Ann Rheum Dis 1999;58:(Suppl I) I107–I113 I107 Ann Rheum Dis: first published as 10.1136/ard.58.2008.i107 on 1 November 1999. Downloaded from Immunomodulation by thalidomide and thalidomide analogues Laura G Corral, Gilla Kaplan Tumour necrosis factor á (TNFá), a key stimulate the anti-inflammatory cytokine IL10. cytokine involved in the host immune re- Similarly to thalidomide, these drugs that do sponse, also contributes to the pathogenesis of not inhibit PDE4 act as costimulators of T cells both infectious and autoimmune diseases. To but are much more potent than the parent ameliorate the pathology resulting from TNFá drug. The distinct immunomodulatory activity in these clinical settings, strategies for the inhi- of these new TNFá inhibitors may potentially bition of this cytokine have been developed. allow them to be used in the clinic for the Our previous work has shown that the drug treatment of a wide variety of immunopatho- thalidomide is a partial inhibitor of TNFá pro- logical disorders of diVerent aetiologies. duction in vivo. For example, when leprosy patients suVering from erythema nodosum TNFá is a key player in the immune leprosum (ENL) are treated with thalidomide, response the increased serum TNFá concentrations TNFá is a pleiotropic cytokine produced characteristic of this syndrome are reduced, primarily by monocytes and macrophages, but with a concomitant improvement in clinical also by lymphocytes and NK cells. TNFá plays symptoms. Similarly, we have found that in a central part in the host immune response to patients with tuberculosis, with or without HIV viral, parasitic, fungal and bacterial infections. infection, short-term thalidomide treatment The importance of TNFá and TNFá signal- reduces plasma TNFá levels in association ling through its receptors in the host immune with an accelerated weight gain. In vitro, we response to disease has become clearer as a have also shown that thalidomide partially result of a number of seminal studies. For inhibits TNFá produced by human peripheral example, mice genetically deficient in TNFá blood mononuclear cells (PBMC) responding have a significantly reduced humoral immune to stimulation with lipopolysaccharide (LPS). response to adenovirus infection.1 In Leishma- Recently, we found that thalidomide can also nia major infection, TNFá signalling is impor- act as a costimulatory signal for T cell tant for protection as mice lacking TNFá p55 activation in vitro resulting in increased receptor (TNFR-p55) show delayed elimina- production of interleukin 2 (IL2) and inter- tion of the parasites compared with controls feron ã (IFNã). We also observed a bi- and the lesions formed failed to resolve.2 Mice directional eVect on IL12 production: IL12 deficient in TNFR-p55 are also significantly http://ard.bmj.com/ production is inhibited by thalidomide when impaired in their ability to clear infection with PBMC are stimulated with LPS, however, Candida albicans and readily succumb to the IL12 production is increased in the presence of infection. TNFá signalling is also crucial in the drug when cells are stimulated via the T cell resisting Streptococcus pneumoniae infections in receptor. The latter eVect is associated with mice.3 In addition, TNFá is essential for upregulation of T cell CD40 ligand (CD40L) protection against murine tuberculosis. expression. Thus, in addition to its monocyte TNFR-p55 deficient mice have been shown to on September 27, 2021 by guest. Protected copyright. inhibitory activity, thalidomide exerts a co- be more susceptible to tuberculosis infection. stimulatory or adjuvant eVect on T cell When TNFá was neutralised in vivo by mono- responses. This combination of eVects may clonal antibodies impaired protection against 45 contribute to the immunomodulating proper- mycobacterial infection was observed. The ties of the drug. data from both models also established that To obtain drugs with increased anti-TNFá TNFá and the TNFR- p55 are essential for activity that have reduced or absent toxicities, production of reactive nitrogen intermediates novel TNFá inhibitors were designed using by macrophages early in infection. thalidomide as template. These thalidomide Celgene Corporation, analogues were found to be up to 50 000 times TNFá contributes to disease pathogenesis Warren, NJ, USA L G Corral more active than thalidomide. The compounds Although TNFá is crucial to the protective comprise two diVerent types of TNFá inhibi- immune response, it also plays a part in the Laboratory of Cellular tors. One class of compounds, shown to be pathogenesis of both infectious and autoim- Physiology and potent phosphodiesterase 4 (PDE4) inhibitors, mune diseases. Increased concentrations of Immunology, The are selective TNFá inhibitors in LPS stimu- TNFá have been