[DRGs as future reimbursement system for hospital services exemplified by multiple sclerosis]. / Die DRGs als zukünftiges Abrechnungssystem der Krankenhausleistungen am Beispiel der Multiplen Sklerose.

Introducing the Diagnosis Related Groups (DRG) system into the German public health sector will prompt important changes for in- and outpatient care. Especially admission to hospital, extent of diagnostic and therapeutic procedures, and duration of hospitalisation might be affected. Taking multiple sclerosis, the most frequent inflammatory disease of the nervous system for Europe, with yearly treatment costs of about 2.3 billion Euro in Germany as example, the effect on reimbursement of complete documentation of the medical output is illustrated. Extensive information on clinically relevant items is given. The possible role of the DRG system as a cost- and quality-controlling tool in the German public health system as well as its potential risks in the absence of broadly accepted treatment guidelines is discussed.

Differential production of interleukin-3 in human T lymphocytes following either CD3 or CD2 receptor activation.

Interleukin-3 (IL-3) is expressed in T lymphocytes and stimulates the growth of multipotent hematopoietic progenitors. Little is known, however, about the stimuli that lead to IL-3 protein release. We examined IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA expression and protein secretion in human T lymphocytes following activation via the TCR/CD3 complex, the CD2 receptor, and the IL-2 receptor. GM-CSF mRNA expression and protein release were found in CD3 and CD2 activated T cells with maximum GM-CSF release following stimulation with IL-2. IL-3 protein release is regulated via the CD2 receptor with virtually no IL-3 release after T cell stimulation via CD3. In contrast, IL-3 mRNA accumulation is more pronounced after CD3 activation than after CD2 activation. This suggests that upregulation of IL-3 protein release following T cell stimulation via CD-2 occurs largely at the translational or posttranslational level. These data also indicate that differential control of cytokine production can occur in response to activation of the alternative T cell receptor. Interaction of the T cell CD2-receptor with its natural ligand LFA-3 expressed on stromal cells might represent a regulatory mechanism for rapid release of IL-3, facilitating proliferation of multipotent hematopoietic cells.

Time course of interferon-gamma production deficiency after autologous and allogeneic stem cell transplantation for malignancies.

While success of autologous bone marrow transplantation (BMT) for malignancies largely depends on the cytotoxicity of the ablative regimen, achievement of relapse-free survival after allogeneic BMT is thought to be enhanced by immunologic effects. We therefore investigated in vivo and in vitro production of interferon-gamma (IFN-gamma), soluble interleukin-2 (IL-2) receptor alpha-chain (sCD25), tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients before and during various time periods up to 2 years after autologous and allogeneic BMT. Cytokine levels were assessed in patient plasma and in supernatants of patient-derived peripheral blood mononuclear cells (PBMNC) cultured for 3 days in the presence of T cell-specific stimulation via CD3 plus IL-2. Our studies show that IFN-gamma plasma levels are decreased in autologous graft recipients before and during the first 30 days posttransplant. In allogeneic graft recipients, IFN-gamma plasma levels are also decreased during the first 30 days posttransplant, but otherwise are comparable to normal control (NC) values. In vitro stimulated PBMNC from autologous graft recipients also exhibit an IFN-gamma production defect before and during the first 30 days posttransplant. In contrast, before and up to 30 days after allogeneic BMT, stimulated IFN-gamma production is comparable to NC values but then gradually decreases, reaching its trough levels at between 61 and 180 days post-BMT. The IFN-gamma production defects in both patient groups seem to be specific, as sCD25, TNF-alpha, and GM-CSF production in stimulated PBMNC is normal or even enhanced at any time after autologous or allogeneic BMT. Deficient IFN-gamma production in patient-derived PBMNC does not correlate with variation in monocyte, T cell, or natural killer (NK) cell numbers during the posttransplantation course.

Interleukin 6-induced differentiation of a human B cell line into IgM-secreting plasma cells is mediated by c-fos.

The role of the protooncogene c-fos in interleukin (IL) 6-induced B cell differentiation was assessed. Treatment of SKW 6.4 cells with IL 6 induced a transient and early stimulation of c-fos sense mRNA expression. The effect appeared within 30 min and returned to basal levels after 2 h. The addition of antisense oligonucleotides to c-fos significantly inhibited IL 6-induced IgM production by SKW 6.4 cells (p less than 0.001), whereas control oligonucleotides had no inhibitory effect. These results indicate that activation of c-fos is involved in IL 6-induced differentiation of SKW 6.4 cells into IgM-secreting cells.

