Bate, Clive Alan Winston; (1991) Induction of TNF by exoantigens of plasmodial species. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Parasitized red blood cells (prbc) stimulate activated macrophages to secrete TNF under conditions that exclude the effects of contaminating bacterial Lipopolysaccharide. Molecules stimulating TNF secretion were released into supernatants collected from prbc cultured for 24 hours in PBS, and referred to as exoantigens. The characterization and immunological properties of these exoantigens were studied. Exoantigens were isolated from all species of Plasmodium tested, including P.falciparum. The active moiety of the exoantigens was resistant to digestion with proteases and nucleases, and to deglycosylation and deamination. Loss of the TNF triggering activity was associated with digestion with lipases, deacylation and dephosphorylation, suggesting that the TNF-stimulating moiety is a phospholipid. Exoantigens are toxic to the point of lethality in sensitized mice, and only supernatants that stimulate TNF in vitro are toxic. Mice can be protected by a Mab neutralizing TNF and by factors that were found to reduce the cytotoxicity of TNF in vitro. Mice immunized with exoantigens are protected against the lethality of injection of exoantigens 12 days later. Antibodies in the serum of such mice can inhibit exoantigen induced TNF secretion in vitro. Inhibitory antibodies are only produced in response to injections of supernatants that stimulate TNF in vitro and which are toxic in vivo; suggesting that the same molecule(s) are being measured in all three assays. Extensive cross reactions between exoantigens from all rodent parasites and P. falciparum exist. However there is no evidence of immunological memory, inhibitory antibodies are predominantly IgM, cannot be increased by repeated injection or by the use adjuvants, and can be raised in T cell deficient mice. Immunization with parasite exoantigens protect mice from dying from an otherwise lethal infection of Pyoelii. Antibodies raised against these exoantigens might provide the basis of an '"anti-toxin" vaccine.

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