Meeting Report Immune-Mediated Drug Hypersensitivity Reactions (IDHR) Workshop.

Immune-mediated drug hypersensitivity reactions (IDHR) are relatively rare reactions to drugs that can be observed in a limited population of patients, yet these reactions can have significant impacts on public health, clinical practice, and drug development. Despite the potentially significant impact of IDHR, research into the causes and mechanisms of action of these reactions has been limited. In order to identify and enhance potential research opportunities in IDHR, the Health and Environmental Sciences Institute (HESI) hosted a two-day workshop involving stakeholders from government, academia, and industry. Discussions focused on ways to increase IDHR research opportunities within both presently existing collaborative structures and new networks. Based on these discussions, workshop participants concluded that a volunteer organization of interested stakeholders could be established to provide for ongoing advocacy and coordination of efforts related to IDHR research. The primary objectives of such an organization would be to increase public awareness of the impact of IDHR, encourage multidisciplinary IDHR research and training, encourage the development and funding of IDHR research network and seed grants, and to establish a framework for the further exchange and dissemination of IDHR information.

A proposed testing framework for developmental immunotoxicology (DIT).

A group of thirty immunotoxicology experts from the U.S. and E.U. representing government, industry, and academia met in May 2003, in Washington, D.C., to reach consensus regarding the most appropriate methods to assess developmental immunotoxicology (DIT) for hazard identification, including under what conditions such testing might be required. The following points represent the major conclusions from this roundtable discussion: (1) the rat is the preferred model; (2) any DIT protocol should be based on immune assays already validated; (3) DIT methods should be incorporated into standard developmental and reproductive toxicity protocols to the extent possible rather than a "stand-alone" protocol; (4) the approach to address DIT potential should be similar for chemicals and drugs, but the experimental design should be flexible and should reflect the specific questions to be answered; (5) it is possible to utilize a study design that assesses all critical windows in one protocol, with the results leading to further study of specific effects, as warranted; (6) animals should be exposed throughout the treatment protocol; (7) the triggers for DIT may include structure-activity-relationships, results from other toxicity studies, the intended use of a drug/chemical and/or its anticipated exposure of neonates and/or juveniles.

2,3,7,8-tetrachlorodibenzo-p-dioxin does not directly alter the phenotype of maturing B cells in a murine coculture system.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), acting through the aromatic hydrocarbon receptor (AhR), elicits numerous toxicological effects, including immunosuppression. Previous work from our laboratory has suggested that TCDD exposure in mice is associated with altered lymphopoietic development, in particular altered B-cell phenotype in the bone marrow. It remains to be determined which specific hematopoietic populations or subpopulations within the marrow cavity are directly targeted by TCDD. To examine the effects of TCDD on developing B cells in vitro, a stromal coculture model was used. Primary bone marrow cells from male, 6- to 7-week-old C57Bl/6 mice were cocultured separately on two AhR-containing stromal cell lines (M2-10B4 and S17) that support B-cell development in the presence of IL-7. The cocultures were treated with 0 to 10 nM TCDD. Shifts in phenotype were quantified by cell surface marker staining and flow cytometry. Four populations in the maturing B cell (very early pre-pro-B, pre-pro-B, pro-B, and pre-B) were defined for quantification. The results show that the only statistically significant effect of TCDD was within the pre-pro-B population in cultures with the S17 stromal cell line. The increase in number of cells with this phenotype was seen in cultures with both wild-type and AhR-/- primary bone marrow cells. These results suggest that the maturing B220+ B cell is not the direct target for TCDD-induced bone marrow B-cell alterations.