Defective interferon gamma production in neonatal T cells is independent of interleukin-2 receptor binding.

Newborns are more susceptible to fungal, viral, protozoan, and certain bacterial infections than adults. This susceptibility is due in part to a decreased interferon gamma (IF gamma) production. The present investigation focuses on the role of the IL-2 receptor in the deficient IF gamma production in neonatal T cells. IL-2-induced IF gamma production in unstimulated neonatal cord blood and adult peripheral T cells was comparable, but the IF gamma production in CD3-stimulated neonatal T cells was only 20% of the adult production. Neonatal and adult T cells showed no difference in the expression of the 55-kD alpha and 75-kD beta chains of the IL-2 receptor. Blocking of the 55-kD alpha chain of the IL2 receptor with TAC MAb resulted in a marginal reduction in IF gamma release from unstimulated or CD3-stimulated neonatal T cells cultured in the presence of IL-2. In contrast, blocking of the 55-kD alpha chain of the IL-2 receptor in adult T cells caused a 92% and 73% inhibition in IF gamma production in unstimulated and stimulated T cells, respectively. Blocking of the 75-kD beta chain of the IL-2 receptor with TU27 MAb had a marginal effect in both unstimulated and CD3-stimulated neonatal and adult lymphocytes. Binding studies with unstimulated cord blood T cells using [125I]-IL-2 showed a binding affinity that corresponded with the intermediate affinity IL-2 receptor. In CD3-stimulated cord blood T cells, a high-affinity receptor was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential regulation of lymphokine production by distinct subunits of the T cell interleukin 2 receptor.

Most biologic responses to IL-2 have been attributed to interaction of IL-2 with a high affinity receptor which consists of a heterodimer composed of two distinct IL-2-binding proteins (IL-2R alpha/IL-2R beta). However, both low affinity IL-2R alpha (55 kD) and intermediate affinity IL-2R beta (70-75 kD) also appear to be expressed independently on the cell surface. We investigated the receptor-specific regulatory effects of IL-2 on cytokine production in unstimulated and activated T cells. T cells were activated by stimulation of the antigen receptor complex with anti-CD3 mAb. IL-2 (10(2) U/ml, 1 nM) stimulation of resting cells resulted in a fivefold increase in GM-CSF release but in only minimal IFN-gamma release. IL-2 markedly augmented mRNA expression of GM-CSF but not IFN-gamma in unstimulated T cells. IL-2R beta mAb but not IL-2R alpha mAb decreased IL-2-induced GM-CSF release and mRNA expression from unstimulated T cells. IL-2 concentrations required for GM-CSF release from resting cells suggested ligand binding to an intermediate affinity receptor. GM-CSF and IFN-gamma release from activated T cells increased four- to fivefold in response to 1 nM IL-2 and IL-2 augmented both GM-CSF and IFN-gamma mRNA. IL-2R beta mAb but not IL-2R alpha mAb reduced GM-CSF release and mRNA expression in activated T cells stimulated with 1 nM IL-2. IL-2R alpha blockade markedly decreased IL-2-induced IFN-gamma release and mRNA expression from activated cells, while IL-2R beta blockade had little effect on IFN-gamma production in activated cells. IL-2R alpha blockade altered the affinity of the receptor mediating activated cell GM-CSF release from a high affinity to an intermediate affinity state. These studies indicate an independent role for IL-2R beta in mediating GM-CSF production from T cells. They also suggest that unstimulated and activated T cells, which express distinct IL-2 receptor moieties, mediate release of separate lymphokines and that different subunits of the IL-2 receptor may play an important role in the regulation of cytokine production.

[Molecular mechanisms of cellular interaction in immune regulation of hematopoiesis]. / Molekulare Mechanismen zellulärer Interaktion in der Immunregulation der Hämatopoese.

Studies are reviewed, which establish a novel regulatory role for the T cell lymphokine IL2: Immunoregulation of hematopoiesis. IL2 induces a receptor-specific inhibition of early erythroid progenitors. IL2-induced inhibition of erythropoiesis is mediated by Interferon-gamma protein release preceded by Interferon-gamma mRNA accumulation. Triggering of the antigen receptor complex induces p55 IL2 receptor expression, which is a prerequisite for IL2-induced erythropoietic inhibition. P55 protein expression on the T cell surface is preceded by an increase of p55 mRNA levels. The studies demonstrate that the regulatory role of IL2 extends beyond governance of the immune system itself and can subserve to control red cell production in vitro.