Higgins, Julie Anne; (1991) A study of lymphocyte dysfunction in multi-transfused haemophilic patients: mechanisms and clinical significance. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Contradictory evidence of activation and inhibition of the immune system has been described in haemophiliacs and attributed to infusion of clotting factor concentrate used in their haemostatic maintenance. The purpose of the study was two-fold. Firstly to assess if the concentrates were activating patients' lymphocytes and thus potentially influencing the progression of HIV disease; and secondly, to assess the mechanisms of the reported concentrate-induced inhibition of T cell function in vitro. Methods were established and markers of acute and chronic T and B lymphocyte activation were measured in matched groups of HIV+ve and HIV-ve haemophiliacs and controls. HIV-ve haemophiliacs had elevated levels of soluble IL2 receptor (sIL2-R) (p<0.05) which were unrelated to concentrate infusion, but related to active liver disease attributed primarily to HCV infection. All other markers were normal. HIV+ve haemophiliacs showed lymphocyte activation consistent with that seen in other HIV+ve groups with significant increases in expression of HLA-DR (p<0.0001), CD45RO (p=0.0058), SIL2-R levels (p<0.02) and all B cell activation markers (p<0.001). These did not correlate with concentrate infusion. Raised sIL2-R levels were associated with chronic liver dysfunction suggesting reactivated liver virus infection. In conclusion infusion of concentrate did not appear to be causing lymphocyte disturbances per se. Immune activation was related to viral infection: either HIV or HCV. A detailed analysis of the inhibitory effects of intermediate purity FVIII/FIX concentrates on T cell activation in vitro showed depression of HLA-DR and CD25 expression. This was not seen with monoclonal purified FVIII/FIX products. Inhibitory products caused a decrease in free calcium levels in the culture medium which correlated with their inhibitory effects. All products inhibited mitogen-induced calcium flux into the cells. Reduction in calcium in culture medium by the concentrates is important in inhibiting T cell activation in vitro. Inhibition of calcium mobilisation suggests that events preceding calcium flux - eg, signal transduction may also be contributing to their inhibitory effects. To conclude concentrate inhibition of T cell function in vitro is probably a laboratory artefact and the lymphocyte disturbances that have been reported are probably related to infection with virus.

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