Non-responsiveness to hepatitis B vaccination in haemodialysis patients: association with impaired TCR/CD3 antigen receptor expression regulating co-stimulatory processes in antigen presentation and recognition

The study was undertaken to evaluate the relationship betweennon-responsiveness to hepatitis B (HBV) vaccination in haemodialysedpatients and HBs antigen (Ag) presentation and recognition dependingon TCR/CD3 receptors expression. We have found that the causeof the blunted response to HBV vaccination is multifactorialand seems to be associated with the following: (1) A reducednumber of TCR/CD3 antigen receptor complexes on freshly isolateduraemic CD4 T cells, especially in non-responders. (2) The bluntedproliferative response of uraemic CD4 T cells isolated fromnon-responders and stimulated for 6 days by autologous monocytespresenting HBsAg was associated with the decreased density ofthe TCR/CD3 receptors. (3) Moreover, in uraemic non-respondersthe expression of adhesion and accessory molecules on monocytes(intercellular adhesion molecule-1/ ICAM-1, HLA-DR/Ia/) wassignificantly decreased following the culture with autologousmonocytes serving as HBsAg-presenting cells. CD4 molecules andlymphocyte function antigen-1ß /LFA-1ß/on helper-inducer T cells were increased before and after theculture. (4) These findings were also associated with a diminishedbinding capacity of IL-1ß and IL-6 to their receptorson helper-inducer T cells. (5) IL-2, IFN- and IL-4 productionwas decreased in uraemic non-responders, especially after 72h of the culture. (6) Inhibited proliferation of helper-inducerT cells in uraemic non-responders was only partially reversiblein the presence of exogenous IL-1ß, IL-6, IL-2 andIFN-. (7) HLA typing of uraemic non-responders was associatedwith extended haplotype: HLA A1, B8, DR3, DR7, DQ2.     

Th1/Th2 balance and CD45-positive T cell subsets in primary nephrotic syndrome

T cells are involved in the pathogenesis of nephrotic syndrome (NS). The aim of the study was to determine whether the activity of T-helper-1 (Th1) and T-helper-2 (Th2) cells and the distribution of the lymphocyte subsets, namely CD45RA+CD4+ (”naive” helper T cells, suppressor-inducer), CD45RA+CD8+ (”naive” suppressor T cells, suppressor-effector), CD45RO+CD4+ (”memory” helper T cells), are predictive for steroid sensitivity in children with primary NS. These parameters were assessed at the onset of disease, before initiation of steroid therapy. Two groups of NS children were retrospectively formed according to steroid sensitivity (SS) or resistance (SR). The activity of Th1 and Th2 cells was defined by the production of interleukin-2 (IL-2), interferon-γ, IL-4, and IL-10 in the supernatants of CD4+ T cell cultures activated with autologous monocytes presenting tetanus toxoid (TT). Peripheral lymphocyte subsets were determined using double- or triple-color flow cytometry. In SS children with NS we found a decreased proliferative response of CD4+ T cells to TT stimulation, cytokine synthesis indicating the predominance of Th2 activity, and an increased percentage of activated suppressor-inducer (CD45RA+ CD4+CD25+, 5.18±0.8, P<0.001) and suppressor-effector (CD45RA+CD8+CD25+, 2.05±0.6, P<0.01) cells, with the concomitant reduction of activated memory cells (CD45RO+CD4+CD25+, 0.2±0.1, P<0.001). In children with SRNS we found an increased proliferative response of CD4+ T cells to TT, a rise in activated memory (CD45RO+CD4+CD25+, 3.82±0.7, P<0.01) and suppressor-inducer peripheral T cells (CD45RA+ CD4+CD25+, 3.85±0.6, P<0.01), but a low percentage of activated suppressor-effector (CD45RA+CD8+ CD25+, 0.5±0.2, P<0.05) T cells. We conclude that prior to treatment the distribution of lymphocyte subpopulations in peripheral blood together with Th1 and Th2 cell activity provides a useful tool for evaluating the likelihood of steroid sensitivity in patients with primary NS. Received: 3 November 1998 / Revised: 1 September 1999 / Accepted: 8 September 1999     

Procalcitonin: a marker of bacteraemia in SIRS

A number of European studies have documented the ability of procalcitonin (PCT), a novel inflammatory marker, to discriminate patients with sepsis from those with other causes of systemic inflammatory response syndrome (SIRS). The aim of this study was to assess procalcitonin's performance in an Australian intensive care unit (ICU) setting to examine whether it could discriminate between these two conditions. One hundred and twenty-three consecutive adult ICU patients fulfilling criteria for SIRS were enlisted in the study. Over a period of five days, daily serum PCT and C-reactive protein (CRP) levels were measured. At least two sets of cultures were taken of blood, sputum/broncho-alveolar lavage (BAL) and urine. Other cultures were taken as clinically indicated. Questionnaires to ascertain clinical suspicion of sepsis were prospectively answered by the ICU senior registrars. PCT values were ten times higher in patients with positive blood cultures; CRP values were also significantly higher in the bacteraemic patients. Both PCT and CRP had a good ability to discriminate bacteraemia from non-infectious SIRS, with the area under receiver operating characteristics (ROC) curves for PCT being 0.8 and for CRP being 0.82. However neither PCT or CRP was able to discriminate patients with localized sepsis from those without. Utilizing both tests resulted in a more sensitive screen than either one alone, while PCT was a more accurate diagnostic test for bacteraemia than CRP. The PCT value also differed between those who died in hospital and those who survived. Measurement of PCT alone or in combination with CRP can aid discrimination of septicaemia/bacteriemia with associated SIRS from non-infectious SIRS in an Australian ICU setting.     

Does uremic environment down-regulate T cell activation via TCR/CD3 antigen receptor complex?

TCR/CD3 receptor complex plays a central role in antigen recognition and T cell activation. Therefore, the present study investigates TCR alpha/beta (TCR-1) and CD3 receptor density (RD, number of receptors per cell) on uremic CD4 T lymphocytes in relation to T cell proliferative response induced by anti-CD3 monoclonal antibodies (mAb). The influence of uremic serum on TCR/CD3 receptor expression of normal and uremic CD4 T lymphocytes was evaluated as well. We found, that: a) percentage of TCR-1 and CD3 positive cells of freshly isolated CD4 T lymphocytes is the same in controls and ESRD-patients, but the TCR/CD3 RD is lower on uremic CD4 T lymphocytes, b) Incubation for 24 h with uremic serum lowers TCR/CD3 RD on normal and uremic CD4 T cells, c) There is positive correlation between TCR/CD3 RD and anti-CD3 induced lymphocyte proliferation. These data might also support the hypothesis that blunted T-cell response to antigen in uremia is due to down-regulation of the TCR/CD3 receptor complex by uremic milieu.     

Comparative efficacy of cefotiam versus cephalothin in the therapy of skin and soft tissue infections

Cefotiam was evaluated by a comparative open-label randomized trial with cephalothin in the therapy of skin and soft tissue infections in 39 patients. The most common organism isolated was Staphylococcus aureus (78%). We established evidence of primary infection with gram-negative bacilli in four patients, three of whom were diabetic. Eight patients had mixed infections or superinfections. No patient was evaluated as a treatment failure; for 10 of 39 patients we were unable to recover an etiological agent but demonstrated a clinical cure. Cefotiam was found to be as effective as cephalothin in the therapy of skin and soft tissue infections.