shown to trigger the lethal Rockefeller University, lated PBMC and have either no eVect or a sup- eVects of septic shock syndrome.6 TNFá has New York, NY, USA G Kaplan pressive eVect on T cell activation. The other also been implicated in the development of class of compounds also inhibit TNFá produc- cachexia, the state of malnutrition that compli- Correspondence to: tion, but do not inhibit PDE4 enzyme. These cates the course of chronic infections and many Dr L G Corral, The compounds are also potent inhibitors of several cancers.7 In rheumatoid arthritis, TNFá is a Rockefeller University, 1230 York Avenue, New York NY LPS induced monocyte inflammatory cy- critical mediator of joint inflammation and 10021, USA. tokines. Also, the latter compounds markedly therefore an important therapeutic target. I108 Corral, Kaplan Ann Rheum Dis: first published as 10.1136/ard.58.2008.i107 on 1 November 1999. Downloaded from Recently, it has been shown that treatment of Thalidomide has T cell costimulatory patients with neutralising anti-TNFá antibod- properties ies produces a dramatic reduction in disease Recently, we reported that thalidomide also has activity in this condition.8 Similarly, it has been a hitherto unappreciated immunomodulatory shown that in inflammatory bowel disease, eVect: the drug was shown to costimulate neutralisation of TNFá results in a profound human T cells in vitro, synergising with stimu- amelioration of clinical symptoms.910 Reduc- lation via the T cell receptor complex to tions in TNFá levels have also been linked with increase IL2 mediated T cell proliferation and a significant reduction of clinical symptoms in T cell IFNã production.23 Optimal T cell acti- leprosy patients with ENL, including fever, vation requires two signals.24 The first signal or malaise, and arthritic and neuritic pain.11 In signal 1 is delivered by clustering of the T cell tuberculosis patients, reduction of TNFá levels antigen-receptor-CD3 complex through en- 12 was associated with accelerated weight gain. gagement of specific foreign peptides bound to MHC molecules on the surface of an antigen presenting cell (APC). Signal 1 can be Thalidomide inhibits TNFá production mimicked by crosslinking the T cell receptor by monocytes (TCR) complexes with anti-CD3 antibodies. The pathology associated with TNFá produc- Signal 2 (or costimulation) is antigen inde- tion is profound and in many diseases leads to pendent and may be provided by cytokines or significant morbidity and mortality. This has by surface ligands on the APC that interact led to a concerted eVort to discover drugs that with their receptors on the T cell. Costimula- will down regulate the production of this tory signals are essential to induce maximal T cytokine. Agents conventionally used in these cell proliferation and secretion of cytokines, diseases may inhibit TNFá production, but are including IL2, which ultimately drive T cell also often broadly immunosuppressive (for clonal expansion. As antigenic stimulation in example, cyclosporin A and corticosteroids) the absence of costimulatory signals leads to T and therefore associated with extensive side cell anergy or apoptosis, costimulation is criti- eVects.13 Drugs that are potentially more cally important in the induction and regulation specific in inhibiting TNFá are under active of cellular immunity. investigation and development. Our previous work has shown that the drug thalidomide Thalidomide appears to act as a costimulator to T cells that have received signal 1 via the (á-N-phthalimidiglutarimide) is a relatively TCR.23 selective inhibitor of TNFá production by In our experiments in vitro, stimulation human monocytes in vivo. This property of of purified T cells with anti-CD3 antibodies, in thalidomide was first described in leprosy the absence of signal 2, induced only minimal patients with ENL, an acute inflammatory T cell proliferation. However, the addition of complication of lepromatous leprosy that is thalidomide to this cell culture system resulted accompanied by increased serum TNF levels. in a concentration dependent increase in á 23 25 Thalidomide treatment of patients with ENL proliferative responses. The thalidomide was shown to induce a prompt reduction of mediated costimulation of T cell proliferation TNFá serum levels with a concomitant abro- was accompanied by increases in IL2 and IFNã http://ard.bmj.com/ gation of clinical symptoms.11 Furthermore, in production. It is noteworthy that in the absence patients with tuberculosis, with or without of anti-CD3, there was no T cell proliferative concomitant HIV infection, thalidomide treat- response to thalidomide, indicating that the ment was found to both decrease plasma drug is not mitogenic in itself. It is also TNFá protein levels as well as