Pharmacological strategies using biologics as immunomodulatory agents

Immunosuppression has been used by physicians for many decades for blocking the unwanted activities of the immune system. In the last century, the history of therapeutic immunosuppression has paralleled the history of immunology as studies on "transplantation immunity" have allowed us to gain a deeper understanding of the rules of activation and regulation of adaptive immunity.1 The discovery of the major histocompatibility complex (MHC) dates back to 1967,2 and since then we have understood the rules of antigen presentation and cross-presentation, cognate interaction, activation of the different T cell subsets, and antibody production. MHC typing has allowed us to better match organ donors with recipients, but has not avoided the need for immunosuppressive treatments to the recipient. Depending on the type of transplant (bone marrow or solid organs), immunosuppressive regimens could include whole body irradiation and immunosuppressive drugs, such as cytostatic molecules (azathioprine was first used as an immunosuppressive treatment in a kidney transplant in 1959), antimetabolites, corticosteroids, and antibodies against leukocytes and their products. The rough concept is that during an immune response against the allotransplant, the specific immune cells start proliferating and are metabolically active, thus they are better targets for drugs inhibiting metabolism and proliferation. The drawback is that several other cell types in the body are metabolically active and proliferating, for instance the epithelial cells of respiratory and gastrointestinal mucosae, hair follicles, and several others, including immune cells when combating an infection or a disease. Thus, life-long generalized immunosuppression may allow the allotransplant to survive in the host, but it can cause side effects that can become severe and life-threatening. Immunosuppressive strategies are used not only for transplanted patients but also, more widely, for treating asthma and allergies, and autoimmune and chronic inflammatory and degenerative diseases, that is, pathologies due to the deranged reaction of the immune system either to innocuous agents (eg, pollens), or to endogenous molecules and structures (autoreactivity), including cell membrane components, nuclei, DNA, and myelin. Most of these diseases have, in addition to the component of anomalous adaptive immune reactivity (for instance the production of autoantibodies), a strong inflammatory component. This includes all the mechanisms of innate immunity, with activation of leucocytes, production of inflammatory factors, and consequent tissue damage/destruction. The persistent inflammatory activation can also bring about the anomalous feed-back activation of repair mechanisms that may lead to nonfunctional neotissue apposition and pathological fibrosis, as in the case of systemic sclerosis. Immunosuppressive and anti-inflammatory treatments are in the vast majority of cases life-long treatments, since the immunosuppressive strategies basically address the damage-inducing immune activation caused by the disease, rather than the cause of the disease.