We examined the expression of the transcription factor NF-kappa B, a nuclear trans-acting factor known to play a key role in cytokine gene regulation, in patients with inflammatory bowel disease (IBD). It was found that LP macrophages in Crohn's disease (CD) and ulcerative colitis (UC) display high levels of NF-kappa B DNA-binding activity accompanied by an increased production of interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)alpha. Western blot studies showed an increased expression of the p50 and c-rel subunits of NF-kappa B; however, the most striking finding was an increased expression level of NF-kappa B p65 in patients with CD and UC. Selective downregulation of p65 in IBD macrophages by a specific antisense phosphorothioate oligonucleotide was sufficient to considerably reduce production of proinflammatory cytokines. These results demonstrate a characteristic increase of NF-kappa B binding levels in patients with IBD. The data suggest that antisense DNA targeting NF-kappa B p65 can be used as a novel molecular approach for the treatment of patients with IBD.

Inhibitors of factor VIII are a rare condition in non-hemophiliacs, but they are frequently responsible for life threatening hemorrhage. Acquired factor VIII:C inhibitors represent the spontaneous development of autoantibodies that partially or completely neutralize the plasma coagulant activity of the clotting factor. The autoantibodies can arise in diverse clinical settings, in older adults they are frequently associated with immunological disorders or malignancies. We report of a 75-year-old man with acquired factor VIII:C inhibitor associated with adenocarcinoma of the prostate and a successful treatment of a severe bleeding complication with porcine factor VIII. A 75-year-old man was admitted because of a hematoma of his right cheek and an isolated prolonged aPTT. Acquired factor VIII:C inhibitor was identified as the cause and immuno-suppressive therapy was begun. In the clinical course severe hemorrhaging occurred and was successfully treated with porcine factor VII (Hyate:C(R)). The initially high inhibitor titer of 32 Bethesda Units (BU) disappeared. As the cause of acquired factor VIII:C inhibitor a newly diagnosed adenocarcinoma of the prostate is likely. After complete remission of acquired factor VIII:C inhibitor radiation therapy was begun. Six months after severe hemorrhaging the patient was clinically stable and PSA levels were normal. This case demonstrated the necessity of a precise diagnosis and therapy regimen of this coagulopathy based on clinical and laboratory data. In the absence of hemorrhage immuno-suppressive therapy with corticosteroids is indicated, in a patient with severe bleeding and high inhibitor titer (greater than or equal to 5 BU) porcine factor VIII should be administered.

Interferon alpha-2a (IFN-alpha) and folinic acid (FA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. A phase II study was initiated to evaluate the effect of a combination of 5-FU/FA/IFN-alpha in patients with advanced pancreatic cancer. Sixty previously untreated patients with advanced adenocarcinoma of the pancreas were treated with 500 mg m-2 FU via an intravenous bolus 1 h after the initiation of a 2 h infusion of 500 mg m-2 FA. Before starting the FA infusion, 6 million units (MU) of IFN-alpha was administered subcutaneously. The treatment was repeated once a week. Of 57 evaluable patients, eight (14%) had a partial response (PR), eight (14%) a minor response (MR) and 28 (49%) no change of disease (NC). Thirteen patients (23%) had progressive disease (PD). The median survival time was 10 months for all patients, 22 months for patients with partial remission and 5 months for patients with progressive disease. Many patients with tumour-related pain whose tumours were affected in terms of PR, MR, NC were free of pain during treatment with this regimen (22/36 patients). The common toxicities observed were fever (56%), nausea (37%) and diarrhoea (33%). These data suggest that biochemical modulation of 5-FU with FA and IFN-alpha has some positive effects in the treatment of pancreatic cancer of moderate toxicity.

