In this chapter, we consider the various ways in which the immune system can be manipulated to suppress unwanted immune responses in the form of autoimmunity, allergy, and graft rejection, or to stimulate protective immune responses. Intentional manipulations of the immune system date back over 500 years to the use of variolation as a measure to protect against smallpox. In the late 1800s these measures advanced greatly with the development of numerous vaccines and antisera against other infectious agents. Later progress, against unwanted immune responses, came with the introduction of a number of now-conventional pharmaceutical agents; although these allow only relatively nonspecific control over unwanted immune reactions, they remain an important component of clinical medicine. More recently, these standard therapeutics have been joined by so-called biological therapeutics, or biologics, which are artificially produced versions of natural products, such as hormones, cytokines, and monoclonal antibodies, or derivatives of these such as engineered fusion proteins. These biologics possess extraordinary specificity, and though some have been used for decades, such as the hormone insulin in patients with type 1 diabetes, recent advances in cell biology and engineering have allowed for the introduction of a broad array of new biologics that allow for very precise manipulation of the immune system. Finally, long-standing efforts to deploy the power of the adaptive immune system against tumors have made major advances, and biologics that target negative regulators of immunity to stimulate protective responses against cancers have made a significant impact in clinical medicine. The categories of agents used to manipulate immune responses are listed in Fig. 16.1. This chapter will discuss these approaches, beginning with pharmaceutical agents used in clinical practice. In the first part of the chapter, we focus on efforts to relieve unwanted immune responses, and on advances in cancer treatment based on immune-system therapies. In the last part of the chapter, we discuss current vaccination strategies against infectious diseases, and consider how a more rational approach to the design and development of vaccines promises to increase their efficacy and widen their usefulness and application.
Treatment of unwanted immune responses.
Unwanted immune responses occur in many settings, such as autoimmune disease, transplant rejection, and allergy, which present different therapeutic challenges. The goal of treatment in all cases is to avoid tissue damage and prevent the disruption of tissue function. Some unwanted immune responses can be anticipated so that preventive measures may be taken, as in the case of allograft rejection. Other unwanted responses may be undetectable until after they become established, as is the case with autoimmune or allergic reactions. The relative difficulty of suppressing established immune responses is seen in animal models of autoimmunity, in which treatments that could have prevented induction of the disease are generally unable to halt it once it is established.
Treatment of unwanted immune responses.
Using the immune response to attack tumors.
Fighting infectious diseases with vaccination.
categories (Fig. 16.2). There are the powerful anti-inflammatory drugs of the corticosteroid family such as prednisone, the cytotoxic drugs such as azathioprine and cyclophosphamide, and the noncytotoxic fungal and bacterial derivatives such as cyclosporin A, tacrolimus (FK506 or fujimycin), and rapamycin (sirolimus), which inhibit intracellular signaling pathways within T lymphocytes. Finally, a recently introduced drug, fingolimod, interferes with signaling by the sphingosine 1-phosphate receptor that controls the egress of B and T cells from lymphoid organs, thus preventing effector lymphocytes from reaching peripheral tissues. Most of these drugs exert broad inhibition of the immune system, and suppress helpful as well as harmful responses. Opportunistic infection is therefore a common complication of immunosuppressive drug therapy.