Chickens are notorious for the fact that they carry bacteria such as Salmonellae and Campylobacter, which can cause zoonoses by contamination of the end product, without hampering growth and development of the chicken itself. This carrier status can only been explained by the inability of the chickens immune system to eliminate the pathogen, this in turn being due to insufficient humoral responses towards the polysaccharides of the bacterial capsule. In a previous study, we demonstrated that in chickens a model thymus-independent type 2 (TI-2) polysaccharide antigen, trinitrophenylated Ficoll (TNP-Ficoll), hardly evokes a humoral immune response. Furthermore this TI-2 antigen was shown to exhibit a very specific initial localization pattern after intravenous injection, i.e. in the periellipsoidal lymphocyte sheaths (PELS) and the surrounding ring of macrophages. The functional equivalent of these macrophages in mammals, the marginal zone macrophages, were shown to suppress the humoral responses against TI-2 antigens. Therefore we investigated whether other standard TI-2 antigen models also induce low antibody responses, whether this low response is dose-dependent, and whether macrophages are responsible for this low response. It was found that other TI-2 antigens, such as hydroxyethyl starch and detoxified lipopolysaccharides, also induced very low IgM and IgG responses, indicating a general phenomenon that could not be overcome by using a higher dose of antigen. In addition, selective depletion of splenic macrophages with liposomes containing dichloromethylene diphosphonate prior to immunization increased the specific humoral response to TD and TI-1 antigens, but failed to do so for TI-2 antigen. This result indicates that the low humoral responses are not (only) due to a macrophage suppressive activity but also to other yet unknown mechanisms, for example the lack of responsive B cells in the splenic PELS.