FOXP3 and scurfy: how it all began

Ramsdell, Fred; Ziegler, Steven F.

doi:10.1038/nri3650

Cited by 194 publications

(167 citation statements)

References 80 publications

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“…26 In agreement with this, germline genetic mutations that disrupt Treg function in mice and humans, including FOXP3, lead to autoimmune syndromes with hepatitis, enteritis, and pneumonitis. 27,28 The rates of grade $3 transaminitis reported here are higher than rates previously reported for this drug, as summarized in Table 3. In the phase 1 trial, subjects were the most heavily pretreated, with a median of 5 prior therapies, and the rate of grade $3 hepatotoxicity was the lowest, at 2%.…”

contrasting

confidence: 52%

Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity

Lampson

Kasar

Matos

et al. 2016

Blood

270

262

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• Idelalisib as upfront therapy for CLL caused an early hepatotoxicity in a subset of primarily younger patients with IGHV-mutated disease.• Multiple lines of evidence suggest that this adverse effect is immune mediated, perhaps through inhibition of regulatory T cells.Idelalisib is a small-molecule inhibitor of PI3Kd with demonstrated efficacy for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as front-line therapy, we enrolled 24 subjects in a phase 2 study consisting of 2 months of idelalisib monotherapy followed by 6 months of combination therapy with idelalisib and the anti-CD20 antibody ofatumumab. After a median follow-up period of 14.7 months, hepatotoxicity was found to be a frequent and often severe adverse event. A total of 19 subjects (79%) experienced either grade ‡1 ALT or AST elevation during the study, and 13 subjects (54%) experienced grade ‡3 transaminitis. The median time to development of transaminitis was 28 days, occurring before ofatumumab introduction. Younger age and mutated immunoglobulin heavy chain status were significant risk factors for the development of hepatotoxicity. Multiple lines of evidence suggest that this hepatotoxicity was immune mediated. A lymphocytic infiltrate was seen on liver biopsy specimens taken from 2 subjects with transaminitis, and levels of the proinflammatory cytokines CCL-3 and CCL-4 were higher in subjects experiencing hepatotoxicity. All cases of transaminitis resolved either by holding the drug, initiating immunosuppressants, or both, and rates of recurrent toxicity were lower in patients taking steroids when idelalisib was reinitiated. A decrease in peripheral blood regulatory T cells was seen in patients experiencing toxicity on therapy, which is consistent with an immune-mediated mechanism. These results suggest that caution should be taken as drugs within this class are developed for CLL, particularly in younger patients who have not received prior disease-specific therapy. This study was registered at www.clinicaltrials.gov as #NCT02135133. (Blood. 2016;128(2):195-203)

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contrasting

confidence: 52%

Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity

Lampson

Kasar

Matos

et al. 2016

Blood

270

262

View full text Add to dashboard Cite

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“…Functional defects in FOXP3, the lineage-defining transcription factor that identifies the best-characterized population of Tregs, result in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in human patients and in the IPEXrelated scurfy phenotype in mice (4). In both species, the severe lymphoproliferation that ensues shows concomitant Th1 and Th2 effector responses, which may counterregulate each other (5), and manifests clinically as a loss of tolerance to self and autoimmunity in combination with elevated IgE levels and food allergies (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy

Lexmond¹,

Goettel²,

Lyons³

et al. 2016

Journal of Clinical Investigation

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“…Their importance is highlighted by the devastating multiorgan inflammation of FoxP3-deficient scurfy mice or immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) patients (4). In addition, Treg cells partake in extraimmune regulatory activities (3).…”

mentioning

confidence: 99%

Unstable FoxP3 ⁺ T regulatory cells in NZW mice

Dépis

Kwon

Mathis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Regulatory T (Treg) cells that express the transcription factor FoxP3 play a key role in self-tolerance and the control of inflammation. In mice and humans, there is a wide interindividual range in Treg frequency, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue in inbred strains of mice, with a special focus on the low proportion of Treg cells found in NZW mice. Mixed bone marrow chimera experiments showed this paucity to be intrinsic to NZW Treg cells, a dearth that could be tied to poor stability of the Treg pool and of FoxP3 expression. This instability was not a consequence of differential epigenetic marks, because Treg-specific CpG hypomethylation profiles at the Foxp3 locus were similar in all strains tested. It was also unrelated to the high expression of IFN signature genes in NZW, as shown by intercross to mice with an Ifnar1 knockout. NZW Tregs were less sensitive to limiting doses of trophic cytokines, IL-2 and -33, for population homeostasis and for maintenance of FoxP3 expression. Gene-expression profiles highlighted specific differences in the transcriptome of NZW Tregs compared with those of other strains, but no single defect could obviously account for the instability. Rather, NZW Tregs showed a general up-regulation of transcripts normally repressed in Treg cells, and we speculate that this network-level bias may account for NZW Treg instability.Treg homeostasis | FoxP3 stability | immunoregulation | inbred mice

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FOXP3 and scurfy: how it all began

Cited by 194 publications

References 80 publications

Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity

Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity

FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy

Unstable FoxP3 ⁺ T regulatory cells in NZW mice

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FOXP3 and scurfy: how it all began

Cited by 194 publications

References 80 publications

Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity

Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity

FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy

Unstable FoxP3 + T regulatory cells in NZW mice

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Product

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Unstable FoxP3 ⁺ T regulatory cells in NZW mice