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Suppressing neuroinflammation: regulatory T lymphocyte immunomodulatory therapy for ALS
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration ; 23(Supplement 1):15, 2022.
Article in English | EMBASE | ID: covidwho-2160818
ABSTRACT
Neuroinflammation plays a prominent role in promoting the disease progression of ALS, mediated in part by the interaction of injured motoneurons with surrounding glia and dysregulated central and peripheral immunomodulatory cells. Prominent among such immunomodulatory cells are the CD4+ CD25highFOXP3+ T-lymphocytes that mediate neuroprotection by suppressing proinflammatory responses. However, Treg suppressive functions are impaired in ALS, but are restored and even enhanced following expansion ex vivo. Autologous infusions of these expanded T regs together with subcutaneous IL- 2 injections formed the basis of two ALS clinical trials. In a Phase 1 pilot study of 3 ALS patients, infusions were safe and well-tolerated and slowed progression rates during early and later stages of the disease. Treg numbers and suppressive function increased after each infusion and correlated with slowing of disease progression. However, the duration of the clinical benefit was limited, possibly related to the serum biomarkers of oxidative stress, 4-hydroxynonenal, and oxidized LDL These lipid peroxide biomarkers were increased prior to Treg infusions, fell with Treg infusions and slowing of disease progression, rose again as disease progression accelerated in the absence of infused Tregs, then fell again when Tregs were reinfused. Thus, the levels of 4-HNE and ox- LDL were effectively responsive to Treg infusions and mirrored the stabilization or deterioration of the subject's clinical status. A Phase 2A study of autologous infusion of expanded Tregs in combination with subcutaneous IL-2 injections was undertaken at Houston Methodist and Massachusetts General Hospitals. The study was planned for 12 ALS pts enrolled in a 24-week randomized control trial (RCT) followed by a 24- week open label extension (OLE). In the RCT Treg/IL-2 treatments were safe and well-tolerated;with increased Treg suppressive function in the active group. Evaluation of relative progression rates in the RCT was precluded by the COVID pandemic which decreased the number of participants. However, 8 ALS patients did complete the 24-week OLE;Treg/IL-2 treatments were safe and well-tolerated, and Treg suppressive function and numbers were increased. Six patients showed slow to no progression in the OLE (mean change of -2.7 points on ALSFRS-R) Two patients progressed rapidly;they were unresponsive to Treg infusions and had elevated markers of peripheral inflammation (IL-17C and IL-17F) as well as elevated markers of oxidative stress (OLR1 and oxidized-LDL). The 6 participants in the slow progressing group had normal levels. Whether Treg/IL-2 treatments can slow disease progression in ALS requires a large double-blind randomized controlled study. Nevertheless, our open-label studies, albeit in a limited population, suggest that Treg therapy is safe and well tolerated, and a promising approach to slowing ALS progression;lipid peroxide biomarkers may not only reflect a heightened pro-inflammatory milieu but may also be useful in monitoring clinical responsiveness to therapy.
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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Year: 2022 Document Type: Article

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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Year: 2022 Document Type: Article