Since common allergies are mediated primarily by IgE antibodies, the objectives of the investigations are (i) the further elucidation of the cellular mechanisms underlying the production of this class of antibodies, and (ii) the synthesis of appropriate conjugates of monomethoxypolyethylene glycol (mPEG) and polyvinyl alcohol (PVA), respectively, with allergens and haptens, which are capable of specifically suppressing the formation of IgE antibodies. Such mPEG conjugates have been shown to abrogate the induction of IgE and IgG antibodies if administered prior to sensitization, but to enhance the production of IgG (i.e., blocking or protective) antibodies in both allergic patients and animals if administered after sensitization. Studies are proposed to unravel the cellular basis for this dual immunological potential of mPEG conjugates which may reflect the heterogeneity of different subpopulations of B cells with respect to their state of differentiation and their reactivity with these conjugates. As a result of the chemical modification of allergens by coupling to mPEG, the products are safer for injection into patients in much higher doses than conventional allergenic extracts. The results of ongoing clinical trials performed in different countries (under the aegis of Pharmacia AB of Uppsala) are promising, in that the patients so treated appeared to have fewer symptoms and required less medication. The effectiveness of mouse monoclonal antibodies (MoAbs), which are being increasingly used for diverse therapeutic purposes in man (in particular in relation to organ transplantation, tumor localization and destruction) is counteracted by their inherent immunogenicity. Preliminary results in our laboratory indicate that this complication can be overcome by pretreatment of the recipients of MoAbs with mPEG conjugates of MoAbs. The use of tolerogenic mPEG conjugates is being also extended to include mPEG derivatives of natural xenogeneic hormones or of diverse biologically active factors synthesized by recombinant DNA technology, which are immunogenic as has been demonstrated for human growth hormone (GH) and insulin. Studies have just been initiated in this laboratory for the synthesis of tolerogenic conjugates of GH.
