Inhibition of natural killing and antibody-dependent cell-mediated cytotoxicity by the plasma protease inhibitor alpha 2-macroglobulin (alpha 2M) and alpha 2M protease complexes.

Over the past few years increasing attention has been given to the relationship between the immune response and proteases. The aim of our present study was to examine the dose-response effect of purified alpha 2-macroglobulin (alpha 2M) with varying degrees of protease (trypsin) saturation on natural killing (NK) and antibody-dependent cell-mediated cytotoxicity (ADCC). The results demonstrated that alpha 2M with 50% trypsin saturation (fast alpha 2M) was more inhibitory in both assays than alpha 2M with no bound protease (slow alpha 2M).

The role of protease in immunoregulation.

Whilst immunodepression is widely recognized in patients subject to trauma or chronic disease, the mechanism of this process is poorly understood. We found that most of the lymphocyte suppressive activity of plasma from severely ill patients was attributable to the protein alpha 2-macroglobulin (alpha 2 M) and low molecular weight peptide (less than 10000). The only major variation in alpha 2 M concentration was found in patients subject to trauma, when it was depressed at times of high plasma suppressive activity. In order to explain qualitative immunosuppressive differences in alpha 2 M we studied its functional role as the main route for binding and degrading proteolytic enzyme (protease). In normal plasma minor degrees of protease complex formation to alpha 2 M caused greatly increased suppressive activity due principally to alpha 2 M and the abnormal appearance of low molecular weight peptide (less than 10000). Study of protease inhibitor function in patients suffering from acute or chronic illness suggested that in these patients their plasma becomes immunosuppressive due to inadequate handling of protease, resulting in alpha 2 M-protease complexes or inhibitory peptides persisting in the circulation. Opportunities for background immunoregulation by altering protease metabolism are considered.

A new mechanism of humoral immunodepression in chronic renal failure and its importance to dialysis and transplantation.

Whilst chronic renal failure (CRF) patients are known to have an impaired immune response the explanation is unclear. We investigated the immunosuppressive effect of plasma from CRF patients on an in vitro assay of normal lymphocyte function. One hundred and sixty regular dialysis patients had significantly greater plasma suppressive activity (PSA) than that of normal healthy subjects. PSA decreased after haemodialysis but increased after blood transfusion. Renal allograft recipients with low PSA were more likely to have accelerated rejection. Assay of the functional capacity of plasma for inhibiting protease (e.g. plasmin, thrombin, trypsin) suggest that high PSA is associated with the excess formation of protease-inhibitor complexes and liberation of immunoregulatory peptide (less than 10,000 daltons).

A possible mechanism of immunoregulation produced by alpha 2-macroglobulin.

Most of the plasma suppressive activity was associated with alpha 2M in both normal subjects and cancer patients. alpha 2M binding to physiological levels of proteases was associated with an increase in the ability to suppress lymphocyte reactivity in the TEEM test. alpha 2M binding to proteases released a peptide that was a component of the alpha 2M; this peptide suppressed lymphocyte reactivity to mitogenic, antigenic, and allogenic stimuli in the TEEM test and in the lymphocyte transformation assay. Physically and biologically similar peptides have been found in the plasma of cancer patients and patients with thermal burns, uremia, and acute pancreatitis.