Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: preliminary results of a clinical cohort study and molecular observations

Bosch, Jutte van der Werff ten; Schotte, Peter; Ferster, Alice; Azzi, Nadira; Boehler, Thomas; Laurey, Geneviève; Arola, Mikko; Demanet, Christian; Beyaert, Rudi; Thielemans, Kris; Otten, Jacques

doi:10.1046/j.1365-2141.2002.03357.x

Cited by 51 publications

(34 citation statements)

References 43 publications

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“…Studies in children with ALPS have demonstrated a correlation between a decrease in DNTs and lymphoproliferation with improvement in autoimmune manifestations. 10,37 MRL-lpr mice are also phenotypically and genotypically similar to humans with ALPS. These mice develop more significant autoantibodies.…”

Section: Discussionmentioning

confidence: 95%

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS)

Teachey

Obzut

Axsom

et al. 2006

Blood

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Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of doublenegative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r ‫؍‬ .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans. (Blood. 2006;108: 1965-1971

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Section: Discussionmentioning

confidence: 95%

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS)

Teachey

Obzut

Axsom

et al. 2006

Blood

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“…The impact of treatment in reducing the IFN-␥-specific response in tuberculosis has been described previously (1,9,15) and suggests that such tests could be used for monitoring patient response to treatment (1). This pattern may be due to a reduction in antigen load originating from parasitic cysts or to a direct effect of pyrimethamine and sulfonamide on activated lymphocytes through activation of the mitochondrial apoptotic pathway (22). A large discrepancy in drug levels observed in babies (5) may explain why this phenomenon is not observed in all infants.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis of Congenital Toxoplasmosis by Using a Whole-Blood Gamma Interferon Release Assay

et al. 2010

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Congenital toxoplasmosis in newborns is generally subclinical, but infected infants are at risk of developing ocular lesions. Diagnosis at birth relies mainly on serological tests. Cell-mediated immunity plays the major role in resistance to infection but is not routinely investigated for diagnostic purposes. Here, we describe a simple test based on the gamma interferon (IFN-␥) response after stimulation of whole blood by crude parasitic antigens. One milliliter of heparinized blood was centrifuged; plasma was kept for routine serological tests, and pellets were resuspended in culture medium. After 24 h of culture in the presence of crude Toxoplasma gondii antigen, the cells were centrifuged and the supernatant was assayed for IFN-␥. For 62 infants under 1 year of age born to mothers who were infected during pregnancy, the sensitivity and specificity of the test were 94% (with positive results for 16 of 17 infected infants) and 98% (with negative results for 44 of 45 uninfected infants), respectively. The false-negative result was for a treated baby who gave positive results after the withdrawal of treatment. The false positive was obtained for a 3-month-old baby. For a cohort of 124 congenitally infected patients between 1 and 30 years of age, the sensitivity of the assay was 100%. We present a simple test based on IFN-␥ secretion to assess cell-mediated immunity in toxoplasmosis. As only 1 ml of blood is required to investigate humoral and cellular immunity, our assay is well adapted for the study of congenital toxoplasmosis in infants. Using purified antigens or recombinant peptides may improve the test performance.

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“…It is used in the treatment of infections caused by protozoan parasites, such as Toxoplasma gondii and Plasmodium falciparum (11). In addition to its antiprotozoal effects, pyrimethamine may exert immunomodulating activities, including the induction of peripheral blood lymphocyte apoptosis (12)(13)(14)(15). We showed that this drug induces apoptosis of activated lymphocytes via a mechanism that brings into play the upstream caspases (16).…”

Section: Introductionmentioning

confidence: 94%

Pyrimethamine Induces Apoptosis of Melanoma Cells via a Caspase and Cathepsin Double-Edged Mechanism

et al. 2008

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The unresponsiveness of metastatic melanoma to conventional chemotherapeutic and biological agents is largely due to the development of resistance to apoptosis. Pyrimethamine belongs to the group of antifolate drugs, and in addition to antiprotozoan effects, it exerts a strong proapoptotic activity, which we recently characterized in human T lymphocytes. However, no data regarding pyrimethamine anticancer activity are available thus far. To this end, we examined the in vitro effects of pyrimethamine on apoptosis, cell cycle distribution, and cell proliferation of human metastatic melanoma cell lines. The in vivo antitumor potential of pyrimethamine was evaluated in a severe combined immunodeficiency (SCID) mouse xenotransplantation model. Our data indicate that pyrimethamine, when used at a clinically relevant concentration, induced apoptosis in metastatic melanoma cells via the activation of the cathepsin B and the caspase cascade (i.e., caspase-8 and caspase-9) and subsequent mitochondrial depolarization. This occurred independently from CD95/Fas engagement. Moreover, pyrimethamine induced a marked inhibition of cell growth and an S-phase cell cycle arrest. Results obtained in SCID mice, injected s.c. with metastatic melanoma cells and treated with pyrimethamine, indicated a significant inhibitory effect on tumor growth. In conclusion, our results suggest that pyrimethamine-induced apoptosis may be considered as a multifaceted process, in which different inducers or regulators of apoptosis are simultaneously implicated, thus permitting death defects of melanoma cells to be bypassed or overcome. On these bases, we hypothesize that pyrimethamine could represent an interesting candidate for the treatment of metastatic melanoma.

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Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: preliminary results of a clinical cohort study and molecular observations

Cited by 51 publications

References 43 publications

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS)

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS)

Diagnosis of Congenital Toxoplasmosis by Using a Whole-Blood Gamma Interferon Release Assay

Pyrimethamine Induces Apoptosis of Melanoma Cells via a Caspase and Cathepsin Double-Edged Mechanism

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