Growing evidence shows that cytokines of the IL-6 family play an important regulatory role in heart physiology such as inducing cardiomyocyte hypertrophy. The purpose of this study was to see if IL-6 and its soluble receptors (sIL-6R and sgp130) could be detected in pericardial fluids, and to see if they are produced by the pericardium. We report that human pericardial fluid from patients with coronary pathologies contained IL-6, sIL-6R, and sgp130. However, the levels present in sera and pericardial fluid did not correlate, which suggests local production. This observation was confirmed by in vitro studies demonstrating massive IL-6 production by cultured pericardial samples, which could be strongly inhibited by methylprednisolone. RT-PCR studies revealed that IL-6 was weakly expressed in fresh tissues and strongly induced after culture. In situ hybridisation and immunohistochemical analysis showed that IL-6 and gp130 were mainly present in mesothelial cells. sIL-6R and sgp130 were also produced by pericardium in vitro, and their synthesis was upregulated by methylprednisolone. Taken together, these results demonstrate that IL-6 is present in pericardial fluid and that its presence could be due to synthesis by pericardial tissue. In vitro studies suggest that IL-6 production by this tissue could be strongly induced and regulated. A potential paracrine role of these factors in cardiomyocyte functions in normal or pathological conditions is discussed.

Antigens, CD↗

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CD138.

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Amino Acid Sequence↗

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Immunological follow-up of 17 patients with rheumatoid arthritis treated in vivo with an anti-T CD4+ monoclonal antibody (B-F5)

Seventeen patients with steroid-refractory rheumatoid arthritis were treated with a monoclonal antibody: anti-T CD4/B-F5 (IgG1) for 10 days. The daily dose was 20 mg. No severe side effects were observed and clinical improvement was seen in 15 patients, accompanied by a steep decline in C reactive protein levels. This improvement persisted as long as 12 months in 3 patients. A decline in lymphocyte counts was observed 2 hours after infusion. CD3+, CD4+, CD8+ and B cells were affected. Monocyte levels also decreased, whereas NK cell levels remained unchanged. After 24 hours a subsequent recovery of lymphocyte cell numbers made it possible to return to pre-treatment levels. Residual CD4+ cells coated with CD4 antibody were sporadically found even if residual antibody could be detected in the serum. These results indicate insufficient mAb concentrations. No patients developed detectable anti-mouse Ig antibodies during the treatment period, but 5 patients developed antibodies 15 to 30 days after the end of the treatment. Proliferative responses (mainly the response to ConA) were reduced at the end of the treatment. One month later the proliferative response returned to pre-treatment levels. mAb treatment did not induce long lasting cell activation, as indicated by the low levels of CD25+ or DR+ cells. Soluble IL2 receptor levels were significantly higher before treatment, but did not change after treatment. Soluble CD8 and soluble CD4 molecules were also more numerous before treatment and this increase was correlated with clinical parameters. Of interest was the correlation between the variations in soluble CD8 and the Ritchie index during treatment. The increased levels of serum TNF alpha and IL6 were not modified by treatment. A randomized study now appears necessary to prove the efficacy of the treatment. Such a study would also provide biological data and thus help to define factors predictive of a response in this heterogeneous disease.

Adult↗

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Monoclonal antibodies in human organ transplantation and auto-immune diseases.

The usefulness of monoclonal antibodies (mAbs) in the transplantation field has become evident over the last couple of years. Different mAbs have been used as a prophylactic treatment after transplantation, in a therapeutic way against acute organ rejection and new diagnostic tools to predict clinical rejection immerge. One can even hope that with humanised mAbs or human mAbs obtained by repertoire cloning the formation of human anti-mouse antibodies will be solved although on the one hand this appeared not to be a big problem and on the other hand anti-idiotypic antibodies can still be expected. However, the most puzzling question is how the mAbs modulates the immuno-response and this not only in organ rejection but also in auto-immune diseases. Only one out of many CD25 mAbs with seemingly similar epitope recognition can be used in therapeutical treatment of acute Graft versus Host Disease. The same mAb is not, however, very efficient in the prophylactic treatment of kidney transplantation without association of suboptimal doses of cyclosporin A. Another example is a CD4 mAb which is efficient in the treatment of polyarthritis with no side effects but which provokes transient but clear side effects when used in psoriasis or multiple sclerosis patients. A second CD4 mAb with high inhibitory activity in several bioassays compared to the first CD4 mAb has no beneficial effect at all on polyarthritis. Also the question why there is a percentage of "no response" patients among apparently identical "good response" patients remains unanswered. However it becomes clear from these experiences that: 1) mAbs recognizing a similar epitope and being of the same isotype will not automatically have the same effect in therapy. 2) side effects may be depending of the disease treated. 3) the activities of mAbs in bioassays and even animal models very often do not reflect the in vivo situation in human. 4) efficiency of the treatment with mAbs can be increased by a better understanding of the mode of action and increased efficiency can be expected by association of several mAb or mAb with drugs for the "no response" patients and should be the next step in the therapeutical use of mAbs.

