Identification of transforming growth factor-beta as a contaminant in factor VIII concentrates: a possible link with immunosuppressive effects in hemophiliacs.
In previous studies, we have shown that some, but not all low-, intermediate-, and high-purity factor VIII concentrates inhibit interleukin-2 (IL-2) secretion from phytohemagglutinin (PHA)-stimulated T lymphocytes. We now present evidence that this inhibitory action of concentrates is, at least in part, due to contamination with transforming growth factor-beta (TGF-beta). Originally identified in platelets, TGF-beta is a 25-kD homodimer that has been shown to be a natural and potent inhibitor of many immunologic responses. Using a specific bioassay, we have measured TGF-beta in various factor VIII concentrates. While some concentrates contained substantial amounts of the cytokine, there was a wide variation in concentrations of TGF-beta in different products. These levels correlated with the degree of inhibition of IL-2 secretion from T cells exhibited by each product (P = .0001). Noninhibitory concentrates contained no detectable TGF-beta. Addition of a specific TGF-beta 1 antibody reversed the inhibitory effect of some concentrates on IL-2 secretion by PHA-stimulated Jurkat T cells and interleukin-5 (IL-5)-induced proliferation of an erythroleukemic cell line. These findings suggest that TGF-beta contamination is a major contributory factor to the inhibitory activity of some factor VIII concentrates on cytokine secretion or activity, and may partially explain the reported immunosuppressive effects in recipients of these blood products.
Wadhwa
M
M
Division of Immunobiology, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, UK.
Dilger
P
P
Tubbs
J
J
Mire-Sluis
A
A
Barrowcliffe
T
T
Thorpe
R
R
D000906:Antibodies / Q000494:pharmacology; D002460:Cell Line; D004340:Drug Contamination; D005169:Factor VIII / Q000032:analysis* / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000139:chemically induced*; D007376:Interleukin-2 / Q000378:metabolism; D015848:Interleukin-5 / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000009:adverse effects / Q000032:analysis* / Q000494:pharmacology
D000906:Antibodies; D007376:Interleukin-2; D015848:Interleukin-5; D010835:Phytohemagglutinins; D016212:Transforming Growth Factor beta; D005169:Factor VIII