Effect of in Vivo Rapamycin Treatment on De Novo T-Cell Development in Relation to Induction of Autoimmune-Like Immunopathology in the Rat1

Jg, Damoiseaux; Lj, Beijleveld; Hj, Schuurman; Pj, van Breda Vriesman

doi:10.1097/00007890-199610150-00019

Cited by 10 publications

(8 citation statements)

References 25 publications

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“…The effects of CsA and Rapa on thymocyte development in rats have been extensively examined [8, 13]. In the experimental design of the present study, we first confirmed the effects of both immunosuppressive reagents on overall thymic weight and on the described maturation arrest.…”

Section: Resultssupporting

confidence: 68%

“…the TCRab neg stages), which are known to undergo the major phase of thymocyte expansion [26], may have obscured the expected effect of Rapa on the cell cycle. Although Rapa, like CsA, is able to induce an autoimmune-like syndrome in mice and rats [13,27], it remains a matter of debate whether Rapa interferes with clonal deletion in the thymus [12,27]. However, it is most likely that the Rapa-induced syndrome is owing to effects on mature T cells and peripheral tolerance, as the Rapa syndrome in mice does not require an intact thymus, and the disease cannot be adoptively transferred [28].…”

Section: Cyclosporin-a and Thymocyte Apoptosis 357mentioning

confidence: 99%

“…As Rapa is known to inhibit cytokine‐driven proliferation, it is expected that these observations are the result of repressed thymocyte proliferation. Although, in contrast to CsA, Rapa seems not to interfere with negative selection in mice [12], both Rapa and CsA are able to induce autoimmune‐like immunopathology in rat [13, 14].…”

Section: Introductionmentioning

confidence: 99%

“…In this view, CsA will cause more apoptosis in cortical thymocytes owing to the inhibition of positive selection, whereas a reduced number of cortico-medullary thymocytes will become apoptotic because CsA also hampers negative selection. With respect to the effect of Rapa on T-cell development, it is evident that Rapa causes significant thymus atrophy and interferes with thymic recovery after lethal X-irradiation and subsequent syngeneic bone marrow transplantation [12,13]. As Rapa is known to inhibit cytokinedriven proliferation, it is expected that these observations are the result of repressed thymocyte proliferation.…”

Section: Introductionmentioning

confidence: 99%

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Cyclosporin‐A Differentially Affects Apoptosis During In Vivo Rat Thymocyte Maturation

et al. 2002

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Maturation arrest and interference with selection are two well-documented effects of cyclosporin-A (CsA) on the thymus. We recently hypothesized that these effects are related and owing to the reduced T-cell receptor (TCR)±CD3 complex-mediated signal transduction in thymocytes upon CsA treatment. In this hypothesis, the maturation arrest is the result of the additional depletion of thymocytes that normally survive by positive selection, whereas the impaired self-tolerance induction is caused by an increased survival of thymocytes that normally undergo negative selection. In this view, it is anticipated that CsA differentially affects thymocyte apoptosis during in vivo thymocyte maturation. Indeed, we report in this study a strong increase in apoptotic cells in the thymic cortex on in situ analysis. Simultaneously, the number of apoptotic cells had decreased at the cortico-medullary zone which is held to be the site for negative selection. Rapamycin (Rapa) also interferes with thymocyte maturation by inhibiting cytokine-driven proliferation. Hence, Rapa preferentially affects the early maturational stages of thymocyte development and is considered not to alter thymocyte selection and subsequent apoptotic events. Indeed, the number of apoptotic events appears not to be altered. However, possibly owing to the decrease in cortical macrophages, the apoptotic cells revealed an atypical enumeration around blood vessels. Taken together, our results favour the hypothesis that the dominant effect of CsA on the thymus is the reduction of the TCR±CD3 complex-mediated signal transduction in thymocytes upon interaction with stromal cells. Furthermore, the preferential localization of apoptotic cells next to blood vessels upon Rapa administration may indicate that endothelial cells are a back-up system for the removal of apoptotic cells.

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Section: Resultssupporting

confidence: 68%

Section: Cyclosporin-a and Thymocyte Apoptosis 357mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cyclosporin‐A Differentially Affects Apoptosis During In Vivo Rat Thymocyte Maturation

et al. 2002

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“…In fact, RAPA did not alter the proportion of CD4 + and CD8 + cells in uninfected hu‐PBL‐SCID mice, which remained consistent with the CD4 + : CD8 + cell levels of the two reconstituted and uninfected control groups. In addition, another study proves that RAPA does not alter the proportion of CD8 + T cells in either Lewis or brown Norway rats [27]. Taken together, these data suggest that the prevention of the increase of the CD8 + T cells observed in the HIV‐1‐infected hu‐PBL‐SCID mice treated with RAPA is selectively secondary to the prevention of HIV infection of the CD4 + T cells from the drug and the subsequent modifications of the CD4 : CD8 ratio that are induced by the virus.…”

Section: Discussionmentioning

confidence: 90%

Inhibition of human immunodeficiency virus (HIV-1) infection in human peripheral blood leucocytes-SCID reconstituted mice by rapamycin

Nicoletti

Lamenta

Donati

et al. 2008

Clinical and Experimental Immunology

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SummaryThe capacity of the immunomodulatory drug rapamycin (RAPA) to inhibit replication of the CCR5 strain of human immunodeficiency virus (HIV) in vitro prompted us to test its effects in a murine preclinical model of HIV infection. RAPA (0·6 or 6 mg/kg body weight) or its vehicle were administered daily, per os, to SCID mice reconstituted with human peripheral blood leucocytes (hu-PBL) starting 2 days before the intraperitoneal challenge with the R5 tropic SF162 strain of HIV-1 (1000 50% tissue culture infective dose/ml). Relative to hu-PBL-SCID mice that received no treatment, HIV-infected hu-PBL-SCID mice treated with the vehicle control for 3 weeks exhibited a severe depletion of CD4 + cells (90%), an increase in CD8 + cells and an inversion of the CD4 + /CD8 + cell ratio. In contrast, treatment of HIV-infected mice with RAPA prevented a decrease in CD4 + cells and the increase of CD8 + cells, thereby preserving the original CD4+ : CD8 + cell ratio. Viral infection also resulted in the detection of HIV-DNA within peritoneal cells and spleen, and lymph node tissues of the vehicle-treated mice within 3 weeks of the viral challenge. In contrast, treatment with RAPA decreased cellular provirus integration and reduced HIV-RNA levels in the blood. Furthermore, in co-cultivation assays, spleens from RAPA-treated mice exhibited a reduced capacity for infecting allogeneic T cells which was dose-dependent. These data show that RAPA possesses powerful anti-viral activity against R5 strains of HIV in vivo and support the use of additional studies to evaluate the potential application of this drug in the management of HIV patients.

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Lessons learned from the diagnostic work-up of a patient with the bare lymphocyte syndrome type II

Damoiseaux

Pico-Knijnenburg

et al. 2022

Clinical Immunology

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Effect of in Vivo Rapamycin Treatment on De Novo T-Cell Development in Relation to Induction of Autoimmune-Like Immunopathology in the Rat1

Cited by 10 publications

References 25 publications

Cyclosporin‐A Differentially Affects Apoptosis During In Vivo Rat Thymocyte Maturation

Cyclosporin‐A Differentially Affects Apoptosis During In Vivo Rat Thymocyte Maturation

Inhibition of human immunodeficiency virus (HIV-1) infection in human peripheral blood leucocytes-SCID reconstituted mice by rapamycin

Lessons learned from the diagnostic work-up of a patient with the bare lymphocyte syndrome type II

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