To analyse the relationship between the presence of liver cirrhosis and hepatic inflammation and the serum concentrations of the aminoterminal propeptide of procollagen type III (P-III-NP) and of hyaluronic acid (HA) in chronic liver disease, we measured P-III-NP and HA concentrations in paired serum samples from 133 patients with various chronic liver diseases, from 22 patients with acute hepatitis and from 50 healthy age-matched controls. In 24 (of the 133) patients with autoimmune chronic liver disease, follow-up determination was performed during therapeutic treatment with immunosuppressive drugs. Compared with controls P-III-NP concentrations (medians) were significantly elevated in 65% of patients with chronic active hepatitis (P = 0.00097) and in 79% of patients with active liver cirrhosis (P = 0.0126) but not in patients with chronic persistent hepatitis (P = 0.06). Serum concentrations (medians) of HA were increased (P = 0.0058) in 32% of patients with chronic active hepatitis and in 91% of patients with active cirrhosis (P < 6 x 10(-7). The difference of HA serum concentrations but not that of P-III-NP serum concentrations in patients with chronic active hepatitis and in patients with active cirrhosis was statistically significant. HA and P-III-NP serum concentrations were significantly elevated in 22 patients with acute hepatitis. Serum concentrations of P-III-NP in patients with autoimmune chronic liver disease significantly decreased during immunosuppressive therapy in patients with autoimmune chronic active hepatitis (P = 0.0001) and in patients with autoimmune active cirrhosis (P = 0.0039); HA serum concentration decreased to normal level in patients with autoimmune chronic active hepatitis (P = 0.0017); in contrast, when cirrhosis was present, serum HA levels decreased but remained elevated (P = 0.129).It is concluded that determination of HA serum concentrations will help to differentiate chronic active hepatitis from active cirrhosis. While elevated P-III-NP serum concentrations mainly correlate with inflammatory activity, elevated HA serum concentrations seem to be an expression of mainly the reduced functional (clearance function) capacity of the liver in chronic liver diseases. Therefore determination of HA serum concentration is of greater diagnostic value, especially when inflammatory activity is low.

Grundsätzlich läßt sich in der Synovialmembran chronischer Polyarthritiker nur ein beschränktes Zytokinprofil nachweisen: Während T-Lymphozytenprodukte wie IL-2, IL-3, IL-4, IFN-gamma und TNF-beta nur spärlich vorhanden sind, finden sich exzessive Mengen von Makrophagen/Fibroblastenprodukten wie IL-1, IL-6, IL-8, TNF-alpha und M-CSF [1, 2]. Auf IL-6 und IL-8, zwei wichtige proinflammatorische und erst neuerdings genauer charakterisierte Zytokine aus Makrophagen und Fibroblasten und deren Funktion bei der Amplifikation und Perpetuierung der chronischen Synovitis, soll hier näher eingegangen werden. IL-6 ist ein 26-kd Protein, welches von Monozyten, T-Lymphozyten und Fibroblasten produziert wird. Die Synthese und Freisetzung erfolgt in erster Linie nach Stimulation mit IL-1 und TNF-alpha, mit denen IL-6 einige biologische Wirkungen gemeinsam hat. Im Unterschied zu IL-1 und TNF-alpha vermag IL-6 jedoch nicht die PGE2- und Kollagenaseproduktion in Chondrozyten und Synovialfibroblasten anzuregen. Hohe Spiegel von IL-6 werden in entzündlichen Gelenkflüssigkeiten, insbesondere bei cP-Patienten gefunden. Diese korrelieren sehr gut mit Parametern der systemischen Krankheitsaktivität wie der BSG und der Menge der Akutphasenproteine. Außerdem wird die Genexpression wie auch die Proteinsynthese von IL-6 sehr stark durch IL-1 und TNF-alpha in Synovialbroblasten stimuliert. Somit ist IL-6 vermutlich in erster Linie ein Verstärker bestimmter Wirkungen von IL-1 und TNF-alpha. Andererseits spielt IL-6 aber auch in der Akutphasenreaktion der Leber eine wichtige Rolle und bei der lokalen Rheumafaktorenproduktion durch B-Zellen bzw. Plasmazellen in der Synovialmembran. Verschiedenen Arbeitsgruppen gelang es, in den letzten Jahren, ein neues inflammatorisches Zytokin, das IL-8, näher zu charakterisieren. IL-8 unterscheidet sich von allen anderen Zytokinen in seiner besonderen Eigenschaft, spezifisch neutrophile Granulozyten zu aktivieren. IL-8 wird von Monozyten/Makrophagen, Fibroblasten, Endothelzellen wie auch von Chondrozyten nach Stimulation mit IL-1 und TNF-alpha freigesetzt. Bei Patienten mit chronischer Polyarthritis konnte zudem gezeigt werden, daß mononukleäre Zellen in der Synovialflüssigkeit besonders stark IL-8 spezifische mRNA exprimieren und sehr viel IL-8 freisetzen [2]. Besonders starke Stimulatoren von IL-8 im Gelenk sind IL-1 sowie rheumafaktorhaltige Immunkomplexe. Bei chronischer Polyarthritis zeigen bereits Blutmonozyten eine erhöhte Spontanfreisetzung für IL-8, welche sehr wahrscheinlich durch IgM-Rheumafaktoren getriggert wird.

