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Abstract
Administration of OKT3 anti-CD3 monoclonal antibody (mAb) to patients for transplant rejection, is associated with a distinct and often severe clinical syndrome related to massive cytokine release. Previous reports have similarly demonstrated increased levels of serum tumor necrosis factor α (TNFα) in normal mice following administration of 1452-C11 anti-CD3 mAb. In this study, we compared serum TNFα levels at baseline and after anti-CD3 stimulation among three groups of mice: normal BALB/c controls, pre-diabetic non-obese diabetic (NOD) mice, and diabetic NOD mice. Baseline serum TNFα levels, as measured by L929 cell bioassay, were 2×higher in diabetic NOD and 3×higher in pre-diabetic NOD compared with BALB/c. Ninety minutes after anti-CD3 mAb stimulation, serum from BALB/c controls and pre-diabetic NOD contained 2-to 8-fold higher levels of TNF-α as compared to untreated control mice. In contrast, following anti-CD3 mAb, there was a dramatic 20-fold increase in serum TNFα in diabetic NOD mice (levels >5000 pg/ml). Additionally, anti-CD3 mAb increased the steady-state TNFα mRNA transcripts. Spleens from diabetic mice given anti-CD3 mAb had higher steady-state TNFα mRNA than spleen from normal mice similarly treated. The enhanced release of circulating TNFα after anti-CD3 mAb in diabetic NOD mice was abrogated by pre-treatment of mice with prostaglandin E1 (PGE1) 30 min prior to anti-CD3 mAb stimulation. Since dietary lipid can influence cytokine generation, serum from BALB/c mice fed fish (FO) or safflower oil (SO) supplemented diets was examined for TNFα before and after administration of anti-CD3 mAb. Mice supplemented with a FO diet had higher serum TNFα levels at baseline and following anti-CD3 mAB compared with mice fed SO. Supplementation of either lipid resulted in higher serum TNFα levels than mice fed standard laboratory chow (LC) (4.5% lipid). Taken together, we suggest the enhanced capacity of OKT3 to induce TNFα in patients with IDDM can be diminished by injection of PGE1. In addition, clearly the amount and composition of dietary lipid should be regulated in patients with IDDM receiving anti-CD3 mAb therapy.