To evaluate the functional significance of
bis(tri-n-butyltin)oxide (
TBTO)-induced thymus
atrophy, lymphocyte depletion in spleen and lymph nodes,
lymphopenia, and increased serum
IgM and decreased
IgG concentrations, in vivo and in vitro function studies were performed for specific and nonspecific resistance. Weaned male rats were fed diets containing 0, 20, or 80 mg
TBTO/kg for at least 6 weeks. Regarding the thymus-dependent immunity, delayed-type
hypersensitivity reactions to
ovalbumin as well as
tuberculin were significantly depressed at both dietary concentrations. Resistance to the nematode Trichinella spiralis was significantly suppressed as shown by a retarded expulsion of adult worms from the small intestine, increased counts of muscle larvae, reduced inflammatory reaction in parasitized musculature, and suppressed serum
IgE titers. Also the secondary
mercaptoethanol-resistant (presumably
IgG) hemagglutinating antibody titer to sheep red blood cells was significantly reduced, while no significant alterations were found in
IgM and
IgG titers to T. spiralis,
ovalbumin, and
tetanus toxoid.
TBTO exposure reduced the response of thymocytes in both treatment groups and of spleen cells in the 80-mg/kg group upon stimulation with T-cell
mitogens and increased the response of spleen cells to B-cell
mitogens. When calculated per whole spleen, the response to T-cell
mitogens was strongly impaired but unaltered by B-cell
mitogens. This difference can be explained by a relative increase of splenic B cells as a result of reduced numbers of T cells, as shown by cell surface marker analysis using
monoclonal antibodies. Reduced splenic T-cell numbers appeared equally due to a decreased number of T helper and to T suppressor cells. From these data and from results of a time-sequence study in which effects of
TBTO on cell count and cell viability of thymus, spleen, and bone marrow were investigated, it is concluded that
TBTO-induced immunodeficiency was primarily due to its direct
toxic action on thymocytes. When cultured in vitro in the presence of
TBTO, viability of thymus and bone marrow cells was equally reduced, while after in vivo treatment viability of bone marrow cells was unaffected. Thus, the in vitro situation does not mimic the in vivo one. Concerning the nonspecific resistance,
TBTO reduced macrophage function as shown by impaired splenic clearance of Listeria monocytogenes bacteria. From in vitro studies it is concluded that impaired in vivo splenic clearance was due to a reduction in both the number of adherent cells in the spleen and bacterial digestion on a cell for cell basis.(ABSTRACT TRUNCATED AT 400 WORDS)