Animals↗

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Interleukin-6 is the central tumor growth factor in vitro and in vivo in multiple myeloma.

When bone-marrow cells from patients with multiple myeloma (MM) were seeded in short-term cultures, a spontaneous proliferation of the myeloma cells occurred for most of the patients with active disease and proliferating myeloma cells in vivo. In all cases, this spontaneous proliferation was inhibited by anti-IL-6 monoclonal antibodies (mabs). Moreover, myeloma cell lines, completely dependent upon exogenous IL-6 for their growth, could be reproducibly established by initially stimulating the myeloma cells with both IL-6 and GM-CSF. These results demonstrate that IL-6 is a major paracrine myeloma-cell growth factor in vitro. High serum IL-6 levels were observed in MM patients with active disease, especially patients with terminal disease. High IL-6 mRNA levels were found in bone-marrow cells of MM patients, mainly in myeloid and monocytic cells, in vivo. The myeloma cells did not express IL-6 mRNA. Injection of anti-IL-6 mabs to MM patients with terminal disease and extramedullary proliferation, completely blocked the myeloma-cell proliferation in vivo and completely inhibited the serum IL-6 bioactivity and the serum CRP levels. One patient with plasma cell leukemia and hypercalcemia was treated for two months with anti-IL-6 mabs and maintain in remission for 2 months without major side effects. Interestingly, the serum calcium levels also decreased in these patients. All these results show that IL-6 is the main cytokine responsible not only for the myeloma-cell proliferation in vivo, but presumably also for the large bone resorption processes observed in human MM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

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[Open therapeutic trial of anti-T CD4 monoclonal antibody in multiple sclerosis].

Twenty-one patients with active multiple sclerosis (16 progressive and 5 recurrent forms) were treated with murine monoclonal anti-T CD4/BF5 antibodies in an open trial. Tolerance was relatively good; 11 patients had side effects including facial swellings, skin eruptions and trembling which occurred only at the first infusion. Treatment had to be stopped in one female patient. Nine months after initiating treatment, no relapse had occurred in any of the 5 patients with a recurrent form and improvement was observed in 3 patients with a progressive form. At the end of the treatment period, there was a clear drop in the number of CD3+ cells and particularly in CD4+ cells, a decrease which was less after one month. All the patients who had side effects showed an increased level of serum IL6 and alpha TNF. These findings demonstrate that this type of long-term treatment is possible in patients with multiple sclerosis and suggest that in another trial it would be important to evaluate the effect in recurrent forms.

Adult↗

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Spontaneous production of interleukin-10 by B lymphocytes and monocytes in systemic lupus erythematosus.

Interleukin-10 (IL-10) production by B lymphocytes has previously been demonstrated for malignant cells and for in vitro activated normal B cells. Spontaneous in vivo production of IL-10 by normal B lymphocytes has only been demonstrated in mice, in which autoreactive Ly 1 + B cells are involved. In the present study, spontaneous expression of the IL-10 gene by peripheral blood mononuclear cells was investigated in systemic lupus erythematosus (SLE), a human disease involving autoreactive B cells. Of the 47 SLE patients tested by coupled reverse transcriptase-polymerase chain reaction, 34 scored positive, contrasting with only 1 positive out of 34 normal subjects (p < 0.001). Spontaneous in vitro production of IL-10 by PBMC, determined using an ELISA assay, was 33 times higher in SLE than in controls (2623 +/- 728 pg/ml vs 79.3 +/- 34.5 pg/ml, respectively) (p < 0.001). The level of production of IL-10 in SLE was unrelated to either clinical or biological markers of disease activity. Among PBMC, monocytes and B lymphocytes both contributed to IL-10 production, whereas T cells did not. IL-10 overproduction in SLE suggests that this Th2-type interleukin plays a role in the production of autoantibodies through pathways involving both paracrine production by monocytes and autocrine IL-10 production by autoreactive B cells.

Adolescent↗