We tested the combination of phosphodiesterase (PDE) 3 and PDE4 inhibitors as an interventional approach to prevent the development of brain damage after Shiga toxin (Stx)-producing Escherichia coli (STEC) infection, using mice with protein calorie malnutrition. The combination consisted of pentoxifylline and rolipram; the dose of each inhibitor was 7.5 mg/kg. Treatment with this combination, which was administered intraperitoneally twice daily at 12-h intervals, increased serum concentrations of each inhibitor to >2 microg/mL and afforded significant levels of protection when it was continued for 3 days, starting on day 2 (95% survival rate; P<.001) or day 3 (63% survival rate; P<.01) of infection. The treatment reduced plasma levels of Stx2; consequently, immunoreactions of Stx2 were not found in the brain, and survivors did not show neurologic symptoms. Protection was associated with decreased levels of tumor necrosis factor (TNF)- alpha and increased production of interleukin-10 in serum, the brain, and the cecum. Although the combination at doses >2 microg/mL reduced Gb3 content of and Stx2 binding to Caco-2 cells, its ability to suppress production of TNF- alpha seemed to be more important for the decrease in cell-bound Stx2 in intestinal epithelial cells. Therefore, the combination of PDE3 and PDE4 inhibitors might be used as an interventional approach to prevent brain damage caused by STEC infection.
Thymocytotoxic autoantibodies were demonstrated in sera of C3H/HeJms, C57BL/6J, and ddY mice infected with 50 cercariae of Schistosoma japonicum, using C57BL/6J thymocytes as target cells in the trypan blue dye exclusion test. Kinetic study revealed that thymocytotoxic activity began to increase at week 6 of infection, reached a maximum at 8 weeks, and thereafter decreased gradually. Thymocytotoxic antibodies had an optimal reactivity at 4°C and were sensitive to 2-mercaptoethanol treatment, suggesting that they were immunoglobulin M in nature. The cytotoxicity was completely abolished by absorption with C57BL/6J thymocytes but not with S. japonicum parasites or eggs. The antigen reacting with thymocytotoxic antibodies was found in the thymus, brain, spleen, and, to a lesser extent, kidney and liver. In parallel with the appearance of thymocytotoxic antibodies, the increase of background plaque-forming cells to trinitrophenyl, polyvinyl pyrrolidone, and sheep erythrocytes in the spleen of S. japonicuminfected mice suggested that the induction of thymocytotoxic antibodies may be the consequence of polyclonal B-lymphocyte stimulation by the infection.
The effector cells responsible for protection to Salmonella typhimurium in C3H/HeJ mice, conferred by L-form S. typhimurium, were determined by cell transfer test. Nonfractionated spleen cells from 6-week immune mice but not from 24-week immune animals transferred anti-S. typhimurium immunity. Treatment with anti-macrophage antiserum and complement most effectively abolished protective capacity in 6-week immune cells, while anti-T cell monoclonal antibody plus complement reduced it to a lesser extent. However, adoptive protection was achieved only by transfer of immune macrophages along with Lyt-2+ T cells selected from 6-week immune spleen cells. These Lyt-2+ T cells were cytotoxic to Kupffer cells from C3H/HeJ mice which had been infected 48 hr previously and from the mice which had been immunized 1 week previously, but not to the cells from 6-week immune mice and from normal animals. Moreover, protective capacity in immune macrophages seemed to be correlated to the degree of colonization by the L forms, and the inability to transfer immunity of 24-week immune spleen cells may be due to the decrease in the L form-colonization. These results suggest that cooperation between the L form-colonized macrophages and L form-induced cytotoxic Lyt-2+ T cells contributes to anti-S. typhimurium immunity, and might imply the immunological difference between the 6-week immune phagocytes and the cells at an early stage of infection or immunization.
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