FACTOR-VIII CONCENTRATES AND THE IMMUNE-SYSTEM - LABORATORY INVESTIGATIONS

Evidence suggests that haemophiliacs treated with factor VIII concentr ates show abnormalities in immune functions. The basis of this is not clear, but some factor VIII concentrates down-regulate Fc receptors on monocytes which may explain the impaired function of these cells. Som e concentrates inhibit lymphocyte proliferation and interleukin-2 secr etion by human T-cell lines and peripheral blood lymphocytes. They can also inhibit activity of other cytokines such as interleukin-4 and in terleukin-5 and secretion of cytokines such as interleukin-1 and granu locyte macrophage colony stimulating factor. These effects are product -related and vary from total inhibition to virtually no detectable inh ibition. Of particular significance is that the degree of inhibition i s not related to the purity or gross protein composition of the produc ts. The inhibitory activity is not due to factor VIII itself as antibo dy affinity purified factor VIII products are entirely non-inhibitory. The main inhibitory protein components appear to be of approximately 200 kDa and 60 kDa (by gel filtration). Recent evidence suggests that transforming growth factor-beta (TGF-beta), derived from the plasma us ed for fractionation, is a major contaminant of 'inhibitory' concentra tes and is responsible for the effects, observed in vitro, of concentr ates on cytokine secretion or activity. The levels of TGF-beta varied between products and correlated with inhibition of interleukin-2 secre tion from stimulated T-cells. The presence of TGF-beta in concentrates may therefore explain the immunosuppression observed in recipients of these products. Correlation of the inhibitory effects with clinically important consequences such as increased susceptibility to infections or decreased CD4 counts also remains to be established.