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The core region of LPS has a relatively similar structure in various Gram-negative bacteria, whereas the outermost O side chains are responsible for the marked antigenic diversity among Gram-negative bacteria. O side chain-specific antibodies protect against homologous strains but not against heterologous strains in animal models . The core region of LPS is exposed at the surface of the O side chain-lacking rough mutants, among which Escherichia coli J5 and Salmonella minnesota R595 have been the most studied. After immunization with such mutants, antisera ofrabbits or humans contain antibodies directed against core LPS. These antisera have been reported to protect against challenge with heterologous Gram-negative bacteria or smooth LPS (1-5). Recent publications of crossprotection afforded by core US mAbs seemed to support the concept that core LPS antibodies might have a role in the management of Gram-negative infections . The crossprotection reported against cutaneous Shwartzman reactions in rabbits or against Gram-negative bacterial peritonitis in mice with an anti-lipid A human IgM mAb HA-1A (6) was so impressive that a major multicenter clinical study has been undertaken in patients with severe Gramnegative bacteremia . The mechanisms ofthe postulated protection afforded by core LPS antibodies remain, however, largely unknown. Whereas O side chain-specific antibodies have been shown to increase the serum bactericidal activity against homologous Gram-negative bacteria and to increase the intravascular clearance of homologous bacteria or LPS (7, 8), core LPS antibodies did not increase significantly This study was supported by grants 3.825-0 .86 and 35-25550 .88 from the Fonds National Suisse de la Recherche Scientifique .

Previously we have reported that in asthmatics an inhalation of 20 micrograms lipopolysaccharide (LPS) produces a bronchial obstruction associated with an inflammatory blood response. The aim of the present study was to evaluate this response in normal subjects. Eight normal non-atopic subjects were challenged by inhalation of a solution containing 20 micrograms LPS (from Escherichia coli 026:B6) a week after bronchial challenge with control solution. The lung function response was evaluated by the changes in forced expiratory volume in one second (FEV1), in specific conductance and in airway resistance while the blood inflammatory response was evaluated by serial measures of total white blood cells (WBC) and polymorphonuclear neutrophils (PMN) count, luminol enhanced-chemiluminescence (luminol-CL, as a marker of the PMN degree of activation), C-reactive protein (CRP), haptoglobin, complement fraction C3, tumour necrosis factor-alpha (TNF-alpha) and adrenocorticotropic hormone (ACTH). No response in lung function was observed for 6 h after the LPS inhalation. The count in WBC and PMN increased 300 (P < 0.01) and 360 (P < 0.01) min after the LPS challenge associated with an increase in the level of luminol-CL (P < 0.001). This rise in luminol-CL level was significant at 120 min (P < 0.05) before any change in the PMN count. After 24 and 48 h the acute-phase protein CRP raised significantly (P < 0.01), the other proteins C3 and haptoglobin being unchanged. A slight increase in ACTH was observed 240 and 360 min (P < 0.05) after the LPS challenge while the TNF alpha detectable level was not modified.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant tumor necrosis factor-alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side-effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the efficient dose in animals. Isolation perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response, compared with 52% after ILP with melphalan alone. Release of nanograms levels of TNF alpha in the systemic circulation was evident but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.

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