Studies being conducted as part of an interagency agreement between NIEHS and FDA as part of the NIEHS AIDS effort are determining the relationship between decrements in immune cell phenotypes and susceptibility to infection or tumors. Studies conducted in the laboratory of Dr. James Weaver at FDA, using monoclonal antibodies (Moabs) against CD4 and CD8, to establish titration curves for the depletion of these cell subpopulations in B6C3F1 mice have been completed. At NIEHS, we are examining the effects of cell depletion in specific host resistance models. These models include infection using bacteria (Listeria monocytogenes or Streptococcus pnuemoniae), an intracellular parasite (Plasmodium yoelii) or virus (Influenza) and a tumor challenge (PYB6 or B16F10). Three host resistance models will be evaluated for each cell subpopulation, with the selected model dependent on the specific target cell. Two PYB6 tumor challenges have been completed in mice depleted of CD4+ or CD8+ cells. As expected, no significant differences were observed in frequency or latency of PYB6 tumors following CD8 depletion. Surprisingly, no significant differences were observed in frequency or latency of PYB6 tumors following CD4 depletion. In contrast, depletion of CD4+ cells had significant effects on clearance of parasitized erythrocytes following infection with Plasmodium yoelii. Studies examining the effects of CD4 and CD8 cell depletion following challenge with Listeria monocytogenes are in progress. The identification of chemicals that have the potential to cause injury to the immune system is of considerable public health significance, as alterations in immune function can lead to increased incidence of hypersensitivity disorders, autoimmune or infectious diseases or neoplasias. Experimental animal data collected over the past 15 years using standardized testing panels has provided a database from which the sensitivity and predictability of a variety of tests commonly used for the screening of chemicals for immunotoxicity has been evaluated. These results have been used as guidelines for risk assessment in immunotoxicity and have been the basis for a number of regulatory activities. In April 1998 a Workshop was held at NIEHS to establish study design to determine the sensitivity and predictability of extended histopathology as an indicator of immunotoxicity as compared with the National Toxicology Program's functional testing battery. Standardized slide sets were generated for 10 chemicals, which had previously been evaluated for their immunotoxicity using functional tests. The histological evaluation of the slides has been completed and the data has been incorporated into a database. Dr. Michael Kashon at NIOSH is examining the correlation between the pathologists for the endpoints examined. The data indicate that for a majority of the outcomes, there was good agreement between the pathologists. However, even for variables with excellent agreement there was some evidence of inconsistency between pathologists. A direct comparison of the ratings for each pathologist indicates that, even where there was good agreement, certain individuals tended to be more conservative while others were more able to discern subtle changes than others. Additional analyses examined the consistency of a pathologist?s ratings in a single tissue by investigating the correlation among all the measures in the same tissue type. When data from all pathologists were combined, measures in each of the fou r tissues seemed highly correlated with the other measures from that tissue. However, when correlations were examined for each pathologist independently, only the thymus evaluations maintained the same high degree of correlation. For spleen, bone marrow and lymph node measures, the outcomes for each pathologist were less well correlated, raising concern about the consistency of a pathologist's ratings across different measure s in each of these tissues. A manuscript reporting these findings is in preparation.
