Clinical Immunology and Immunopathology

INTRODUCTION ENL (4–6). However, there was no explanation for the mode of action of thalidomide in lepra reactions. In the early 1980s, with the increasing understandSince the synthesis of thalidomide (a-N-phthalimiing of the roles of particular cells in the developing doglutarimide) by Kunz and others in 1956 (1) for use immune response, it became clear that some diseases as a sedative, no drug has had a more tumultuous hisare actually manifestations of the host cellular immune tory. When first marketed in Europe, thalidomide was response to an infectious agent. One of the diseases touted as a safe, potent, nonbarbiturate drug which characterized by a significant immunological compowas very useful in producing sound sleep (2). It was nent was leprosy (7). The spectrum of the clinical manidistributed throughout Europe, Australia, and Canada, festations of leprosy was found to reflect the extent of but was never approved for marketing in the United activation of antigen-specific T cells. The generation of States. Thalidomide also had a remarkable anti-emetic a granulomatous response was associated with both T effect and was widely used to quell the nausea of firstcell and macrophage activation at the site of infection trimester morning sickness. Then, in November 1961, in the skin. Patients who developed a strong cellular after a rapid rise in reports of catastrophic fetal abnorimmune response to the infectious agent (Mycobactemalities in Europe and Australia associated with tharium leprae) manifested a restricted disease (tuberculidomide use in early pregnancy, the drug was removed loid leprosy) with few skin lesions containing very few from the market. acid-fast bacilli. In contrast, at the other end of the spectrum were patients in whom the cellular immune EARLY USE OF THALIDOMIDE IN LEPROSY response to M. leprae was deficient. In these patients, REACTIONS the infection was disseminated throughout the skin with many lesions containing numerous acid-fast baWhile thalidomide was still available, an Israeli phycilli (lepromatous leprosy). Superimposed on these difsician (Dr. Jacob Sheskin) had used the drug as a sedaferent clinical presentations of leprosy were the reactive in patients suffering from the acute reactional tional states, including ENL. ENL was observed prestate of lepromatous leprosy (erythema nodusum leprodominantly in lepromatous leprosy patients, often sum, ENL). ENL is characterized by a painful vasculiimmediately following initiation of anti-leprosy chemotic rash which may occur together with systemic symptherapy. The underlying mechanism for the developtoms of fever, muscle and joint pain, malaise, lymphment of ENL was unknown. adenopathy, insomnia, and weight loss. Peripheral Since thalidomide had such a profound effect on the neuritis is often associated with ENL and is the most symptoms of ENL, we hypothesized that the drug had important pathological manifestation of this reactional an effect on a soluble mediator or immune cell involved state. In 1965 Sheskin reported 6 cases of acute, severe in the development of ENL. In an attempt to underleprosy reactions in which symptoms quickly and drastand the factors involved in the induction of ENL, we matically resolved after the use of thalidomide as a set out to determine how thalidomide interrupts the sedative (3). He then carried out a series of placeboENL process. Using in vitro models of leukocyte funccontrolled studies and determined that thalidomide tion, we began an investigation of the immune paramewas responsible for the clinical improvements observed ters affected by thalidomide. in patients suffering from ENL. Sheskin concluded that EFFECT OF THALIDOMIDE ON TUMOR NECROSIS while thalidomide efficiently ameliorated the sympFACTOR (TNF-a) PRODUCTION BY PERIPHERAL toms of moderate to severe ENL, it was not bacterioBLOOD MONOCYTES IN VITRO cidal nor did it cure leprosy. Within a few years of Sheskin’s initial observations, thalidomide became the When human monocytes were cultured and then stimulated with bacterial lipopolysaccharide (LPS), pudrug of choice for the treatment of the symptoms of