Boosting regulatory T cell function for the treatment of autoimmune diseases – That’s only half the battle!

Schlöder, Janine; Shahneh, Fatemeh Zare; Schneider, Franz-Joseph; Wieschendorf, Björn

doi:10.3389/fimmu.2022.973813

Cited by 31 publications

(16 citation statements)

References 160 publications

(175 reference statements)

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“…This naive Treg subset exhibits enhanced migration to non-lymphoid or in amed tissues, supporting immunological tolerance and potential immune homeostasis modulation. [37]. Although our sample size is small, we showed that the number of naive Tregs in the blood form RR-MS patients was not signi cantly different compared to healthy volunteers and that they could be transduced and expanded in vitro as e ciently as Tregs isolated from the blood of healthy patients.…”

Section: Cd4 + Cd25 + Foxp3+mentioning

confidence: 72%

MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis

Frikeche,

David,

Mouska

et al. 2024

Preprint

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Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) T cell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR-T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR-Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR-Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR-Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR-Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients.

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Section: Cd4 + Cd25 + Foxp3+mentioning

confidence: 72%

MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis

Frikeche,

David,

Mouska

et al. 2024

Preprint

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“…This study provides quantitative measurements and new evaluation methods for the prevention of RA. Based on the results of this study Treg cell-based therapies, which target defective Treg cell functions, may be a promising therapeutic approach to RA ( Schlöder et al, 2022 ; Yan et al, 2022 ). Previous studies have shown that Treg cell-based therapy can delay the onset of autoimmune inflammation ( Dijke et al, 2016 ).…”

Section: Discussionmentioning

confidence: 92%

High-throughput Treg cell receptor sequencing reveals differential immune repertoires in rheumatoid arthritis with kidney deficiency

Zhang

Jiao

Deng

et al. 2023

PeerJ

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Background Regulatory T (Treg) cells are important immune cells that are regulated by adaptive immunity in the composition of Treg-cell subsets and T-cell receptors (TCRs). Treg cells are related to most autoimmune diseases, such as rheumatoid arthritis (RA). In traditional Chinese medicine (TCM), RA is typically attributed to kidney deficiency (KD) associated with the immunosenescence that causes immune dysfunction and the impaired function of Treg cells. So far, however, no mechanism related to KD and immune repertoires has been identified in RA. Methods Flow cytometry and high-throughput Treg-cell receptor sequencing were used to investigate the amount of different Treg-cell subsets and the diversity of TCRs between RA patients and healthy subjects, as well as between KD RA and non-KD RA patients. RT-qPCR was used to validate the high-throughput sequencing results. Results The data showed that the amount of naïve Treg cells in KD patients was less than in non-KD RA patients (P = 0.004) with no significant differences observed between other subsets. In the TCR of Treg cells, the length of complementarity determining region 3 (CDR3) was low and clonotypes increased in the KD group compared with the non-KD group. The diversity and abundance of Treg TCRs were low, as determined by the Hill number. In addition, several V(D)J combinations, such as T-cell receptor beta variable 7-2 (TRBV7-2), TRBV11-1, TRBV13, TRBV15, and TRBJ2-3, varied significantly between the two groups, indicating that KD causes Treg dysfunction. RT-qPCR shows that FOXP3 expression in peripheral blood Treg is lower in KD than in non-KD. Conclusion The results demonstrate the close correlation between KD and immune repertoires in RA and provide a new evaluation method for RA in TCM.

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“…The Tfh/Tfr ratio correlates with SLE disease activity ( 20 ). Selective enrichment of Tregs has been used to treat immune-mediated diseases ( 21 , 22 ). Administration of low-dose IL-2, an essential cytokine for the maintenance and proliferation of Tregs, specifically expands Tregs in vivo ( 23 ) and is a promising approach for treating autoimmune diseases and graft versus host disease (GVHD) ( 24 , 25 ).…”

Section: Introductionmentioning

confidence: 99%

Concomitant use of interleukin-2 and tacrolimus suppresses follicular helper T cell proportion and exerts therapeutic effect against lupus nephritis in systemic lupus erythematosus-like chronic graft versus host disease

Nasa,

Satake,

Tsuji

et al. 2024

Front. Immunol.

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IntroductionDefective interleukin-2 (IL-2) production contributes to immune system imbalance in patients with systemic erythematosus lupus (SLE). Recent clinical studies suggested that low-dose IL-2 treatment is beneficial for SLE and the therapeutic effect is associated with regulatory T cell (Treg) expansion. Pharmacological calcineurin inhibition induces a reduction in the number of Tregs because they require stimulation of T cell receptor signaling and IL-2 for optimal proliferation. However, the activation of T cell receptor signaling is partially dispensable for the expansion of Tregs, but not for that of conventional T cells if IL-2 is present.AimWe examined whether addition of IL-2 restores the Treg proportion even with concurrent use of a calcineurin inhibitor and if the follicular helper T cell (Tfh) proportion is reduced in an SLE-like murine chronic graft versus host disease model.MethodsUsing a parent-into-F1 model, we investigated the effect of IL-2 plus tacrolimus on Treg and Tfh proportions and the therapeutic effect.ResultsTreatment with a combination of IL-2 and tacrolimus significantly delayed the initiation of proteinuria and decreased the urinary protein concentration, whereas tacrolimus or IL-2 monotherapy did not significantly attenuate proteinuria. Phosphorylation of signal transducer and activator of transcription 3, a positive regulator of Tfh differentiation, was reduced by combination treatment, whereas phosphorylation of signal transducer and activator of transcription 5, a negative regulator, was not reduced.ConclusionAddition of calcineurin inhibitors as adjunct agents may be beneficial for IL-2-based treatment of lupus nephritis.

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Boosting regulatory T cell function for the treatment of autoimmune diseases – That’s only half the battle!

Cited by 31 publications

References 160 publications

MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis

MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis

High-throughput Treg cell receptor sequencing reveals differential immune repertoires in rheumatoid arthritis with kidney deficiency

Concomitant use of interleukin-2 and tacrolimus suppresses follicular helper T cell proportion and exerts therapeutic effect against lupus nephritis in systemic lupus erythematosus-like chronic graft versus host disease

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