the cytokine, thereby interfering with the cytokine’s ability to stimulate its receptor on immune cells. As an example, the Fc-fusion protein containing the TNF-receptor ligand-binding domain has also been used as an effective treatment for patients with rheumatoid arthritis.
Antibody administration can also be used to augment the immune response by interfering with T-cell surface receptors, such as CTLA-4 or PD-1. When engaged by their ligands, these receptors normally function to downregulate the immune response. From experiments in mice, antibodies that bind to and inhibit these receptors have been found to enhance immune responses to tumors, leading in some cases to tumor eradication. Currently, these strategies are being tested in humans for a variety of tumor types, and the initial results have shown great promise.
In vivo administration of antibodies can also be used to deplete specific cell populations. The efficiency with which a given antibody functions for in vivo depletion is quite variable, as the mechanism relies on a process known as antibodydependent cellmediated cytotoxicity (ADCC) (see Section 10-23 and Fig. 10.36). When a cell is coated with antibodies, it becomes a target of natural killer (NK) cells that express the Fc receptor known as CD16 or FcγRIII. The cross-linking of FcγRIII induces the NK cell to kill the antibody-coated target cell. While FcγRIII is a receptor for IgG, it does not bind with equal affinity to all IgG subtypes; thus the efficiency of ADCC after administration of a given antibody is determined by its ability to cross-link FcγRIII and induce NK cell killing. Common uses for this technique include the depletion of CD4+ T cells with an antibody to CD4, or the depletion of CD8+ T cells with an antibody to CD8. In human patients undergoing organ transplantation, T cells are transiently depleted by administering an antibody to the CD3 component of the T-cell receptor complex. This produces a severe, but temporary, state of immunosuppression during the early stages of post-transplantation. As with all in vivo antibody depletion regimens, the depleted cell population gradually returns as cells of that subset are replenished by ongoing lymphocyte development.
Fig. A.42 In vivo administration of antibodies is an effective therapeutic.