Nonclinical evaluation of therapeutic cytokines: immunotoxicologic issues.
Cytokines are a diverse family of immunoregulatory proteins whose function has been the focus of intensive research for the past 25 years. Modern molecular biology techniques have resulted in production of these proteins in quantities sufficient to consider them as candidates for drug development. Due to the often pleiotropic nature of their action, in order to design meaningful nonclinical safety assessment studies, the practicing toxicologist must be able to differentiate between an exaggerated, but expected pharmacologic response and toxicity associated with their administration. Species specificity, nontraditional dose-response relationships, antigenicity, and unanticipated immunotoxicity are a few issues that must be considered when designing study protocols and interpreting data. In addition, despite validated methodology to examine the immune system as a potential target organ for toxicity, limitations exist in the ability to predict the autoimmune and allergenic potential of proteins such as these. Despite these challenges and limitations, over the past decade, many of these molecules have found clinical utility to treat a wide variety of diseases.
Thomas
Peter T
PT
Covance Laboratories Inc., Madison, WI 53704, USA. peter.thomas@covance.com
D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D013045:Species Specificity
D016207:Cytokines