World Allergy Forum: Immune Intervention
Lawrence M. Lichtenstein
We have, at present, more new therapeutic possibilities than at anytime in the past. The first of these is already in the clinic: Humanized anti-IgE. When this antibody is delivered intravenously, it decreases the free IgE level by more than 99% within minutes. The decrease in serum IgE causes a marked decrease in the IgE receptors on basophils and mast cells, with a half life of about 3 days. In the appropriate patients, that is, multiply allergic asthmatics, this therapy leads to mast cells and basophils which have too few IgE molecules directed against any single allergen to respond and therefore, the release of histamine, leukotrienes and cytokines is completely prevented. Note that because of the very low number of IgE receptors which need to be crosslinked, singly allergic patients or those allergic to only a few antigens will not respond in a clinically useful fashion.
For many decades, we and others interested in the immunotherapy of allergic disorders, have sought a particular type of adjuvant: One in which the allergenicity is decreased while the immunogenicity is maintained or increased. All previous attempts have led to molecules in which both allergenicity immunogenicity decreased in tandem. Allergen linked to oligonucleotides, obtained from bacterial DNA, changes an ongoing Th2 response to a Th1 response by decreasing specific IgE, increasing specific IgG, decreasing proinflammatory cytokines such as IL-3, -4, and -5, and increasing IFNg. The decreased allergenicity has been demonstrated in man by basophil histamine release and skin testing, while the increased immunogenicity has been demonstrated in primates. By the time of this meeting, I fully expect that this will be in man.*
Another equally promising new therapeutic approach deals with molecules which can block the function of chemokines and adhesion molecules. These come in many varieties. The first is humanized antibodies and this is typified by anti-IL-5 which has been put into man and shown to markedly decrease eosinophil number, although, surprisingly, without significant effect on bronchial reactivity. An anti-TNF is also in man but clinical results are not yet available. Another type of molecule is typically a soluble IL-4 receptor which has the effect of blocking IL-4's attachment to the cell-bound receptor. This, too, is in man. A soluble IL-13 receptor is being developed. Other molecules are being developed include antagonists to adhesion molecules on endothelium and on inflammatory cells. The one currently close to being in clinic is a VLA4 receptor antagonist.
I find it difficult to include airways remodeling in this introduction, but perhaps it fits the topic quite well. When these powerful anti-immune agents are used in man, the final question will be how far they can reverse already remodeled airways.
*Dr. Lichtenstein has equity in the company Dynavax, which is developing this product.