Treatments for unwanted immune responses, such as graft rejection, autoimmunity, or allergic reactions, include conventional drugs—anti-inflammatory, cytotoxic, and immunosuppressive drugs—as well as biologic agents such as monoclonal antibodies and immunomodulatory proteins. Anti-inflammatory drugs, of which the most potent are the corticosteroids, have a broad spectrum of actions and a wide range of toxic side-effects. Their dose must be carefully controlled, and they are normally used in combination with either cytotoxic or immunosuppressive drugs. The cytotoxic drugs work by killing dividing cells and thereby prevent lymphocyte proliferation, but they suppress all immune responses indiscriminately and also kill other types of dividing cells. The immunosuppressive drugs, such as cyclosporin A and rapamycin, interfere in specific signaling pathways and are generally less toxic, but are more expensive and still suppress the immune response somewhat indiscriminately.
Several types of biologic agents are now established in the clinic for treating transplant rejection and autoimmune diseases (Fig. 16.11). Many monoclonal antibodies have been approved for human use that deplete lymphocytes either generally or selectively, or inhibit lymphocyte activation through receptor blockade, or prevent lymphocyte migration into tissues. Immunomodulatory agents also include monoclonal antibodies or fusion proteins that inhibit the inflammatory actions of TNF-α, a triumph of immunotherapy.
16.2 and 16.8 can act in one of three general ways. First (red), they can act by depleting cells from inflammatory sites, causing global cell-specific depletion, or blocking integrin interactions, thereby inhibiting lymphocyte trafficking. Second (blue), agents may block specific cellular interactions or inhibit various co-stimulatory pathways. Third (green), agents may target the terminal effector mechanisms, such as the neutralization of various pro-inflammatory cytokines.
Fig. 16.12 Tumor rejection antigens are specific to individual tumors. Mice immunized with irradiated tumor cells and challenged with viable cells of the same tumor can, in some cases, reject a lethal dose of that tumor (left panels). This is the result of an immune response to tumor rejection antigens. If the immunized mice are challenged with viable cells of a different tumor, there is no protection and the mice die (right panels).
Using the immune response to attack tumors.
Cancer is one of the three leading causes of death in industrialized nations, the others being infectious disease and cardiovascular disease. As treatments for infectious diseases and the prevention of cardiovascular disease continue to improve, and the average life expectancy increases, cancer is likely to become the most common fatal disease in these countries. Cancers are caused by the uncontrolled growth of the progeny of transformed cells. A major problem in treating cancer is controlling metastasis, or the spread of cancerous cells from one part of the body to unconnected parts. Curing cancer therefore requires that all the malignant cells be removed or destroyed without killing the patient. An attractive way of achieving this would be to induce an immune response against the tumor that would discriminate between the cells of the tumor and their normal-cell counterparts, in the same way that vaccination against a viral or bacterial pathogen induces a specific immune response that provides protection only against that pathogen. Immunological approaches to the treatment of cancer have been attempted for more than a century, but it is only in the past decade that immunotherapy of cancer has shown real promise. An important conceptual advance has been the integration of conventional approaches such as surgery or chemotherapy, which substantially reduce tumor load, with immunotherapy.
16-13 The development of transplantable tumors in mice led to the discovery of protective immune responses to tumors.