EDGAR PICK, STANLEY COHEN and JOOST J. OPPENHEIM

Publisher Summary

This chapter provides an overview of lymphokines. Lymphokines are soluble substances produced by lymphoid cells cultured in vitro for relatively brief intervals. The production of lymphokines is one of the many manifestations of lymphocyte activation. Lymphokine production can be induced by the specific antigenic stimulation of lymphocytes derived from sensitized animals and by the nonspecific stimulation of lymphocytes of nonsensitized animals. Both T- and B-lymphocytes can be activated to produce lymphokines, provided that they are stimulated by the appropriate agent. Lymphokines are not immunoglobulins or immunoglobulin fragments. They do not possess structural similarity to any known immunoglobulin molecule. They are normally synthesized and released as the result of stimulation by agents interacting with membrane receptors. Lymphokines are also produced by lymphocytes in continuous culture in the absence of external stimulation. All lymphokines are proteins. A number of lymphokines appear to affect their target cells by reacting with specific membrane receptors, although such receptors are not demonstrated for most lymphokines. For the most part, lymphokines do not appear to be enzymes. The basic mechanism of lymphokine action can best be visualized as being similar to that of glycoprotein hormones involving (1) binding to a specific membrane receptor, (2) the delivery of a secondary messenger, and (3) an intracellular biochemical sequence causing the specific lymphokine effect. Lymphokines and related factors have also been implied in phenomena not directly related to immunity, such as hyperkeratinization, angiogenesis, and wound healing.

I HISTORICAL PERSPECTIVE

The science of immunology had its beginnings in attempts to understand how an organism recognizes substances that are foreign to it and how it then mounts specific responses against those substances. The earliest investigations, which grew out of attempts to immunize against infectious diseases, focused on the latter aspect, namely, the mechanisms of specific response. This led to the golden age of immunochemistry, with a great deal of attention devoted to the nature of antigens and antibodies, and to the interaction of antibody with complement. Studies of cellular effector mechanisms were largely confined to investigation of the interactions between the specific group of cell‐sensitizing antibodies and antigens that give rise to anaphylactic reactions. Studies on mechanisms of recognition remained fairly primitive until elegant experiments involving immunogenetic concepts, and studies of antigen‐receptor interactions, provided firm support for selective theories of antibody formation. However, it was not until we developed an appreciation of the complex interactions between different cell populations and subpopulations that are involved in the induction of an immune response that the era of modern cellular immunology began. This field was dependent on the development of a whole new methodology for cell identification and separation and for tissue culture models to study in vitro sensitization and antibody production.

It was rapidly discovered that many of the cell interactions involved in the afferent arm of the immune response involved soluble helper or suppressor substances elaborated by these cells. These nonantibody mediators produced by lymphocytes generated a degree of interest comparable to that previously lavished on the antibodies themselves.

During this time, other lines of investigation were providing information about another class of mediator substances. Reactions of delayed hypersensitivity were known for many years, but it awaited two major discoveries, made almost simultaneously in several laboratories, to allow the understanding of this form of immunologic reactivity. The first was the observation that the bulk of the cells at sites of delayed hypersensitivity reactions were nonspecific inflammatory cells, and that only a small number of randomly arriving, specifically sensitized lymphocytes were necessary to initiate the lesion. The second was the observation that lymphocytes from delayed hypersensitive animals, when stimulated with antigen in vitro, released a relatively small molecular weight, nonantibody mediator (MIF) that inhibited macrophage migration. This, in turn, led to the discovery of a whole class of lymphocyte‐derived mediators with multiple effects on inflammatory cells, and with proliferative and cytodestructive activities as well. These mediators have been called lymphokines. Although they were first defined as in vitro correlates of delayed hypersensitivity, they are now known to participate in a greater spectrum of biological reactions. Lymphokine‐dependent reactions, as well as those involving the direct cytotoxic effects of lymphocytes, are collectively known as cell‐mediated immunity. Although there is no longer any doubt as to the in vivo significance of the lymphokines, we still know very little about their precise chemical nature, and we cannot yet account for their various properties in terms of underlying biochemical events. Even less is known about regulatory mechanisms in lymphokine production and activity.

A third development that relates to the above considerations involves the discovery that macrophages themselves can produce and release biologically active soluble factors. These factors are involved in some of the afferent and effector immune processes previously shown to be macrophage dependent. Finally, many long‐term nonlymphoid cell cultures can produce mediators with physicochemical and biological properties similar to or identical with conventional lymphokines. These diverse but similiar mediators have been defined by one of us as cytokines (Cohen et al., 1974). The relationship of cytokines to other biological mediators— such as interferon, various endocrinological growth factors, and certain bacterial products such as endotoxins—remains to be explored.

II WHAT LYMPHOKINES ARE

This book was begun as an attempt to coordinate knowledge about lymphokines. However, as we began to review the compilation of available information concerning them, it became clear that the concept of lymphokines itself is almost impossible to define. Some scientists, including contributors to this volume, are asking whether the use of the term “lymphokine” (or any of its numerous synonyms) is justified at all. We would like to answer this question in the affirmative, recognizing, however, that it is at present neither possible nor desirable to rigidly define the concept, since the vast majority of materials to which it has been applied have not been characterized by biochemical criteria. The constant expansion of the set of lymphokines, and its extension to the more general concept of cytokines, makes the task of excluding a mediator from the lymphokine class a difficult one.

In determining whether to include a given mediator in this book, we had three alternatives: (1) to define lymphokines by their cell of origin (meaning that they have to be lymphocyte products), but excluding antibodies and their fragments; (2) to define lymphokines by their chemical structure, which proved to be an impossible task at present; or (3) to include in the book soluble cell products of all categories to which a function in the central or peripheral regulation of the immune response has been attributed, with the exception of classical antibodies. We opted for the last choice. This was motivated by both humility, the result of our ignorance of both the chemistry and cell biology of lymphokine action, and expedience, and is the reason for the consideration in this volume of prostaglandins, low‐molecular‐weight macrophage products, and thymic factors, materials not commonly considered lymphokines. We have, however, not included complement components, transferrin, fetuin, α-fetoprotein, chalones, C-reactive protein, normal immunosuppressive protein, or mast‐cell‐derived factors mediating immediate‐type hypers‐sensitivity reactions. Some of these have a similar claim for inclusion among lymphokines but have been excluded because their activities are not as closely interwoven with lymphokines.

It therefore appears that the rapid expansion of the lymphokine concept brought about a situation that makes the very use of the term questionable. In many respects the usefulness of the term is similar to that of “hormone,” which in spite of an ever‐increasing difficulty in defining it, has nevertheless survived.

The word lymphokine (first proposed by Dumonde et al., 1969), is synonymous with the following terms: lymphocyte mediator (or soluble lymphocyte mediator), lymphocyte activation product, soluble lymphocyte product (or factor), mediator (or soluble mediator) of cellular (or cell‐mediated) immunity, and the recently suggested soluble mediator of immunologic regulation (Waksman and Namba, 1976). We prefer the term lymphokine because of its...