CEA is widely used as a human tumour marker and was first defined by Gold and Freedman in 1965 as an antigenic component in cancers derived from gastrointestinal tract epithelium. It is a member of a large family of immunologically related glycoproteins that vary in size and tissue distribution. Studies with c-DNA clones for CEA and NCA reveal that this family consist only of a limited number of different proteins with variable glycosylation, due to post-transcriptional modifications. The complete gene family includes about 10 closely related genes. Recently it was published that in contrast to mRNA coding for CEA, mRNA coding for NCA was expressed predominantly in cancerous tissues. A monoclonal antibody recognizing an epitope expressed on both CEA and NCA could therefore be a useful diagnostic reagent.

Hepatitis B markers were studied in seven patients with reactivated liver disease. Reactivation of chronic type B hepatitis, as indicated by the reappearance of hepatitis B e antigen (HBeAg) in the serum, was characterised by the appearance of hepatitis B virus‐DNA (HBV‐DNA) in the serum. The expression of pre‐S 1 encoded protein remained unchanged in five of seven patients, and poly‐HSA as a marker for pre‐S 2 encoded protein remained detectable in six of seven patients before and after reactivation of chronic hepatitis. The level of serum HBV‐DNA correlated well with the level of liver enzymes, which rose from normal to various levels after reactivation of the liver disease. The data suggest that inflammatory activity of the liver disease is not related to the expression of pre‐S encoded protein but to viral replication. Possibly pre‐C and C‐gene encoded antigens, which are produced together with viral nucleic acid and expressed on the surface of HBV‐infected liver cells, play the key role in liver damage believed to be mediated by cytotoxic T cells.

Acute hepatitis A is diagnosed by IgM-anti-HAV antibodies. Cytotoxic immune reactions seem to play a key role in the pathogenesis of hepatitis A, which is an acute self-limited disease. - Acute hepatitis B is diagnosed by IgM-anti-HBc antibodies and can thus be differentiated from other HBV-associated liver diseases. The detection of HBV-DNA in serum serves to differentiate between HBsAg/anti-HBe positive patients, with active viral replication and progressive chronic liver disease, and HBV-DNA negative asymptomatic HBsAg-carriers usually with normal liver histology. In the pathogenesis of HBV-associated liver diseases cytotoxic immune reactions against virus-infected hepatocytes are thought to mediate liver cell destruction. Membrane expressed virus as well as host antigens are candidate target antigens for these immune reactions. Hepatitis delta is always associated with acute and chronic HBV infection. Acute hepatitis delta is diagnosed by delta-RNA in serum and later by antibodies against the delta virus. Little is known about the pathogenesis of delta virus infection. Autoimmune type chronic active hepatitis (CAH) is classified into classical autoimmune type "lupoid CAH" with antinuclear antibodies and liver membrane antibodies as markers, liver-kidney-microsomal (LKM) antibody positive CAH, CAH associated with autoantibodies against a soluble liver antigen (SLA), and CAH associated with high titers of anti-smooth muscle antibodies (SMA). In the pathogenesis of autoimmune type CAH an antibody-mediated cellular cytotoxicity (ADCC) may play a significant role. Primary biliary cirrhosis is to be differentiated as a clinical syndrome associated with cholestasis and anti-mitochondrial antibodies (AMA). By immunoblotting and radioimmunoassay at least two PBC-specific subtypes of AMA can be defined. Immune reactions against self-antigens are thought to be involved in the pathogenesis of PBC, although the precise reactions are unknown.