Where is biological therapy going?

The substantial progress in our understanding of molecular and cellular biology has allowed us to design biological therapeutics ('biologicals') with defined targets and effector functions. These biologicals have greatly contributed to our current knowledge of pathogenetic mechanisms in autoimmune diseases. However, although some of the biologicals have been extremely successful in treating the symptoms of chronic inflammation, biological therapy has not yet met the expectations of permanently silencing the chronic immune response.

IgA and IgG autoantibodies against alpha-fodrin as markers for Sjögren's syndrome. Systemic lupus erythematosus.

Objective: To determine the prevalence of IgA and IgG autoantibodies against alpha-fodrin in patients with primary and secondary Sjögren's syndrome (SS) and controls.

Methods: An ELISA detecting IgA and IgG antibodies against alpha-fodrin was developed. We examined the prevalence of IgA and IgG antibodies against alpha-fodrin in patients with primary and secondary SS, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) and blood donors.

Triggering Fc alpha-receptor I (CD89) recruits neutrophils as effector cells for CD20-directed antibody therapy.

CD20 Abs induce clinical responses in lymphoma patients, but there are considerable differences between individual patients. In (51)Cr release assays with whole blood as effector source, RAJI cells were effectively killed by a mouse/human chimeric IgG1 construct of CD20 Ab 1F5, whereas ARH-77 proved resistant to killing by this Ab. When whole blood was fractionated into plasma, mononuclear cells, or granulocytic effector cells, RAJI cells were effectively killed in the presence of complement-containing plasma, whereas the mature B cell line ARH-77 proved complement resistant.

Etiopathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus is an autoimmune disease of unknown etiology. Research efforts of the last few years have mainly focused on basic molecular and cellular pathogenetic processes of the disease. Consequently, this paper reviews the etiopathogenetic hallmarks, such as impaired amount and presentation of nuclear antigens, production of antinuclear antibodies by T-cell-dependent B cell stimulation and organ damage by anti-dsDNA antibodies or immune complexes that are discussed at the present time.

Chlorpromazine induces apoptosis in activated human lymphoblasts: a mechanism supporting the induction of drug-induced lupus erythematosus?

Objective: Drug-induced lupus erythematosus is a serious side effect of certain medications, such as procainamide, quinidine, hydralazine, chlorpromazine, and isoniazid, the underlying pathogenesis of which is unresolved. In this study, we examined the influence of these drugs on the regulation of apoptosis, or programmed cell death, in quiescent and activated human lymphocytes. We also discuss the dysregulation of apoptosis as a pathogenetic factor in systemic lupus erythematosus.

UVB-irradiated T-cells undergoing apoptosis lose L-selectin by metalloprotese-mediated shedding.

Purpose: L-selectin (CD62L) is a prerequisite for leucocyte adhesion to endothelial cells of blood vessels and consequently for transmigration. Its expression on the cell surface therefore regulates the ability of lymphocytes to enter lymph nodes, to re-enter blood vessels or to invade tissues at sites of inflammation. The aim of this study was to determine the expression of CD62L on apoptotic lymphocytes after UVB irradiation.

Positive influence of the Delta32CCR5 allele on response to highly active antiretroviral therapy (HAART) in HIV-1 infected patients.

The heterozygous 32 base pair deletion of the chemokine receptor 5 (Delta32CCR5) has been associated with a more benign course of HIV-1-infection. To study the influence of Delta32CCR5 on the response to antiviral therapy we analyzed the presence of Delta32CCR5 by PCR in PBMC from 107 randomly selected HIV-1-infected patients treated with HAART for at least three months. 24 of 107 patients were heterozygous for Delta32CCR5 (22.

[Guideline for the joint swelling symptom--primary physician problem management and referral indications. German Society of Rheumatology "Quality Assurance" Committee].

The guideline "Joint Swelling" is addressed to primary care physicians--general practitioners, internists or orthopedists without special experience in rheumatology. It provides a framework for interviewing patients, as well as for physical, laboratory and imaging examinations and for selection of treatment appropriate to the level of primary care. Situations which call for urgent evaluation and criteria for referral to rheumatologists are described.

Flow cytometric discrimination between viable neutrophils, apoptotic neutrophils and eosinophils by double labelling of permeabilized blood granulocytes.

Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) is frequently used to detect apoptotic cells in tissues, cytospins and suspensions. Here we show that TUNEL staining of freshly isolated granulocytes results in non-specific positivity of a distinct population, which can be observed in the presence or absence of TdT. The morphological features of the false-positive cells examined in fluorescence microscopy suggest that the non-specifically stained cells are eosinophilic granulocytes.

Co-stimulation of IL-2 production by CD28 is independent of tyrosine-based signaling motifs in a murine T cell hybridoma.

In addition to the antigen-specific stimulus delivered by the TCR, T cells under most circumstances require a co-stimulatory signal for complete activation. CD28 can provide this signal, and the importance of CD28-mediated co-stimulation has been well documented both in vitro and in vivo, but the intracellular pathways downstream of CD28 are less well characterized. So far, maximal co-stimulation of IL-2 production has been attributed to tyrosine-based signaling motifs, either including the first cytoplasmic tyrosine residue that binds phosphatidylinositol 3'-kinase (PI3-K), or the third tyrosine residue.

CD 95-independent mechanisms of IL-2 deprivation-induced apoptosis in activated human lymphocytes.

Growth factor deprivation-induced apoptosis plays an important role in several cellular systems. However, knowledge of the molecular mechanisms involved are restricted to a few murine models or tumor cell lines. Therefore, we aimed studying signaling pathways leading to apoptosis in activated human peripheral T cells after IL-2 withdrawal.

Specific recognition of lamivudine-resistant HIV-1 by cytotoxic T lymphocytes.

Objective: The reverse transcriptase (RT) M184V mutation within the HLA-A2-restricted HIV-1 cytotoxic T lymphocyte (CTL) epitope VL9 (VIYQYMDDL; RT 179-187) not only induces drug escape against lamivudine but also abolished recognition by a CTL clone derived from a long-term non-progressor. To test whether the variant VL9 epitope containing the M184V mutation represents a new CTL epitope, we studied recognition of this epitope in a cohort of HLA-A2-positive HIV-1-infected patients.

Methods: Peripheral blood mononuclear cells isolated from 28 HIV-1-infected patients were stimulated with the peptide VIYQYVDDL, containing the M1 84V mutation.

Rheumatoid factors in systemic lupus erythematosus: association with clinical and laboratory parameters. SLE study group.

The prevalence and clinical and laboratory associations of IgM, IgG and IgA rheumatoid factors (RF) were determined in 352 patients with systemic lupus erythematosus (SLE). IgM, IgG, and IgA class RF were detected in 17.9%, 20.

123I-antileukoproteinase scintigraphy reveals microscopic cartilage alterations in the contralateral knee joint of rats with "monarticular" antigen-induced arthritis.

Objective: To assess the involvement of the contralateral knee joint in monarticular antigen-induced arthritis (AIA) by scintigraphy with the cationic (pI >10), 123I-labeled, serine proteinase inhibitor antileukoproteinase (123I-ALP) and to compare the scintigraphic findings with those of radiography and high-resolution ex vivo magnetic resonance imaging (MRI).

Methods: Lewis rats with chronic AIA were examined 2.5 months following arthritis induction (injection of 500 microg of methylated bovine serum albumin/saline into the ipsilateral [arthritic] knee joint and injection of phosphate buffered saline into the contralateral knee joint following systemic immunization).

In vivo blockade of tumor necrosis factor-alpha in patients with rheumatoid arthritis: longterm effects after repeated infusion of chimeric monoclonal antibody cA2.

Objective: To investigate the longterm consequences of tumor necrosis factor-alpha (TNF-alpha) blockade in patients with rheumatoid arthritis (RA), to compare changes after repeated infusion of cA2 monoclonal antibody with those occurring after the initial treatment, and to investigate significant correlations of cellular or serological changes to the duration of clinical benefit for each patient.

Methods: A clinical trial testing TNF-alpha monoclonal antibody cA2 in treatment of RA showed this therapeutic agent is highly effective. A dosage of 1 mg/kg or 10 mg/kg cA2, given in a single infusion, was compared to placebo.

Thrombomodulin in systemic lupus erythematosus: association with clinical and laboratory parameters.

Thrombomodulin is an endothelial cell membrane glycoprotein and is detected in plasma and serum after endothelial injury. In our study comprising 311 patients with systemic lupus erythematosus (SLE) clinical and laboratory associations of elevated thrombomodulin serum concentrations were examined. Elevated thrombomodulin concentrations were detected in 7.

Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group.

Background: Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate.