A direct comparison of the antigen-specific antibody profiles of intravenous immunoglobulins derived from US and UK donor plasma.

BACKGROUND AND OBJECTIVES: Intravenous immunoglobulin (IVIG) is used in a range of immunodeficiency states that require a broad spectrum of protective antibodies to a range of common pathogens. A comparison of the antigen-specific antibody profile of preparations of an IVIG (Vigam) derived from US and UK sourced plasma was performed, and these preparations were also compared with three other IVIG products from different manufacturers. MATERIALS AND METHODS: Antibodies against a range of bacterial and viral pathogens were measured by immunoassay. RESULTS: Similar profiles were found for Vigam made from UK and US source plasma and also for the other three IVIGs tested, but some specific differences were observed. CONCLUSIONS: IVIG preparations have a similar therapeutic spectrum of antibodies when prepared from plasma sourced either from the UK or the US.

Clinical experience with a new solvent detergent-treated intravenous immunoglobulin free of hypotensive effects.

OBJECTIVE: To see if modifications to the processing of intravenous immunoglobulin to include a virus inactivation stage alter immunoglobulin G (IgG) resulting in hypotension in patients. METHODS: Clinical trials were done involving extensive patient monitoring during infusion: in vitro - testing for markers of hypotension, and in vivo - an animal model which closely simulates clinical use. RESULTS: No hypotensive response was seen in the animal model or clinical trial. CONCLUSIONS: The production process used does not damage IgG or create vaso-active kinins as the preparation was free of hypotensive effects.

Relationship between alpha 1-antitrypsin inactivation and tumor necrosis factor alpha concentration in the synovial fluid of patients with rheumatoid arthritis.

OBJECTIVE: To examine the relationship between alpha 1-antitrypsin (alpha 1AT) specific activity and tumor necrosis factor alpha (TNF alpha) concentration in synovial fluid from 48 patients with rheumatoid arthritis. METHODS: The specific activity of alpha 1AT was calculated from the measurement of alpha 1AT concentration (by rocket immunoelectrophoresis) and elastase inhibitory capacity. TNF alpha was detected by enzyme-linked immunosorbent assay. RESULTS: TNF alpha concentrations correlated with the extent of alpha 1AT inactivation. CONCLUSION: Our findings are consistent with a role of elastase in TNF alpha release within the inflamed joint.

Proteolysis of human native and oxidised alpha 1-proteinase inhibitor by matrilysin and stromelysin.

Matrilysin is shown to rapidly inactivate alpha 1PI, an inhibitor of elastase, by cleaving the Pro357-Met358 peptide bond of its reactive centre. The rate of inactivation of alpha 1PI by matrilysin is four times higher than stromelysin. Matrilysin cleaves oxidised alpha 1PI at the Phe352-Leu353 bond, whilst stromelysin cleaves oxidised alpha 1PI at the Met358-Ser359 bond. We conclude that matrilysin is a potent serpinase which could play a role in inflammatory tissue damage by proteolytically inactivating alpha 1PI.

Inactivation of synovial fluid alpha 1-antitrypsin by exercise of the inflamed rheumatoid joint.

alpha 1-Antitrypsin (alpha 1AT) is known to be oxidised by reactive oxygen species both in vitro and in vivo, leading to its inactivation. We report here that synovial fluid (SF) alpha 1AT is inactivated during exercise of the knee-joints of rheumatoid arthritis (RA) patients. Sequential SF sampling from exercised RA patients showed a marked decrease in the mean activity of alpha 1AT after exercise with no change in the molecular forms of alpha 1AT. No such inactivation was found in the control (continuously resting) RA patients. We suggest that oxidation may contribute to alpha 1AT inactivation as a consequence of 'hypoxic-reperfusion' injury after exercise of the inflamed joint.

Inhibition of neutrophil superoxide production by human plasma alpha 1-antitrypsin.

We report here that human plasma alpha 1-antitrypsin (alpha 1-AT) inhibited human neutrophil O2.- release elicited by a variety of stimulants. In comparison, the inhibitory capacities of two serine protease inhibitors, L-1-tosylamide 2-phenylethyl chloromethyl ketone (TPCK) and soybean trypsin inhibitor (SBTI), and the human recombinant alpha 1-AT mutant, alpha 1-AT-Arg358 were in the order: alpha 1-AT = TPCK much greater than alpha 1-AT-Arg358 greater than SBTI when cells were stimulated with concanavalin A plus cytochalasin E. These data suggest that, in human inflammatory fluids containing relatively high concentrations of alpha 1-AT (such as rheumatoid arthritis synovial fluid), (i) alpha 1-AT may down-regulate the inflammatory process by inhibiting the neutrophil respiratory burst and (ii) serpin oxidation by neutrophil-released reactive oxygen species is unlikely to occur.

Inactivation of the elastase inhibitory activity of alpha 1 antitrypsin in fresh samples of synovial fluid from patients with rheumatoid arthritis.

The proteinase inhibitory ability of alpha 1 antitrypsin was measured in 23 samples of rheumatoid arthritis synovial fluid, eight osteoarthritic synovial fluids and nine normal control serum samples. For each sample a detailed kinetic analysis was performed with porcine pancreatic elastase as the target proteinase. Samples were stored for less than 24 hours at 4 degrees C before analysis, which does not significantly alter the proportion of inactive alpha 1 antitrypsin. In rheumatoid synovial fluid the elastase inhibitory ability was disproportionately depressed relative to the immunochemically determined concentrations of alpha 1 antitrypsin.

Proteolytic inactivation of human alpha 1 antitrypsin by human stromelysin.

alpha 1 Antitrypsin (alpha 1AT) is the main physiological inhibitor of neutrophil elastase, a serine protease which has been implicated in tissue degradation at inflammatory sites. We report here that the connective tissue metalloproteinase, stromelysin, cleaved alpha 1AT (54 kDa), producing fragments of approximately 50 kDa and 4 kDa, as shown by gel electrophoresis. The cleavage of alpha 1AT was accompanied by inactivation of its elastase inhibitory capacity. Isolation of the 4 kDa fragment by reversed-phase HPLC, followed by N-terminal amino acid sequencing, demonstrated that the cleavage of alpha 1AT occurred at the Pro357-Met358 (P2-P1) peptide bond, one peptide bond to the N-terminal side of the inhibitory site. We suggest that stromelysin may potentiate the activity of neutrophil elastase by proteolytically inactivating alpha 1AT.