David H. Katz

The Allergic Phenotype: Manifestation of‘Allergic Breakthrough’and Imbalance in Normal‘Damping’of IgE Antibody Production

Antibody responses of the IgE class are, like other immxinoglobulin classes, regulated by a finely-txined network of complex cellular and molecular interactions (reviewed in Tada 1975, Ishizaka 1976, Katz 1977, 1978). The IgE system, however, has certain unique aspects to it in terms of regulatory controls for reasons that probably pertain to the biological importance of the IgE system itself. We believe, for example, that the IgE antibody system plays an important defense role against certain offending exogenous antigens, particularly those which gain access through mucoepithelial and epithelial surface linings such as the respiratory and gastrointestinal tract and skin. This defense role is performed predominantly as a consequence of the property of IgE molecules unlike other immunoglobulin molecules to bind specifically and avidly to the surface membranes of tissue-fixed mast cells and circulating basophils which express on their surfaces specific receptors for the determinants on the Fc portion of IgE. Since both of these cell types possess abundant quantities of pharmacologically-active mediators, and since their Fc receptors for IgE molecules do not discriminate such molecules on the basis of their antigen specificity, an enormous amplification mechanism exists within this system for permitting relatively small numbers of molecules to exert the desired biological effect Hence, it seems that the overall regulatory control of IgE antibody production has been tailored to

Adaptive Differentiation of Lymphocytes: Theoretical Implications for Mechanisms of Cell—Cell Recognition and Regulation of Immune Responses

Publisher Summary This chapter discusses cell–cell interactions in immune responses and their relationship to immune response (Ir) and other major histocompatibility complex (MHC) genes. The chapter presents concept involving cell interaction (CI) molecules of primary importance in self-recognition, which is envisioned as the products of Ir genes. It explains the high degree of polymorphism among the MHC genes and the frequency of lymphocytes in any one individual that appear to be specific for histocompatibility antigens of other individuals. The MHC is a family of genes encoding a variety of cell surface marcomolecules first identified and studied for their role in transplantation rejection reactions. The transplantation antigens encoded by MHC genes in several different species have been thoroughly analyzed serologically and by modern biochemical techniques. Two features of the MHC have been particularly provocative in stimulating numerous speculations and posing questions. These are (a) the high degree of polymorphism within the family of MHC genes in any given species and (b) the high frequency of immunocompetent lymphocytes existing in any one individual that appear to be specific for MHC products displayed on cells of other individual members of the species. The process of adaptive differentiation is one in which highly effective selective mechanisms are initiated by contact between developing cells and the normal cell interaction molecules predominantly expressed in the surrounding environment.

Control of IgE antibody production by suppressor substances

The incidence of diagnosed allergies and allergic disease-related problems is certainly not decreasing by any means. Moreover, despite enormous technological advances in many areas of modem science, the therapeutic alternatives offered to allergic patients today are not that much better than those offered ten years ago. Understanding, in every detail, the controlling mechanism(s) regulating IgE antibody production is the goal that must be reached in order to permit development of new therapeutic approaches that are, at the same time, comprehensive, effective, and safe for use in a variety of human allergic diseases in which the IgE antibody system plays an important pathogenetic role. Our own involvement in studies of this system has left us with the strong impression that detailed knowledge of the regulatory phenomena controlling responses of the IgE antibody class could very well shed valuable insights on the nature of genetic, cellular, and molecular regulatory events governing the general immune system, in addition to furthering our understanding of the pathophysiology of allergic states. Moreover, it is our optimistic belief that we are rapidly approaching a new threshold in our understanding of the mechanisms controlling allergic responses such that in the very near future we may be able to offer more effective modes of therapy for alleviation of many allergic disorders. In this presentation, an overview will be given of the modem concepts of the cellular and molecular mechanisms controlling IgE antibody production, at

The Induction of Autoreactive T Lymphocytes by Allogeneic Effect Factor (AEF): Relevance to Normal Pathways of Lymphocyte Differentiation

Soon after the discovery of the collaboration between thymus-derived (T) and bone marrow-derived (B) lymphocytes in the development of humoral immune responses (Claman et al. 1966, Davies et al. 1966, Mitchell & Miller 1968), it was found that a soluble mediator generated in a mixed lymphocyte culture {MLC) could have profund effects on in vitro antibody responses to T-dependent antigens (Dutton et al, 1971), In the subsequent 9-year period there have been numerous reports about the ability of antigen-nonspecific soluble mediators, derived mostly by alloantigen or mitogen stimulation of T cells, as well as antigen-specific factors, to replace the normal requirement for carrier-specific helper T cells in antibody responses (reviewed in Katz 1977),

