Immunomodulatory therapy

Abstract

In veterinary dermatology, the therapeutic approach to numerous diseases (e.g. hypersensitivity and autoimmunity) centres upon suppression of an overactive immune system. By contrast, in other situations such as infectious diseases and cancer, it may be desirable to enhance an ineffective immune response. Currently available methods of such immunomodulation are relatively crude. Immunosuppression is generally achieved with systemic administration of glucocorticoids, with or without concurrent cytotoxic agents. These drugs affect the function of a wide range of immune cells and produce a blanket immunosuppression that not only inhibits the desired immune response, but may also nonspecifically inhibit protective responses to potential pathogens. Even more refined agents, such as cyclosporin A, have broad immunosuppressive effects on T lymphocytes of a wide range of antigenic specificity. Similarly, current immunomodulatory drugs (e.g. levamisole and bacterial derivatives) are relatively crude agents with poorly characterised modes of action and poor clinical efficacies.There are some exceptions amongst the current broad‐spectrum approach to immunomodulation, including hyposensitization therapy for atopic dermatitis, autogenous vaccination for staphylococcal pyoderma, and the use of intravenous gammaglobulin therapy for immune‐mediated skin disease. These procedures may be clinically effective, but the mechanisms of their effects are not fully understood. The use of recombinant cytokine therapy (e.g. omega interferon) is a further example of the beginnings of the use of more targeted immunotherapy in veterinary medicine.Future approaches to the treatment of numerous diseases will involve novel immunomodulatory agents. Such therapies derive from rapid progress in understanding basic immunological mechanisms, particularly the concept that most immune responses are regulated by cytokines released by specific populations of T lymphocytes: Th1, Th2, Th3 and Treg. Currently, much attention focuses on the cytokine IL‐10, which has a key role in the suppression of autoimmune and allergic responses. With this knowledge, therapies aimed at manipulating the cytokine milieu, or inducing a particular cytokine profile at the time of antigen exposure, are under investigation. There are various approaches to achieving this aim, including: (1) administration of recombinant cytokines; (2) administration of monoclonal antibodies that can neutralise specific cytokines or block other immunological processes; and (3) administration of genes encoding cytokines via carrier microbes or naked DNA therapy that may be enhanced by the use of molecular adjuvants. Other novel therapeutic approaches focus on the delivery of antigens, small peptides derived from such antigens, or genes encoding antigens delivered via novel routes, including percutaneous, intranasal and oral. Depending upon the protocol, use of these delivery routes can stimulate potent mucosal immune responses, often using mucosal adjuvants, or alternatively, induce systemic tolerance to an autoantigen or allergen. The final application of molecular biology to disease management is gene replacement therapy for animals with absent or mutated genes. This methodology has already been experimentally applied to dogs with Factor IX deficiency (haemophilia B). In reality, gene replacement is likely to be considered less important than elimination of particular monogenic traits from animals by genetic testing.