Factor VIII concentrates and the immune system--laboratory investigations

Evidence suggests that haemophiliacs treated with factor VIII concentrates 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. Some concentrates inhibit lymphocyte proliferation and interleukin-2 secretion by human T-cell lines and peripheral blood lymphocytes. They can also inhibit activity of other cytokines such as interleukin-4 and interleukin-5 and secretion of cytokines such as interleukin-1 and granulocyte macrophage colony stimulating factor. These effects are product-related and vary from total inhibition to virtually no detectable inhibition. Of particular significance is that the degree of inhibition is not related to the purity or gross protein composition of the products. The inhibitory activity is not due to factor VIII itself as antibody 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 used for fractionation, is a major contaminant of 'inhibitory' concentrates and is responsible for the effects, observed in vitro, of concentrates on cytokine secretion or activity. The levels of TGF-beta varied between products and correlated with inhibition of interleukin-2 secretion 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.