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A number of years ago several groups reported that Interleukin 10 (IL10) was vigorously overproduced in disseminated lupus erythematosus (reviewed in Llorente et al., 2000). This hyperproduction obeys two different patterns. In one pattern, IL10 serum concentrations become elevated during disease and evolve in parallel with them. In the other, the patients' blood mononucleated cells spontaneously release increased IL10 quantities; contrary to serum variations in the first pattern, this increased output is not correlated with disease spurts. Interestingly an increase of this type is frequently found in disease-free parents of these patients (Llorente et al., 1997; Gröndal et al., 1999). Some studies relate this IL10 hyperproduction to a genetic origin (Mehrian et al., 1998; Mok et al., 1998), while others seem to indicate an environmental cause (Gröndal et al., 1999). Together these findings suggest two different possible origins for lupus IL10 overproduction. The first would be due to intrinsic anomalous IL10 production by some immune cells, the second would result from high IL10 output by tissues damaged by the inflammatory process. Considering the properties of IL10, which activates B lymphocytes and inhibits T lymphocytes, overproduction in lupus could explain the immune anomalies of this disease, which is characterized by anti-self antibodies production and by deficient T responses. Interestingly several of these anomalies are found independently from disease outbreaks and, in the case of some, in relatives of patients. The part played by IL10 in lupus has been inferred from the murine NZB-W model, in which an anti-IL10 monoclonal antibody prevents development of the disease (Ishida et al., 1994); this antibody also prevents the appearance of human anti-ADN autoantibodies in immune-deficient mice restored with patients' lymphocytes. A direct demonstration of the role of IL10 in the etiology of lupus symptoms has recently been adduced in a pilot study bearing on six lupus patients, refractory to anti-inflammatory and immuno-suppressive treatments, who were treated for 3 weeks with a murine anti-IL10 monoclonal antibody (Llorente et al., 2000). This treatment brought about a rapid amelioration of the clinical picture, in particular of the cutaneous and articular symptoms, which was maintained for six months after this trial. This symptomatic amelioration was accompanied by a decrease of the biological signs of immune system hyperactivity and a partial amelioration of T lymphocyte function. The better clinical control of the disease allowed a significant decrease of corticotherapy. While this was an open study, without a control group and without randomisation, the rapid and important evolution of clinical and biological parameters towards normal strongly pleads for a favorable effect of the treatment. While confirming previous hypotheses about the rote of IL10 in lupus, this study leaves several points unexplained. First the clinical and biological amelioration in these patients treated with anti-IL10 monoclonal antibody occurred independently of circulating anti-ADN auto-antibodies, indicating that the role of this interleukin in the disease is more complex than could be thought from the initial experiments in mouse. This unexpected result does not exclude that the beneficial effect of the antibody could be mediated by its action on B lymphocytes, since it is well known that these cells play important parts in development auto-immune processes other than only the production of auto-antibodies. It is also possible that the negative effect of IL10 in this disease exerts on other targets than B lymphocytes, in particular on fibroblasts and endothelial cells. Indeed it should be recalled that, while IL10 has often been held as an anti-inflammatory cytokine, its biological properties are more ambiguous, since it can immuno-stimulate some cell types. Among other remaining unknowns, the reason why some IL10 overproducing individuals, belonging to the family of lupus patients, do not develop lupus, is not understood. This fact underlines the multi-factorial origin of this disease, which must stem from associated genetic and environmental causes. IL10 overproduction, while it apparently promotes the symptoms, is certainly not sufficient. The efficiency of anti-IL 10 monoclonal antibodies during lupus, which are well tolerated, points to their usefulness in the therapeutic arsenal, especially in forms that are refractory to conventional anti-inflammatory and immunosuppressive treatments. In order to be validated, this hypothesis must be submitted to more in depth, randomized, studies. Moreover humanized antibodies should be developed, which would make it possible to reiterate the treatment during further outbreaks. Once all these conditions are fulfilled, the place of anti-IL10 treatment in lupus and the benefice-risk ratio should be compared to these of therapeutic approaches currently used in refractory forms. If further studies confirm the efficiency of- and tolerance to- IL10 neutralizing antibodies in lupus, it is well possible that these antibodies will eventually equate, for this disease, the recent use of TNF antagonists in the treatment of rheumatoid arthritis. |
