Cytokine Release as a Mechanism Mediating IGIV Adverse Reactions Basil Golding, M.D., Medical Officer, Plasma Derivatives Laboratory, OBRR T helper cell can be divided into different subsets based on the cytokines they secrete following stimulation. Thus ThO cells secrete IL-4 and IFNg, Th1 cells release IL-2 and IFNg and Th2 cells produce IL-4, and IL-5. In addition to T cells, monocytes/macrophages secrete cytokines such as IL-12, TNFa and IL-1. These cytokines play important roles in immune responses but have also been implicated in adverse effects following the use of immunoglobulins (IG) and antibodies against T cells used to induce immunosuppression. We have studied these cytokines during immune responses to different conjugates in mice. Peptides or proteins were covalently linked to heat-inactivated Brucella abortus (BA) and to keyhole limpet hemocyanin (KLH). BA induced IL-12 and IFNg, whereas KLH elicited IL-4. Consequently the IgG isotype patterns evoked corresponded to the cytokines such that KLH immunization was associated with IgG1>IgG2a ratio, whereas BA elicited IgG2a>IgG1. Similar patterns were observed when BA was administered together with ovalbumin (ova) and alum. In contrast to ova + alum given alone, the combination of BA and ova + alum was associated with IL-12 and IFNg mRNA and protein induction. The isotype patterns observed following ova + alum were high titers of IgG1 and IgE, whereas in the presence of BA, IgG2a predominated and IgG1 and IgE levels were suppressed. BA was also studied for effects on human cells in culture. It had been shown to induce IFNg from human T cells. BA induced IL-12 from human monocytes as shown by increased p40 mRNA and protein. Functional IL-12 was elicited since supernatants from BA-stimulated monocytes caused T cells to secrete IFNg, and this could be blocked by addition of anti-IL-12 antibody. BA also increased expression of B7.1 and B7.2 on human monocytes. These molecules are costimulatory molecules involved in stimulation of T cells. IG preparations were shown to induce IL-1, TNFa and IL-6 from human monocytes. This ability was abrogated by passage of these preparation over polymyxin columns which were shown to remove lipopolysaccharide as determined by limulus amebocyte assays. These studies suggest that the small amounts of LPS contained in IG preparations can elicit cytokines that may explain frequently observed side effects such as fever chills, and headache.
