Regulatory T Cells Are Reduced During Anti-CD25 Antibody Treatment of Multiple Sclerosis

Oh, Unsong; Blevins, Gregg; Griffith, Caitlin; Richert, Nancy; Maric, Dragan; Lee, C. L Richard; McFarland, Henry F.; Jacobson, Steven

doi:10.1001/archneurol.2009.16

Cited by 86 publications

(86 citation statements)

References 41 publications

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“…Daclizumab has been generally well tolerated, with the notable exception of skin rashes and transient liver function abnormalities. 4,8 This is the first report of CNS vasculitis in a patient treated with daclizumab.…”

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confidence: 89%

CNS vasculitis in a patient with MS on daclizumab monotherapy

Ohayon

Richert

et al. 2013

Neurology

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Objective: To report the development of CNS vasculitis in a patient with multiple sclerosis (MS) treated with daclizumab.Methods: This report includes clinical, MRI, immunologic, and pathology data and CSF analysis.Results: After completing a phase II daclizumab monotherapy study with an optimal response as evidenced by significant decrease in MRI disease activity and stable clinical examinations, the patient elected to continue daclizumab therapy outside of NIH study. Daclizumab was discontinued after 21 doses due to the onset of new clinical symptoms and evidence of a vascular pattern of contrast enhancement on brain and spine MRI. Because of continued clinical deterioration, stereotactic brain biopsy was performed, showing small-vessel CNS vasculitis. Treatment was initiated with IV methylprednisolone followed by a regimen of cyclophosphamide. Immunologic studies suggest that unexpected lack of expansion of CD56 bright NK cells and predictable decline in FoxP31 T-regs combined with a transient interruption in daclizumab dosing may have contributed to this serious side effect.Conclusions: Only safety data from larger phase III studies and potentially postmarketing experience will define the exact risk of daclizumab-induced immunopathologies. Nevertheless, our case provides plausible hypothesis and potential biomarker that may be used to screen susceptible patients and implement preventive safety measures during potentially vulnerable periods. Neurology Daclizumab is a humanized monoclonal antibody specific for interleukin (IL)-2Ra receptor (CD25) and has been approved for the prevention of allograft rejection in solid organ transplantation. Multiple phase II studies of daclizumab in multiple sclerosis (MS) have reported significant efficacy in reducing contrast-enhancing lesions (CEL) and clinical disability. [1][2][3][4][5][6] Clinical efficacy of daclizumab treatment in MS has been linked to the expansion of CD56 bright NK cells, 3,6,7 which can regulate adaptive immunity by killing activated autologous T cells. 7 We describe a 42-year-old Caucasian woman (ZAP10) with a 5-year history of relapsing-remitting MS (RRMS) who completed a phase II clinical trial of daclizumab monotherapy in MS. 2METHODS Magnetic resonance images were obtained at the height of the patient's symptoms using described methodology.2 CSF was collected during pretreatment baseline, month 1.5, and month 6.5 on daclizumab therapy on NIH protocol, and during clinical deterioration on daclizumab therapy outside of NIH clinical trial. CSF was spun within 30 minutes of collection and cell-free supernatants were cryopreserved until analysis. CSF supernatants were concentrated (up to 10-fold) by centrifugation through Millipore Amicon Ultra 3 kDa filters and analyzed in multiplex for IL-12p40, CCL19, and interferon-g as described.2 CXCL13 was measured by ELISA (R&D Systems, Minneapolis, MN; Catalogue number DY801).Standard protocol approvals, registrations, and patient consents. The study was approved by the NIH/CNS Institutional Review ...

