Immunotoxicology: fifty years of global scientific progress.

The Immunotoxicology Specialty Section of the Society of Toxicology (SOT) celebrated the 50(th) Anniversary of the SOT by constructing a poster to highlight the milestones of Immunotoxicology during that half-century period. This poster was assembled by an ad hoc committee and intertwines in words, citations, graphics, and photographs our attempts to capture a timeline reference of the development and progressive movement of immunotoxicology across the globe. This poster was displayed during the 50(th) Annual SOT Meeting in Washington DC in March, 2011. The poster can be accessed by any Reader at the SOT Website via the link http://www.toxicology.org/AI/MEET/AM2011/posters_rcsigss.asp#imss. We dedicate this poster to all of the founders and the scientists that followed them who have made the discipline of Immunotoxicology what it is today.

Evaluation of a lymph node proliferation assay for its ability to detect pharmaceuticals with potential to cause immune-mediated drug reactions.

Hypersensitivity reactions to systemically administered drugs cannot be predicted using available preclinical models. This research is a collaborative project to evaluate the ability of the Lymph Node Proliferation Assay (LNPA) to predict systemic hypersensitivity caused by pharmaceuticals. The assay design is a modification of the Local Lymph Node Assay with the major modification being injection of the test substance subcutaneously to achieve a known systemic exposure to the drug. Fourteen compounds were evaluated in the LNPA. These were two clinically negative drugs (Metformin, phenobarbital), an assay positive control (streptozotocin), eight human hypersensitivity positive drugs (sulfamethoxazole, procainamide, clonidine, ofloxacin, nevirapine, abacavir, lamotrigine, zomepirac), and 3 investigational drugs (CM40874, CM40954 and CM40420), one of which caused hypersensitivity in primates. Hypersensitivity-positive drugs were classified as such based on at least two of three independent data sources: U.S. FDA postmarketing database, drug labeling information, and clinical trial data. All drugs were tested in multiple laboratories for a total of 2-12 evaluations per compound. The pure drug substance was used for testing if it could be obtained commercially, otherwise the marketed drug formulation was used. Neither of the negative control drugs showed a positive reaction in the test system. Four of the eight hypersensitivity positive drugs showed a mixed or positive reaction. Two of the three investigational compounds gave a positive response. A smaller number of LNPAs were run concurrently using footpad injection and evaluation of the popliteal lymph node and gave generally comparable results. Additional development may increase the reproducibility of the assay and facilitate detection of drugs that require metabolic activation to become allergenic, or drugs for which there is dose-limiting toxicity. The data suggest that this method might be useful as a first-line screen to identify candidate drugs that are more likely to cause a high prevalence of human drug hypersensitivity.

A brief history of immunotoxicology and a review of the pharmaceutical guidelines.

This article provides a brief history of the development of the field of immunotoxicology from one individual perspective and separates the discussion into five phases: the methods development and validation phase; the compound testing phase; the many meetings and organization of the specialty section phase; the mechanistic studies phase; and the guidelines phase. During the discussion of each phase, major highlights, accomplishments, contributors and key references are provided. The immunotoxicology guidelines for the testing of pharmaceutical chemical entities across the three major geographic axes are also presented and compared, along with some of the concerns raised by industry with these guidelines. The mandatory requirement of functional tests represents the major concern and difference between the Committee of Proprietary Medicinal Products (CPMP) and the new Food and Drug Administration (FDA) guidance. The scientific basis for the recommendation of the functional tests proposed in the guidance documents based on National Institute of Environmental Health and Safety/National Toxicology Program (NIEHS/NTP)-sponsored studies is described. Experience at Sanofi-Synthelabo, with the testing of 29 new chemical drug entities developed across a broad range of therapeutic classes using this testing paradigm and functional tests to define their immunotoxic potential, yielded a low number of compounds (6.8%) that produced any abnormal reaction. The two positive compounds might have been anticipated based on their pharmacology.

Consensus workshop on methods to evaluate developmental immunotoxicity.

A workshop cosponsored by the National Institute of Environmental Health Sciences and the National Institute for Occupational Safety and Health was convened in Washington, DC, on 17-18 October 2001 with the goal of developing a consensus document on the most appropriate experimental approaches and assays available to assess developmental immunotoxicity. The work group was composed of scientists from academia, the chemical and pharmaceutical industries, and federal agencies with expertise in developmental immunology, developmental toxicology, immunotoxicology, and risk evaluation. This consensus document presents an overview of the major summations made by the work group. A summary of early work in the field is provided, which includes potential immunotoxic agents, followed by brief discussions of our current understanding of developmental immunology. This report concludes with the work group's consensus of the most appropriate experimental design and tests to screen for potential developmental immunotoxic agents in experimental models, including potential limitations and data gaps.