The pathogenesis and modulation of the post-treatment reactive encephalopathy in a mouse model of Human African Trypanosomiasis

Drug treatment of late-stage human African Trypanosomiasis (HAT) in which t he central nervous system (CNS) is involved may be complicated by a severe post-treatment reactive encephalopathy (PTRE) which can be fatal in up to 1 0% of cases, In order to understand the immunopathogenesis of this complica tion, an experimental mouse model has been developed that mirrors many of t he pathological features of the PTRE in humans, and which allows various an ti-inflammatory therapeutic regimes to be evaluated. Following the developm ent of the PTRE in this model a number of cytokines are increased within th e CNS including tumour necrosis factor (TNF) alpha, interleukins 1, 4 and 6 , and macrophage inflammatory protein (MIP)-1. These cytokines appear at th e same time as astrocyte activation which is an early event occurring befor e the development of the marked meningoencephalitic inflammatory response. The immunosuppressant drug azathioprine prevents but does not reduce the se verity of an established PTRE and has a minimal effect on astrocyte activat ion. The ornithine decarboxylase inhibitor eflornithine prevents the induct ion, and ameliorates the severity, of the PTRE; and also reduces the degree of astrocyte activation. The Substance P antagonist RP-67,580 ameliorates the severity of an established PTRE, and also reduces astrocyte activation, indicating an important role of SP in the generation of the inflammatory r esponse. Continued use of this mouse model should lead to further enhanceme nt of our understanding of the pathogenesis of the PTRE and to improved dru g regimes to prevent and/or treat it. (C) 1999 Elsevier Science B.V. All ri ghts reserved.