Objectives

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Human African trypanosomiasis (HAT) is a deadly vector-born disease caused by an extracellular parasite, the trypanosome. Little is known about the cellular immune responses elicited by this parasite in humans. We used multiparameter flow cytometry to characterize leukocyte immunophenotypes in the blood and cerebrospinal fluid (CSF) of 33 HAT patients and 27 healthy controls identified during a screening campaign in Angola and Gabon. We evaluated the subsets and activation markers of B and T lymphocytes. Patients had a higher percentage of CD19+ B lymphocytes and activated B lymphocytes in the blood than did controls, but lacked activated CD4+ T lymphocytes (CD25+). Patients displayed no increase in the percentage of activated CD8+ T cells (HLA-DR+, CD69+ or CD25+), but memory CD8 T-cell levels (CD8+CD45RA−) were significantly lower in patients than in controls, as were effector CD8 T-cell levels (CD8+CD45RA+CD62L−). No relationship was found between these blood immunophenotypes and disease severity (stage 1 vs 2). However, CD19+ B-cell levels in the CSF increased with disease severity. The patterns of T and B cell activation in HAT patients suggest that immunomodulatory mechanisms may operate during infection. Determinations of CD19+ B-cell levels in the CSF could improve disease staging.

Abstract. Human glioblastomas that express Fas/CD95 receptor are highly resistant to conventional brain tumour therapies. The aim of this study is to evaluate anti-tumour properties of a combination of Fas ligand (FasL) plus etoposide with or without dexamethasone on intracerebral experimental glioblastomas. The human Fas-expressing glioblastoma cell line, U-87 MG, was firstly studied in vitro for apoptosis and proliferation assays in the presence of FasL and etoposide, separately or associated, in order to detect a supra-additive effect on FasL or etoposide-induced apoptosis. The tumourigenicity of the U-87 MG cell line and therapeutic effects of FasL-etoposide alone or combined with dexamethasone were next studied on U-87 MG cells xenografted to nude-rat brain and tumour size was hence examined by histological and immunohistochemical stainings. We demonstrated in vitro that the combination of both molecules strongly inhibited the proliferation rate and increased the sensitivity of glioblastoma cells to Fas or etoposide-mediated apoptosis. Moreover, analysis of rat brains was performed 30 days after xenograft of glioblastoma cells. These data show that the combination of FasL and etoposide could reduce significantly the tumour size and that the addition of dexamethasone enhanced the inhibiting effect of FasL and etoposide on tumour growth in vivo.

It has long been known that the vervet monkey, Chlorocebus (C.) aethiops, can be infected with Trypanosoma rhodesiense, but this model has not been described for T. gambiense. In this study, we report the development of such a model for human African trypanosomiasis. Twelve vervet monkeys infected with T. gambiense developed chronic disease. The duration of the disease ranged between 23 and 612 days (median 89 days) in five untreated animals. Trypanosomes were detected in the blood within the first 10 days post-infection and in the cerebrospinal fluid, with a median delay of 120 days (n = 4, range 28-348 days). Clinical changes included loss of weight, adenopathy, and in some cases eyelid oedema and lethargy. Haematological alterations included decreases in haemoglobin level and transitory decreases in platelet count. Biological modifications included increased gamma globulins and total proteins and decreased albumin. Pathological features of the infection were presence of Mott's cells, inflammatory infiltration of either mononuclear cells or lymphocytes and plasma cells in the brain parenchyma, and astrocytosis. These observations indicate that the development of the disease in vervet monkeys is similar to human T. gambiense infection. We conclude that C. aethiops is a promising experimental primate model for the study of T. gambiense trypanosomiasis.

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Human African trypanosomiasis remains a difficult health problem to treat because of the few compounds available nowadays and their toxicity. The disease also affects animals and is therefore responsible for economic difficulties and zoonotic risks. There is an urgent need to develop new drugs for treatment of African trypanosomiasis. Methylene blue is a safe and easy-to-use drug employed in human therapy. It is also known to have antimalarial activity. In this study, methylene blue trypanocidal activity was found in vitro but it failed to cure trypanosome infection in mice when administered at 300 mg/kg p.o.or at 200 mg/kg i.p. Differences between in vitro and in vivo activities are discussed, and further in-depth studies are warranted.

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