Regulation of IgE production in pre-sensitized animals: in vivo elimination of alveolar macrophages preferentially increases IgE responses to inhaled allergen.

Intratracheal inoculation of dichloromethylene diphosphonate encapsulated in liposomes leads to the rapid accumulation of this drug in alveolar macrophage (AM) phagolysosomes, and the death of the majority of these cells over the ensuing 24-48 hr. The technique is highly selective for phagocytes and has no detectable side-effects on other cells in the lung. The present experiments demonstrate that following AM depletion, pre-sensitized animals respond to aerosol challenge via secondary serum IgE (but not IgG) responses, and the accumulation of large numbers of allergen-specific and non-specific antibody forming cells in respiratory tract regional lymph nodes and in lung and airway tissues; the latter comprise both IgE and IgG plasma cells, which were detected in the approximate ratio of 2.5:1. Moreover, aerosol challenged AM-depleted animals develop large mononuclear cell infiltrates in the lung and airways, which includes a substantial CD4+ T-cell component. These results suggest a major role for AM in regulating the magnitude of secondary IgE responses to inhaled allergen.

The distribution of IgE plasma cells in lymphoid and non-lymphoid tissues of high-IgE responder rats: differential localization of antigen-specific and 'bystander' components of the IgE response to inhaled antigen.

Repeated exposure of high-IgE responder rats to antigen-containing aerosols stimulates IgE responses which last for several weeks, and are eventually terminated with the onset of immunological tolerance. Studies on the distribution of total and antigen-specific IgE plasma cells and IgE mRNA during antibody production, identified the lymph nodes draining the lower respiratory tract as the primary site for initiation of the IgE response to inhaled antigen; subsequently the response seeded to mucosa-associated lymph nodes but not to central lymphoid organs. A vigorous 'bystander' IgE response (approx. x 10 the specific response) was also observed, but this was restricted to areas directly draining sites of deposition of inhaled antigen, including non-lymphoid respiratory mucosal tissues. Despite the rapid termination of the specific IgE response after the fourth week of exposure, the bystander component persisted. These results are discussed in relation to the role of cognate/non-cognate T-B interactions in the IgE response to inhaled antigens, and the relative susceptibility of each component to T-cell regulation in vivo.

Regulation of T-cell sensitization at epithelial surfaces in the respiratory tract: suppression of IgE responses to inhaled antigens by CD3+ Tcr alpha-/beta- lymphocytes (putative gamma/delta T cells).

Repeated exposure of Brown Norway rats to an aerosol of ovalbumin (OVA) induced a state of antigen-specific immunological tolerance, particularly in the IgE isotype. Tolerance was transferable to naive syngeneic animals by inoculation of splenic T cells from tolerant rats. Sequential depletion of tolerant spleen cells by sorting techniques prior to adoptive transfer, employing T-cell subset-specific monoclonal antibodies, indicated that the cells mediating tolerance were CD3+, CD4-, CD5+ and CD8+, but lacked alpha or beta chains in the T-cell receptor (TcR), suggesting that they may be part of the gamma/delta T-cell lineage. Consistent with this suggestion, the sorted population demonstrated considerable enrichment for TcR gamma chain-specific mRNA. As few as 2 x 10(3) cells are sufficient to adoptively transfer tolerance in 200-g adult rats in this model.

Regulation of IgE responses to inhaled antigens: cellular mechanisms underlying allergic sensitization versus tolerance induction.

Previous research from our laboratory has established that the natural response of the respiratory mucosal immune system to inhaled allergens involves initial 'recognition' accompanied by transient low-level IgE production, followed by the development of protective immunological tolerance. Recent studies indicate that the crucial cellular events in this process occur at the level of the upper respiratory mucosa and in the local draining lymph nodes. Salient findings from ongoing studies, detailed below, include identification of a highly developed network of dendritic antigen-presenting cells within the airway epithelium which trap inhaled antigen, and definition of the surface phenotype of the suppressor T cells mediating tolerance as TcR gamma + delta +.