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The importance of tumor necrosis factor (TNF) in the pathophysiology of trauma and hemorrhagic shock is not known. In addition, TNF bioactivity may be modulated by soluble forms of the 55-kd and 75-kd membrane receptors (TNFR). This study was undertaken to determine circulating levels of TNF and TNFR after trauma. Nine severely injured male patients were studied. The mean age was 30 ± 10 years (range, 15-45). The mean Injury Severity Score (ISS) was 31.3 ± 17.6 (range, 10-59), and the mean Revised Trauma Score (RTS), 5.7 ± 2.2 (range, 0.7-7.8). Serum was obtained immediately upon arrival at our trauma center, within 1 hour of injury. The TNF and TNFR levels in the serum were measured using ELISA techniques. After trauma, 55-kd and 75-kd TNFR levels were significantly elevated above those of controls (6.99 ± 4.57 ng/ml and 5.42 ± 1.88 ng/ml, respectively, p < 0.01); TNF levels were not increased. Patient serum containing TNFR inhibited in vitro TNF cytotoxicity and correlated with 55-kd TNFR levels (p < 0.05). We conclude that TNF is a strong releasing factor for TNFR; the presence of TNFR may be indirect evidence that TNF is present after trauma, despite low measured levels. Both TNF and TNFR may be more important in trauma and hemorrhagic shock than previously thought. THE ROLE OF TUMOR NECROSIS FACTOR (TNF) in the pathophysiology of trauma and hemorrhagic shock remains unclear. Several animal studies have demonstrated systemic release of TNF after hemorrhagic shock. 1 • 2 However, previous human studies of both elective surgery and trauma have not demonstrated significant circulating levels of TNF. 3-5 Although the numerous functions of TNF have been extensively studied, there is a relative paucity of information regarding the regulation of TNF. In recent years, two soluble receptors for TNF (TNFR) have been identified. These soluble receptors have been found in the serum and urine of patients with chronic renal failure as well as in the serum and ascites of cancer patients. 6-8 These TNFR are shed or secreted from the extracellular segments of the 55-kd and 75-kd TNF membrane receptors and may be important in the regulation of TNF activity. 8-10 The TNFR are capable of binding TNF and preventing binding to cellular membrane receptors, thus decreasing the biologic effects of the cytokines. In vitro the TNFR have been found to inhibit the lytic activity of TNF on murine L929 and WEHI 164 cells. 8 • 10 In addition, TNFR inhibits in vivo necrosis of cutaneous

Interleukin-6 (IL-6) is a cytokine that has been implicated as a growth factor in human ovarian carcinoma, yet the in vivo source of IL-6 in patients remains undefined. We measured IL-6 by ELISA in cell-free ascites (CFA) of 19 patients with ovarian carcinoma. IL-6 was detectable in all samples (mean level 3.3 ng/ml). To identify the cellular source of IL-6, we measured this cytokine by ELISA in 24-48 h supernatants of cultured lymphocyte-, macrophage-, and tumor cell-enriched populations purified from three solid ovarian carcinomas by centrifugal elutriation. All cell populations spontaneously released IL-6; however, tumor cells and tumor-associated macrophage released levels of IL-6 that greatly exceeded those released by tumor-associated lymphocytes. Kinetic studies revealed that IL-6 was detectable at 6 h and that levels increased in all cultures examined over a 48 h time course. These data suggest that both tumor and infiltrating host cells may be the source of the high levels of IL-6 found in carcinomatous ascites. Furthermore, although all three cell types examined may contribute to IL-6 production in patients with ovarian carcinoma, tumor cells are perhaps the most clinically significant source.

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OBJECTIVE:We initiated studies to develop cytokine-secreting human ovarian carcinoma cells for the purpose of using these cells as vaccines for the treatment of advanced epithelial ovarian cancer. STUDY DESIGN: A human ovarian carcinoma cell line (UC1-107) was genetically engineered to secrete the cytokine interleukin-2 by retrovirai-mediated gene transduction. RESULTS: Qne clone, termed UCI-107A IL-2 AS, constitutively secreted high levels of interteukin-2 (i.e., 2000 to 2300 pg/ml/10 s cells per 48 hours) for >55 passages and 8 months of study. Unlike parental-and vector-transduced cells, UCI-IO7A IL-2 AS cells were aneuploid and failed to express major histocompatibility complex class I and HER2/neu surface antigens. UCI-107A IL-2 AS cells were highly resistant to killing by gamma irradiation and continued to produce high levels of intedeukin-2 even after irradiation with 10,000 cGy. Balb/C nude mice injected intraperitoneally with UCI-107A IL-2 AS cells survived significantly longer than control animals, with 25% of the animals totally rejecting their tumors. UCI-107A IL-2 AS was totally resistant to killing by fresh allogeneic peripheral blood lymphocytes in four hour chromium 51 release assays but induced high levels of killing in 72-hour long-term cytotoxic assays. CONCLUSION: The potential use of these interteukin-2-secreting ovarian carcinoma cells as vaccines for women with advanced ovarian cancer will be discussed. (AM J OBSTET GYNECOL 1996;174:633-40.)