TRANSGENIC MICE EXPRESSING HIGH-LEVELS OF SOLUBLE TNF-R1 FUSION PROTEIN ARE PROTECTED FROM LETHAL SEPTIC SHOCK AND CEREBRAL MALARIA, AND ARE HIGHLY SENSITIVE TO LISTERIA-MONOCYTOGENES AND LEISHMANIA-MAJOR INFECTIONS

Mice bearing a transgene coding for a soluble tumor necrosis factor receptor type 1 (TNFR1)-FcIgG3 fusion protein and placed under the control of the alpha-l-antitrypsin gene promoter were generated. Depending on the mouse line, blood levels of the protein ranged from 25 ng/ml to over 100 mu g/ml; this level of expression was most often transmitted to the transgene-bearing progeny as a relatively stable feature. High-expressor mice were completely resistant to lipopolysaccharide-induced shock and lethality, including after D-galactosamine sensitization, and mice expressing about 1 mu g of the fusion protein/ml were partially (60 %) protected. In contrast, mice expressing less than 0.1 mu g of the protein/ml were more sensitive than controls with respect to incidence and time of death, even though the biological activity of serum tumor necrosis factor (TNF) was partially neutralized. High-expressor mice of the adequate genetic background were markedly although not completely protected from death by cerebral malaria after injection with Plasmodium berghei. They were highly susceptible to Listeria monocytogenes, dying from bacterial dissemination after sublethal infection, and to Leishmania major; displaying severe, non-healing lesions after local infection. Under the same conditions, mice expressing about 1 mu g protein/ml were only partially sensitive to these last agents, compared to non-transgenic littermate mice which were fully resistant. These transgenic mice represent a model of permanent, complete or partial, impairment of TNF use, which compares favorably, for ease of breeding and for the range of effects, to mice bearing gene disruptions.