The Biology of Monoclonal Lymphokines Secreted by T Cell Lines and Hybridomas

Publisher Summary Because of recent methodological developments in two major areas—namely, the ability to immortalize functional T lymphocytes by somatic cell hybridization or viral transformation and cloning of such functional T cell lines—the biology of monoclonal lymphokines (LK) has come under light. Combination of these two methodologies enables to establish cloned T cell lines that secrete only one or very few LK species in practically unlimited quantities. Purified LK has a tremendous potential as therapeutic tools. This potential should first be explored in experimental models and, subsequently, translated into clinical situations. The suppression of immunity in an antigen-specific or nonspecific manner may be beneficial in autoimmune diseases, organ transplantation, and IgE-mediated allergic responses. On the other hand, the potentiation of immune responses would be desirable in all kinds of diseases that result in generalized immunosuppression, for example, cancer, viral disease, and parasitic infections. The best evidence for the intensity and productivity of research on LK production by cloned T cell lines should probably come in the form of a long list of related reports. Thymus-dependent T lymphocytes play a pivotal role in the complex interactions between various effector and regulatory cells of the reticuloendothelial system. T cells are known to interact with B cells, with macrophages, and among themselves. It has been documented that soluble mediators produced predominantly by activated T cells can have profound regulatory effects on the immune system, and others, of the multicellular organism. The technique of somatic cell hybridization for immunologically relevant cells has provided a revolutionary tool for immunological studies. Because the search for antigen-specific neoplastic T cells has been so unsuccessful, in contrast to the many antigen-binding plasmacytomas that were discovered, immunologists have sought other ways for creating deliberately neoplastic T cells expressing antigen-specific function.

The Allogeneic Effect on Immune Responses

The allogeneic effect cannot be elicited by the transfer of lymphoid cells from allogeneic or semiallogeneic donors under circumstances where the transferred cells are incapable of reacting immunologically against tissue antigens of the host. This is true despite the fact that, in the intact animal model, the transferred cells, by virtue of possessing foreign histocompatibility antigens, elicit a specific rejection response on the part of the host. The central requirement for obtaining an allogeneic effect is the occurrence of a mixed lymphocyte reaction. Whereas this is most favorable when major histocompatibility differences exist, it is also possible to obtain an allogeneic effect across other transplantation differences. In the mouse, for example, it has been clearly shown that an allogeneic effect can be induced by transfer of cells identical at H-2 but differing at the Mls locus either in vivo or in vitro . The fact that concomitant development of a host rejection response, or reaction of the primed cell population against those of the aggressor, is not required for expression of the phenomenon has important implications concerning the nature of the cellular interactions involved, and is discussed in the chapter.

The IgE Antibody System Is Coordinately Regulated by FcR Epsilon-Positive Lymphoid Cells and IgE-Selective Soluble Factors

Recent studies in mice have demonstrated that exposure of lymphocytes to appropriate levels of IgE initiates a cascade of cellular and molecular interactions which function as a network to control IgE synthesis. A key manifestation of these events is the expression of Fc receptors for IgE (FcR epsilon) on both B and T lymphocytes, and the fact that such expression of FcR epsilon can be selectively modulated by the isotype-specific regulatory mediators, suppressive factor of allergy (SFA) and enhancing factor of allergy (EFA). In humans, we have previously shown that the in vitro induction by pokeweed mitogen (PWM) of IgE biosynthesis by peripheral blood lymphocytes (PBL) can also be selectively suppressed by SFA. Herein we show that PWM also induces expression of FcR epsilon+ and FcR gamma+ cells among human PBL by day 2 or 3 in culture, and this early development of FcR epsilon+ lymphocytes appears to be a coordinate event with the ultimate de novo synthesis of IgE in this system. Moreover, as previously documented for IgE synthesis, the presence of SFA causes a 50% reduction of FcR epsilon+ cells induced by PWM. This inhibition is selective, since FcR+ cells for IgG are not affected by exposure to human SFA derived from a recently constructed human T cell hybridoma line which constitutively secretes large quantities of biologically active human SFA. These findings further support the regulatory role that FcR epsilon+ lymphocytes must play in the development of IgE responses by human cells in vitro, and suggest a mechanism by which SFA can selectively inhibit IgE synthesis in PWM-stimulated cultures of human PBL.

New concepts concerning the clinical control of IgE synthesis

Prospects for new therapeutic approaches to IgE‐mediated allergic diseases have arisen from (1) recent experimental observations that have suggested new concepts concerning the pathogenesis of the allergic phenotype, and (2) adaptation of previously‐described methods for induction of specific immunological tolerance to problems in allergy. The bases for these new approaches to allergic diseases are summarized herein.

Genetic controls and cellular interactions in antibody formation.

Both thymus-derived lymphocytes (T cells) and bone marrow--derived lymphocytes (B cells) play critical roles in specific antibody responses to antigens. Genetic controls of the antibody response in mammals have been found to reside largely within the major histocompatibility complex where different genes appear to code for immune response (Ir), immune suppression (Is), and cell interaction (CI) molecules.

Induction of immunologic tolerance to the trimellitate haptenic group in mice: model for a therapeutic approach to trimellitic anhydride-induced hypersensitivity syndromes in humans?

IgE and IgG antibody responses to the trimellitate (TM) hapten group were elicited in mice by the intraperitoneal injection of the hapten coupled with keyhole limpet hemocyanin (KLH). Treatment of such previously sensitized mice with the same hapten coupled to synthetic copolymer of D-glutamic acid and D-lysine (D-GL) after primary immunization resulted in significant and specific suppression of anti-TM antibody responses in both IgE and IgG classes. These results provide direct evidence for the potential clinical usefulness of the D-GL immunotherapeutic approach to TMA sensitivity in humans.