There was an inverse relation between the CD(4) counts and the incidence and severity of skin diseases in the HIV/AIDS patients. Cutaneous manifestations of HIV can be considered as good clinical indicators to predict and access the underlying immune status in resource-poor countries.

Over the past 30 years, the world of pharmaceutical toxicology has seen an explosion in the area of cytokines. An overview of the many aspects of cytokine safety evaluation currently in progress and evolving strategies for evaluating these important entities was presented at this symposium. Cytokines play a broad role to help the immune system respond to diseases, and drugs which modulate their effect have led to some amazing therapies. Cytokines may be "good" when stimulating the immune system to fight a foreign pathogen or attack tumors. Other "good" cytokine effects include reduction of an immune response, for example interferon β reduction of neuron inflammation in patients with multiple sclerosis. They may be "bad" when their expression causes inflammatory diseases, such as the role of tumor necrosis factor α in rheumatoid arthritis or asthma and Crohn's disease. Therapeutic modulation of cytokine expression can help the "good" cytokines to generate or quench the immune system and block the "bad" cytokines to prevent damaging inflammatory events. However, care must be exercised, as some antibody therapeutics can cause "ugly" cytokine release which can be deadly. Well-designed toxicology studies should incorporate careful assessment of cytokine modulation that will allow effective therapies to treat unmet needs. This symposium discussed lessons learned in cytokine toxicology using case studies and suggested future directions.

Despite the potential for the chemokine class as therapeutic targets in immune mediated disease, success has been limited. Many chemokines can bind to multiple receptors and many receptors have multiple ligands, with few exceptions. One of those exceptions is CCL20, which exclusively pairs to CCR6 and is associated with several immunologic conditions, thus providing a promising therapeutic target. Following successful evaluation in a single dose, first time in human clinical study, GSK3050002-a humanized IgG1 monoclonal antibody against human CCL20-was evaluated in a 26-week cynomolgus monkey toxicology study. A high incidence of unexpected vascular and organ inflammation was observed microscopically, leading to the decision to halt clinical development. Here we report a doseresponsive increase in the incidence and severity of inflammation in multiple organs from monkeys receiving 30 and 300 mg/kg/week by either subcutaneous or intravenous injection. Histomorphological changes resembled an immune complex-mediated pathology, which is often due to formation of anti-drug antibodies in monkeys receiving a human protein therapeutic and thus not predictive of clinical outcome. However, the presentation was atypical in that there was a clear dose response with a very high incidence of inflammation with a low incidence of ADA that did not correlate well individually. Additionally, the immunohistologic presentation was atypical in that the severity and distribution of tissue inflammation was greater than the numbers of associated immune complexes (i.e., granular deposits). An

The minipig has long been identified as the nonrodent animal of choice for preclinical safety evaluation of topically applied materials. This article reviews types of topical applications, study designs, and practical considerations. Dermal administration to the minipig presents multiple challenges. Issues to be considered are the area of exposure, the nature of the test article, the need for covering of the dose site, preparation of the dose site, and procedures for administration. The potential for cross-contamination (exposure of control animals to test article) is very high in topical studies and appropriate safeguards to prevent this are discussed. Topical administration to the intact skin is the most commonly utilized form of safety evaluation, but procedures have also been developed for intradermal administration and for the use of nonintact/wounded skin; these will be discussed. Evaluation of local (topical) effects is critical and can become complicated. Considerations in evaluations of the skin are interobserver variability, use of different scoring systems and discrepancies between in vivo observations, necropsy observations, and microscopic pathology findings. Causes for apparent discrepancies and suggestions for practical resolution through appropriate procedures are discussed. Practical issues in necropsy and histotechnology procedures and techniques to optimize preservation of skin are also discussed.