Serum cytokine levels and mononuclear cell subpopulations in the spleen and peripheral blood of patients with visceral leishmaniasis before and after antimony therapy were analyzed. The percentages of activated monocytes/macrophages, T cells, and possibly B cells; of gamma/delta T cell receptor (TCR)-bearing T cells; of CD4- CD8- alpha/beta TCR-bearing T cells; and serum levels of tumor necrosis factor-alpha (TNF alpha), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6) were high in patients with active visceral leishmaniasis. The proportion of both helper and suppressor CD4+ cells and of cells with NK and cytotoxic T phenotypes were depressed. Successful chemotherapy normalized these parameters with the exception of activated monocytes. Thus, the impaired cell-mediated immunity in human Leishmania donovani infection is primarily due to a decrease in the proportion and possibly the activity of helper CD4+ cells, while suppressor cells do not seem to play a relevant role. TNF alpha, IL-6, and IFN-gamma may prove to be useful markers for monitoring response to therapy.
Ribosomes from Trypanosoma brucei rhodesiense and from Leishmania infantum were isolated and optimal conditions for in vitro translation were established. The effect of ribosome-inactivating proteins extracted from several plants was then assessed in order to identify those suitable for the preparation of immunotoxins against these organisms. Ribosomes from both species were inactivated by some ribosome-inactivating proteins (dianthins, saporins, pokeweed antiviral proteins, and the ribosome-inactivating chain of abrin). The similarity of the effects on the ribosomes from the two species examined indicates that ribosome-inactivating proteins should also be effective in a similar way on ribosomes from other species of Trypanosoma and Leishmania.
This communication reports 7 Ethiopian visceral leishmaniasis (VL) patients co-infected with human immunodeficiency virus (HIV). The clinical and laboratory findings in 6 patients did not differ from classical VL. All patients had highly elevated anti-leishmanial antibody titres, determined by immunoglobulin G-based enzyme-linked immunosorbent assay; they most probably acquired the Leishmania infection before HIV. Amastigotes were identified in the splenic aspirates of 6 patients and in the lymph node aspirate of the 2 patients whose lymph nodes were examined. The CD4:CD8 lymphocyte ratio was depressed in those patients whose ratio was determined. Most patients showed some initial response to pentavalent antimonial therapy.
1. Ribosome-inactivating proteins were found in high amounts in one line of cells of Phytolacca americana (pokeweed) cultured in vitro and, in less quantity, in lines of Saponaria officinalis (soapwort) and of Zea mays (corn) cells. 2. The main ribosome-inactivating protein from pokeweed cells was purified to homogeneity. It is a protein with Mr 29,000 and basic pI, similar to the 'pokeweed antiviral protein' (PAP), a ribosome-inactivating protein from pokeweed leaves. We propose to call the pokeweed antiviral protein isolated from pokeweed cells PAP-C. 3. PAP-C inactivates ribosomes in a less-than-equimolar ratio, thus inhibiting protein synthesis by a rabbit reticulocyte lysate with an IC50 (concentration causing 50% inhibition) of 0.067 nM (2 ng/ml), and modifies rRNA in a manner apparently identical to that of ricin and other ribosome-inactivating proteins. It inhibits protein synthesis by intact cells with an IC50 of 0.7-3.4 microM, and is toxic to mice with an LD50 of 0.95 mg/kg.
A protein, here named trichokirin, was extracted from the seeds of Trichosanthes kirilowii and purified by ionexchange and gel-filtration chromatography. Trichokirin is a basic glycoprotein of apparent relative molecular mass of 27000 with a strong ribosome-inactivating activity. Alignment of the trichokirin, trichosanthin and momordin N-terminal sequences shows a substantial degree of homology. Trichokirin was conjugated to a monoclonal antibody directed against the Thy 1.2 antigen with the cleavable dimethyl 3,3'-dithiobispropionimidate cross-linking reagent. This immunotoxin selectively killed leukemia cells expressing the Thy 1.2 antigen. The addition of ammonium chloride, which increases the cytotoxicity of ricin A-chain immunotoxins, blocks that of the trichokirin immunotoxin, suggesting that they enter cells by different mechanisms. In vivo studies showed that the pharmacokinetic properties of the trichokirin immunotoxin could be more advantageous than those of the ricin A-chain immunotoxins for in vivo applications.We describe here the purification and partial characterization of a new protein, which we propose to call trichokirin, from the seeds of Trichosanthes kirilowii Maximowicz, a Cucurbitacea growing in China. Trichokirin has all the properties of ribosome-inactivating proteins (reviewed in [l -31) like the A-chains of ricin and related toxins (reviews in [4, 51). Ribosome-inactivating proteins are widely distributed and possibly ubiquitous in the plant kingdom. They were found in, and purified from, several plant materials including leaves, seeds, roots and lattices [6-81, in which their concentration varies greatly and cannot be predicted. However, they seem to be abundant in some plant families, amongst which is that of Cucurbitaceae. Thus several ribosome-inactivating proteins were purified from plants that are members of this family: momordin from Momordica churantiu seeds [9], luffin from Lufla cylindrica seeds [lo] and bryodin from Bryonia dioica roots [I 11. The roots of T. kirilowii contain trichosanthin, an abortifacient protein which was found recently to be a ribosome-inactivating protein [12 -151.Ribosome-inactivating proteins are currently used to prepare 'immunotoxins', by conjugation to monoclonal antibodies specific for cell-surface antigens. A highly potent immunotoxin specifically toxic to cells bearing the Thy 1.2 antigen was obtained by linking trichokirin to an anti-Thy 1.2Correspondence to P. Casellas,
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