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confidence: 89%

CNS vasculitis in a patient with MS on daclizumab monotherapy

Ohayon

Richert

et al. 2013

Neurology

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“…An increased frequency of skin rashes on sun-exposed areas and with dry, scaling skin have been observed, and the routine use of sunscreen and skin moisturizers has been advised by some [Bielekova et al 2013]. Hypothetical mechanisms that have been proposed to explain daclizumab-associated skin reactions are the inhibition of CD4+CD25+ Foxp3+ Treg cells in the skin [Oh et al 2009], and the expansion and local tissue infiltration of CD56 bright NK cells [Oh et al 2012].…”

Section: Safetymentioning

confidence: 99%

“…Several cases of psoriasis in previous trials and the attribution of some daclizumab-associated skin reactions to immune dysregulation raise some concerns about autoimmunity secondary to daclizumab treatment that could be associated with a reduction of CD4+CD25+ Foxp3+ Tregs [Oh et al 2009]. …”

Section: Safetymentioning

confidence: 99%

The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis

Milo

2013

Ther Adv Neurol Disord

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Daclizumab is a humanized monoclonal antibody of the immunoglobulin G1 (IgG1) isotype that binds to the α-subunit (CD25) of the high-affinity interleukin-2 (IL-2) receptor expressed on activated T cells and CD4+CD25+FoxP3+ regulatory T cells. Based on the assumption that it would block the activation and expansion of autoreactive T cells that are central to the immune pathogenesis of multiple sclerosis (MS), daclizumab was tested in several small open-label clinical trials in MS and demonstrated a profound inhibition of inflammatory disease activity. Surprisingly, accompanying mechanistic studies revealed that the most important biological effect of daclizumab was rather a dramatic expansion and activation of immunoregulatory CD56 bright natural-killer (NK) cells that correlated with treatment response, while there was no or only minor effect on peripheral T-cell activation and function. These CD56 bright NK cells were able to gain access to the central nervous system in MS and kill autologous activated T cells. Additional and relatively large phase IIb clinical trials showed that daclizumab, as add-on or monotherapy in relapsing-remitting (RR) MS, was highly effective in reducing relapse rate, disability progression, and the number and volume of gadolinium-enhancing, T1 and T2 lesions on brain magnetic resonance imaging (MRI), and reproduced the expansion of CD56 bright NK cells as a biomarker for daclizumab activity. Daclizumab is generally very well tolerated and has shown a favorable adverse event (AE) profile in transplant recipients. However, several potentially serious and newly emerging AEs (mainly infections, skin reactions, elevated liver function tests and autoimmune phenomena in several body organs) may require strict safety monitoring programs in future clinical practice and place daclizumab together with other new and highly effective MS drugs as a second-line therapy. Ongoing phase III clinical trials in RRMS are expected to provide definite information on the efficacy and safety of daclizumab and to determine its place in the fast-growing armamentarium of MS therapies.

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“…Daclizumab therapy reduces the number of circulating Tregs (21,23). Based on the well-defined role for IL-2 in supporting Treg homeostasis, this effect is not unexpected.…”

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confidence: 91%

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

Huss

Mehta

Sharma

et al. 2015

The Journal of Immunology

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Regulatory T cells (Tregs) mediate immune tolerance to self and depend on IL-2 for homeostasis. Treg deficiency, dysfunction, and instability are implicated in the pathogenesis of numerous autoimmune diseases. There is considerable interest in therapeutic modulation of the IL-2 pathway to treat autoimmunity, facilitate transplantation tolerance, or potentiate tumor immunotherapy. Daclizumab is a humanized mAb that binds the IL-2 receptor α subunit (IL-2Rα or CD25) and prevents IL-2 binding. In this study, we investigated the effect of daclizumab-mediated CD25 blockade on Treg homeostasis in patients with relapsing-remitting multiple sclerosis. We report that daclizumab therapy caused an ∼50% decrease in Tregs over a 52-wk period. Remaining FOXP3+ cells retained a demethylated Treg-specific demethylated region in the FOXP3 promoter, maintained active cell cycling, and had minimal production of IL-2, IFN-γ, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2Rβγ signaling induced STAT5 phosphorylation and sustained FOXP3 expression. Treg declines were not associated with daclizumab-related clinical benefit or cutaneous adverse events. These results demonstrate that Treg phenotype and lineage stability can be maintained in the face of CD25 blockade.

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Regulatory T Cells Are Reduced During Anti-CD25 Antibody Treatment of Multiple Sclerosis

Cited by 86 publications

References 41 publications

CNS vasculitis in a patient with MS on daclizumab monotherapy

CNS vasculitis in a patient with MS on daclizumab monotherapy

The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

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