Increased plasma levels of soluble tumor necrosis factor-receptors in uraemic patients: effects of dialysis, type of membrane, and anticoagulation method

Enhanced levels of soluble TNF-receptors (sTNF-R) have beenreported in patients with chronic renal failure. The aim ofthe present study was to evaluate the effects on sTNF-R levelsin plasma of haemodialysis patients of the anticoagulation methodand of the type of membrane used, as well as the variabilityof predialysis sTNF-R levels during time. All haemodialysispatients tested (n = 35) showed increased levels of both sTNF-R55(72.4 ± 5.7 ng/ml, P<0.001) and sTNF-R75 (18.2±2ng/ml,P<0.00l) before dialysis, as compared with normal healthycontrols (<2.5 ng7sol;ml for both sTNF-R), confirming previousobservations. sTNF-R levels were determined before and duringhaemodialysis at different time intervals in patients receivingeither heparin (2500 U, 5000 U, or 10000 U), low molecular weightheparin, or periodic saline flushing to prevent coagulationof the extracorporal circuit. A transient, small decrease inboth sTNF-R levels occurred at the beginning of haemodialysis(t=15 mm) with all anticoagulation methods used. At the endof haemodialysis, sTNF R55 and sTNF-R75 concentrations wereonly minimally affected (P<0.05). Predialysis sTNF-R levelswere similar in patients dialysed on either cellulose diacetateor polyacrylonitrile. Finally, there were only minimal variationsin predialysis sTNF-R levels in individual patients during the1 week observation period. Although the biological consequencesof the increased TNF-binding ability of serum from haemodialysispatients is still unclear, it could play a role in the compleximmunological perturbations of uraemic patients.     

sTNF‐RII: is it useful for the early diagnosis of rejection and for prognosis after renal transplantation?

Changes in soluble tumour necrosis factor receptor II (sTNF-RII) correlate with transplant rejection, and it increases in the course of sepsis. These changes might help to identify rejection early, and thus lead to more effective treatment. Serum and urine sTNF-RII levels were measured in 70 patients during the first 3 weeks after kidney transplantation and correlated with clinical and laboratory findings. Retrospectively, three groups were identified: I. stable transplant function ( n=23), II. at least one rejection episode ( n=38) and III. other complications (infection or reperfusion injury) ( n=9). The pre-operative maximum for serum sTNF-RII was 22.4 +/- 10.7 ng/ml. In group I it decreased to 9.5 +/- 6.7 ng/ml on day 6 after transplantation ( P<0.01), while in group II sTNF-RII serum levels were significantly higher on day 6 (24.9 +/- 15.0 ng/ml, P<0.01). High levels of sTNF-RII in serum (>40 ng/ml for at least 2 days) predicted a higher risk of an unfavourable outcome. High serum levels of sTNF-RII are not specific but seem to be a prognostic indicator of a complicated course; sTNF-RII in urine has no diagnostic value.     

Neutrophil expression of tumour necrosis factor receptors (TNF-R) and of activation markers (CD11b, CD43, CD63) in rheumatoid arthritis.

In vitro analysis of polymorphonuclear neutrophils (PMN) has allowed various stages of cell activation to be distinguished, characterized by the expression level of specific membrane markers and of functional receptors. Among those, TNF-alpha receptors (TNF-R) are modulated by various PMN activators, a mechanism which may be important to control cell responses to TNF in inflammatory reactions such as rheumatoid arthritis (RA). PMN, isolated from the blood of 36 RA patients and from the synovial fluid of 23 of them, were analysed for membrane expression of the two TNF-R (p55 and p75). Soluble p55 and p75 (sTNF-R) and TNF concentrations were measured in the plasma and synovial fluid by specific ELISA assays. Our results show that PMN from the blood of RA patients bear a normal number of TNF-R, with a normal p55/p75 ratio, compared with PMN from normal controls. Soluble TNF-R levels were similar in patients and normal plasma. In spite of high endogenous TNF concentration, patients' circulating PMN were not activated, as shown by a CD11b/CD18 expression similar to that of control resting cells. In contrast with blood neutrophils, PMN from RA patients' synovial fluids had an activated phenotype, characterized by increased expression of CD11b, decreased expression of leukosialin, CD43, and the appearance on the plasma membrane of an azurophil granule protein, CD63. High levels of soluble TNF-R were measured in RA synovial fluids. Nevertheless, membrane TNF-R levels and p55 and p75 proportions were similar to those of PMN from normal blood. These results suggest the existence of regulatory mechanisms which maintain a stable neutrophil expression of TNF-R as well as a balance between both types of receptors in inflammatory situations where neutrophils are strongly activated.     

Isotype-specific regulation of MHC class II gene expression in human monocytes by exogenous and endogenous tumor necrosis factor

The control of expression of MHC class II molecules on antigen-presenting cells is important for the induction of immunity, while aberrant expression of these molecules plays a role in the immunopathology of autoimmune diseases. This study explored the role of tumor necrosis factor alpha (TNF) in controlling the level of HLA class II mRNA in human monocytes. Exposure of monocytes to exogenous recombinant TNF (rTNF) selectively up-regulated DR-mRNA but not DP or DQ-mRNA. Inhibitors of TNF synthesis, pentoxifylline (PTX) and thalidomide, inhibited TNF mRNA accumulation in LPS-activated monocytes and down-regulated DR mRNA but not DP or DQ mRNA. The inhibitory effect of anti-TNF monoclonal antibody (MAb) indicated that endogenously generated TNF acted extracellularly. Anti-p75 TNF-R2 receptor and to a lesser extent anti-p55 TNF-R1 MAbs inhibited TNF-mediated up-regulation of DR mRNA and TNF mRNA. Taken together, this implies that endogenously generated TNF plays a role in controlling isotype-specific MHC class II gene expression in human monocytes/macrophages. These results may have some implications for anti-tumor response and autoimmunity.