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Lymphotoxin and TNF: How it all began—A tribute to the travelers

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Abstract

The journey from the discoveries of lymphotoxin (LT) and tumor necrosis factor (TNF) to the present day age of cytokine inhibitors as therapeutics has been an exciting one with many participants and highs and lows; the saga is compared to that in “The Wizard of Oz”. This communication summarizes the contributions of key players in the discovery of the cytokines and their receptors, the changes in nomenclature, and the discovery of the LT family’s crucial role in secondary and tertiary lymphoid organs. The remarkable advances in therapeutics are detailed as are remaining problems. Finally, special tribute is paid to two pioneers in the field who have recently passed away: Byron H. Waksman and Lloyd Old.

Introduction

Our knowledge of the lymphotoxin (LT)/tumor necrosis factor (TNF) family has been gained over the course of many years. I was asked to provide some insight into the early days of the field as one who has been involved for a long time. “The Wizard of Oz” by Frank Baum [1] is a popular book and movie about Dorothy from Kansas and her friends who encounter many obstacles and much excitement as they travel in search of their hearts’ desires, to be fulfilled by the great and powerful Oz in the Emerald City. Here I provide a somewhat biased account of the adventures of a group of travelers who journey along the “yellow brick road” and unlock the mysteries of LT and TNF from the discoveries of the molecules and receptors, to understanding their beneficial and harmful functions, to developing therapeutics that have transformed treatment of some autoimmune diseases. Special attention will be given to two pioneers: Byron H. Waksman and Lloyd Old, who were key movers in the LT/TNF field.

The immediate LT/TNF family consists of three tightly liked genes within the major histocompatibility complex [2]: TNFα, LTα, and LTβ. TNF is produced as a membrane bound molecule that is clipped by the TNF converting enzyme (TACE) to be released as a homotrimer to bind to one of two receptors, TNFR1 or TNFR2. LTα is released as a homotrimer and also binds to the two TNF receptors, hence explaining its similar activities to TNF. LTα3 also binds to an additional receptor, the herpes virus entry mediator (HVEM) as does LIGHT, which is not a member of the immediate LT/TNF immediate gene family. LTα is crucial for the transport of LTβ to the cell surface [3], resulting in the expression of the cell surface the LTα1β2 complex that binds to the LTβR. A recent report indicates that the LTα1β2 complex can be released via a metalloproteinase [4]. The interactions of ligands and receptors are depicted in Fig. 1. Distinctions between the ligands include their regulation and cells of r origin. A wide range of cells produces TNFα; this includes macrophages after stimulation by Toll-like receptors and CD4 and CD8 T cells after interaction with antigen. A more limited range of cells, including CD4 and CD8 T cells, B cells [5], and notably, lymphoid tissue inducer (LTi) cells [6], produces LTα and LTα1β2.

Section snippets

Lymphotoxin

The 1960s saw the description of a secreted cytotoxic material produced by lymphocytes after stimulation by mitogen [7] or interaction with a specific antigen [8], [9]. Granger and his colleagues named this factor lymphotoxin [10]. (In fact, it is likely that these culture supernatants also contained TNFα). Aggarwal’s purification of human LT from a lymphoblastoid cell line [11] provided information for its cloning in 1984 by Patrick Gray [12]; murine LT was cloned in 1987 [13], [14]. Werner

LT is crucial for secondary lymphoid organ development

In order to determine whether there were biologically significant differences between LT and TNF, and whether either molecule could induce Type 1 diabetes, mice transgenic for LTα or TNF under the control of the rat insulin promoter (RIP) were produced [31]. Both mice exhibit florid infiltrates in the islets of Langerhans that were later realized, at least in the RIPLTα mouse, to resemble lymphoid organs [35] (see below). Although the morphological appearance of the infiltrates differs slightly

TNFα inhibitors

Once it became apparent that TNF would not be an effective anti-tumor agent because of its unfortunate activity that mimicked septic shock, attempts were made to develop reagents that could inhibit sepsis. Robert Schreiber and colleagues developed an anti-mouse TNF antibody that also appeared to have anti LT activity that was effective against sepsis in mice, but only if administered before LPS. Vilçek and colleagues developed a monoclonal mouse human chimeric monoclonal antibody, cA2 [61],

Byron H. Waksman (1918–2012)

Byron Waksman’s early studies were on the role of the thymus in delayed type hypersensitivity in rats [77], [78], [79], [80] and he can be considered a discoverer of the functions of that hitherto mysterious organ. He revealed the role

The yellow brick road from Coley’s toxins to therapeutidcs

In this communication, I have presented a brief history of the LT/TNF field with high and low points along the way. These are summarized in Fig. 2. I leave it to the reader to decide who embodies the characteristics of the Good Witch Glinda, who could be the Wicked Witch of the North, and who are the most likely embodiments of Dorothy, the Tin Woodman, the Cowardly Lion, and the Scarecrow. In all seriousness, the field has brought out the best in the travelers who have persisted in the face of

Acknowledgments

These studies were supported by: NIH R21HL098711, NIH U19-AI082713, and JDRF 4-2007-1059. I acknowledge the excellent graphic support of Miriam Hill.

Nancy H. Ruddle, Ph.D., is the John Rodman Paul Professor Emerita of Public Healthand Immunobiology at Yale University. A 1962 graduate of Mount Holyoke College, Dr. Ruddle earned her Ph.D. in Microbiology at Yale University in 1968 with Byron Waksman where she was one of the discoverers of lymphotoxin (LT). She did postdoctoral work at Yale with Frank Richards and Martine Armstrong working on murine leukemia viruses (1971 to 1974). She joined the faculty as an assistant professor (1975) and

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    Nancy H. Ruddle, Ph.D., is the John Rodman Paul Professor Emerita of Public Healthand Immunobiology at Yale University. A 1962 graduate of Mount Holyoke College, Dr. Ruddle earned her Ph.D. in Microbiology at Yale University in 1968 with Byron Waksman where she was one of the discoverers of lymphotoxin (LT). She did postdoctoral work at Yale with Frank Richards and Martine Armstrong working on murine leukemia viruses (1971 to 1974). She joined the faculty as an assistant professor (1975) and became full professor in 1991. Dr. Ruddle’s studies on LT and TNFα revealed their roles in mouse models of multiple sclerosis and type 1 diabetes and LT’s role in lymphoid organ development. Her observations have given rise to the concept of lymphoid neo-organogenesis, a process that contributes to tertiary or ectopic lymphoid tissues (TLOs) in chronic inflammation. She studies regulation and function of lymphoid organs and TLOs through her analysis of high endothelial venules and lymphatic vessels, most recently by in vivo imaging. Dr. Ruddle has served on advisory panels of the National Science Foundation, the National Institutes of Health, the Multiple Sclerosis Society, Inc.,the Juvenile Diabetes Society, and the Lymphatic Research Institute. She is a member of the American Association of Science and the American Association of Immunologists and past president of the International Cytokine Society, and the recipient of its Lifetime Achievement Award.

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