Neutralizing antibodies to granulocyte-macrophage colony-stimulating factor, interleukin-1 alpha and interferon-alpha but not other cytokines in human immunoglobulin preparations

Human immunoglobulin preparations are used therapeutically for various diso rders. Such therapy is generally safe but adverse effects occasionally occu r in recipients. It has been suggested that antibodies to cytokines present in clinical immunoglobulin products may contribute to undesirable effects in recipients. Therefore, we investigated intravenous and intramuscular imm unoglobulin products for the presence of cytokine-specific neutralizing ant ibodies. Using validated bioassays, we detected neutralizing activity again st human granulocyte-macrophage colony-stimulating factor (GM-CSF), interfe ron-alpha 2a (IFN-alpha 2a) and interleukin-1 alpha (IL-1 alpha) in immunog lobulin products. We found no neutralization of granulocyte colony-stimulat ing factor, macrophage colony-stimulating factor, stem cell factor, IL-1 be ta, IL-2, IL-3, IL-4, IL-6, IL-9, IL-10, IL-12, tumour necrosis factor-alph a, oncostatin M (OSM) and IFN-gamma. Most batches which neutralized IFN-alp ha 2a activity also neutralized other IFN-alpha subtypes, IFN-w and IFN-bet a. Most products (94%) neutralized the biological activity of GM-CSF. No co rrelation between batches and their ability to neutralize bioactivities of GM-CSF, IFN-alpha 2a and IL-1 alpha was found. This neutralizing activity c ould be traced to plasma pools used for manufacture of immunoglobulins. The neutralization was mediated by specific cytokine antibodies contained with in immunoglobulin products as it was present in specific immunoglobulin G ( IgG) fractions eluted from cytokine affinity chromatography columns. Specif ic binding of such IgG fractions to cytokines in immunoblots and in enzyme- linked immunosorbent assays (ELISAs) was observed. This contrasts with the broad non-specific recognition of cytokine proteins observed using unfracti onated immunoglobulins in ELISAs. This is the first comprehensive study sho wing the presence of neutralizing antibodies against GM-CSF, IL-1 alpha, or IFN-alpha 2a in immunoglobulin products.