Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria.

Abstract

Abstract. Single doses (250, 500, 1,000, or 2,000 units/kg) of an ovine polyclonal-specific Fab fragment directed against tumor necrosis factor-␣ (TNF-␣) were given to 17 adult patients with severe falciparum malaria immediately before treatment with artesunate in a pilot study to assess safety and optimal dosage with a view to future studies. Clinical and laboratory variables were compared with 11 controls. In the groups given Fab, there was a tendency for a faster resolution of clinical manifestations and reduction of fever but also a tendency towards longer parasite clearance times. Adverse events were more common in the control group and no early anaphylactic or late serum sickness reactions occurred in the Fab treated patients. On admission all patients had markedly elevated levels of TNF-␣ (85-1,532 ng/L) and interleukin-6 (IL-6) (30-27,500 ng/L). Also, 86% had elevated interferon-␥ (IFN-␥) levels, 75% had increased IL-2 levels, 36% had increased IL-8 levels, and 21% had increased IL-1␤ levels. Antibody treatment reduced IFN-␥ concentrations in a dose-related manner, but had no obvious effects on levels of other cytokines in this small study, although unbound TNF-␣ was undetectable after Fab treatment. Circulating concentrations of soluble E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not affected by Fab treatment. The Fab exhibited a two-compartment, dose-proportional kinetics with an average elimination halflife of 12.0 hr, with about 20% being excreted renally. These results encourage a randomized, placebo-controlled trial in patients with cerebral malaria and provide some guidance about dosage.

Cytokines in the Pathogenesis of and Protection against Malaria

“…Treatment with anti-TNF-␣ monoclonal antibody results in a tendency toward longer times for parasite clearance. Interestingly, this effect is associated with reduced levels of IFN-␥ (43). Supporting this general view, an association between the ability to produce high levels of TNF-␣ and an accelerated cure and improved prognosis has been reported in humans (61).…”

“…(8). Interestingly, patients treated with neutralizing anti-TNF-␣ antibodies show a faster resolution of clinical symptoms (43). In addition, a focal accumulation of TGF-␤1, -2, and -3 during reorganization of brain parenchyma was found in patients with CM, suggestive of endothelial activation and immunologic dysfunction (18).…”

Recombinant PfEMP1 peptide inhibits and reverses cytoadherence of clinical Plasmodium falciparum isolates in vivo

“…The spread of drugresistant parasites increases the likelihood of such events and requires the development of novel adjunct therapies to rapidly halt the disease process. In the past few years, anticytokine therapy in the form of anti-TNF-␣ antibodies 27,28 and pentoxifylline 29 that inhibits TNF-␣ production has been tried with limited clinical improvement. Exchange transfusion is used to correct hyperparasitemia, 30 but this therapy is difficult to administer in developing countries and carries obvious risks in transmission of diseases.…”

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…However, although animal studies with the murine parasite P. berghei suggested the efficacy of anti-TNF-a therapy, 80 results of anti-TNF-a in human clinical trials in both adult and pediatric patient populations were disappointing. 81,82 The lack of efficacy of the monotherapy, as in the case of sepsis, 83 was likely due to the fact that by the time patients present for treatment, other inflammatory or inhibitory pathways would have been activated. In at least the adult patients, the anti-inflammatory cytokine IL-10 was also found to be markedly elevated, 84 which suggests that perhaps the ratio and time course of TNF-a to IL-10 production may be more predictive of outcome.…”