The long-term objectives are to elucidate further (i) the cellular mechanisms underlying the regulation of IgE antibody responses and their specific suppression by conjugates of haptens and antigens with, respectively, polyvinyl alcohol (PVA) and monomethoxypolyethylene glycol (mPEG) and (ii) the cellular basis for persistent IgE antibody production. The IgE antibody response in atopic patients and appropriately immunized mice lasts for many months and even years. This protracted IgE antibody response may include (i) the generation of long-lived antibody forming cells and (ii) the sustained recruitment of B cells by persistent antigen, bound possibly in the form of antigen-antibody complexes to lymphoid follicular dendritic cells. Hence, experiments will be performed (a) to evaluate the relative contributions of these two mechanisms to the overall IgE response and (b) to determine the susceptibility to suppression of the persistent IgE antibody component. Protein-mPEG conjugates may bind to cells by intercalation of the mPEG chains into the cell membrane lipid bilayer. It is proposed to study the uptake of such conjugates by lymphocytes and antigen presenting cells and to establish the in vivo and in vitro effects of mPEG conjugate pulsed cells. mPEG conjugates lead to a decrease in antibody levels and the residual persisting IgE antibodies have reduced affinity for antigen. Studies will be conducted to determine the cellular basis for this phenomenon and to characterize the effects of such changes in antibody affinity on the sensitivity of mast cells. IgE responses to trimellitic anhydride (an industrial chemical responsible for occupational respiratory disorders) will be induced in mice and rats by the respiratory route. Anti-trimellityl (TM) responses will be suppressed by TM-PVA conjugates and the degree of suppression will be assessed by in vitro techniques and measurements of respiratory responses. The immunotherapeutic potential of mPEG conjugates with common allergens is being explored in clinical trials in Canada, Switzerland and Sweden. The broader application of these immunosuppressive modalities to human disorders will be tested by the use of mPEG conjugates with biologically active foreign proteins that are therapeutically employed.
