SUMMARYThalidomide is an effective immunomodulatory drug in man, but its mechanism of action remains unclear. We hypothesized that, in addition to its reported inhibitory effects on production of monocyte-derived tumour necrosis factor-alpha (TNF-a), thalidomide might be effective at the level of Th immunoregulation. In a comparative study with the immunosuppressant cyclosporin A. we have demonstrated a potent and specific effect of thalidomide on cytokine production relating to the distinct Th 1 and Th2 subsets. It induced and enhanced the production of IL-4 and IL-5 and, at the same dose (lOOOng/ml), significantly inhibited interferon-gamma (IFN-7) production in phytohaemagglutinin (PHA)-stimuIated human peripheral blood mononuclear cell (PBMC) cultures. Stimulation of PBMC with recall antigen (streptokinase:streptodorn:ise (SKSD))at i44h in the absence of thalidomide resulted in a predominantly Thl response, with the production of IFN-7 and IL-2. Thalidomide switched this response from a Thl to a Th2 type. The effect was most pronounced at lOOOng/ml thalidomide, where inhibition of IFN--. and enhancement of IL-4 production was maximal. In unstimulated Lulturcs thalidomide alone induced IL-4 production. Cyclosporin A, in contrast, inhibited both Thl and Th2 cytokine production by PHAstimulated PBMC. Time course data from thalidomide-treatcd cultures revealed that the augmented IL-4 production diminished as the culture time increased, whereas IFN--> production was significantly increased. This response might be due to activation-induced apoptosis of Th2 cells or the induction of Th2 cell anergy. in the continued presence of stimulating agents, with the emergence of IFN-->-secreting Th I cells when Th2 antagonism declines. The effects of thalidomide and related compounds may enhance our understanding of the mechanisms of T helper cell selection, offer the possibility of controlled therapeutic switching between Thl and Th2 responses, and may lead to a rational approach for the treatment of some T cell-mediated immunological disorders.
SUMMARYSystemic capillary leak syndrome (SCI.S) is a rare disease characterized by episodes of collapse due to rapid transfer of considerable volumes of plasma from the intravascular to the extravascular compartment. The pathogenesis of this disease is unknown. The diagnosis is made largely on ehnical grounds, and investigations are unhelpful. The only consistent abnormality is that an IgG paraprotein is found in most patients, raising the possibility that the paraprotein may be invohed in the pathogenesis of the disease. Reduction of the paraprotein level in our patient was associated with remission. Blood samples from three SCLS patients and one probable SCLS have been studied. All patients had monoelonal IgG paraproteins. The pttrified paraproteins were all of IgG 1 subelass and had K light chains. However, they differed in size and charge. Antibodies against each of the paraproteins were raised in rabbits, Alfinity-puritied anti-idiotypie antibodies were tested for crossreaetivity against the other paraproteins using immunoblotting and Ouehterlony assay. These assays showed that the anti-idiotypic antibodies reacted only with the immunizing paraprotein and not with any of the other paraproteins, i,e. thai the paraproteins do not share a common Idiotype. Paraproteins did nol bind t() cultured endothelial cells, either unaetivated or following activation with interferon-gamma (IFN-;-)-lL-2 or IL-6, In addition, we were unable to demonstrate any eytotoxicity towards cultured htmian endothclial cells by paraprotein alone, or in the presence of netJtrophils (pronounced neutrophrlia being ;( fealure of attacks). The relationship betwetn the paraproteins and the disease retnains unclear. It is likely that additional, as yet unidentilied. factors are required for the paraprotein to lead to capillary leak.
We have developed a model to measure cytokine production by peripheral blood mononuclear cells (PBMC) in vitro. In this report, we examine the production of interleukin-2 (IL-2), IL-6, and interferon-gamma (IFN-gamma) by PBMC of house-dust-mite (Dermatophagoides pteronyssinus)-allergic subjects. When stimulated with specific allergen (D. pteronyssinus), PBMC of patients produced significant levels of IL-2 and high levels of IL-6, but little or no IFN-gamma. Nonatopic control PBMC also produced IL-6, although at lower levels, but no IL-2 or IFN-gamma. A ubiquitous antigen, streptokinase/streptodornase (SKSD), induced high levels of IL-2 in patients, but only low levels of IFN-gamma and IL-6. Nonatopic controls produced similar levels of IL-2 and IL-6, but high levels of IFN-gamma to SKSD. IL-2 and IFN-gamma levels induced by the T-cell mitogen phytohaemagglutinin (PHA) were similar in patient and control groups, but IL-6 levels were significantly lower in the patients. IgE synthesis in vitro was shown only in atopic PBMC cultures stimulated with specific allergen. The major points can be summarized as 1) IL-2 production by atopic patients in response to allergen; 2) IL-6 production to allergen by both atopic and nonatopic patients, but significantly increased in atopic patients; and 3) defective IFN-gamma production by atopic patients to both allergen and antigen.(ABSTRACT TRUNCATED AT 250 WORDS)
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