CTLA4-Ig Effectively Controls Clinical Deterioration and Immune Condition in a Murine Model of Foxp3 Deficiency,Journal of Clinical Immunology

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CTLA4-Ig Effectively Controls Clinical Deterioration and Immune Condition in a Murine Model of Foxp3 Deficiency
Journal of Clinical Immunology ( IF 7.2 ) Pub Date : 2023-05-08 , DOI: 10.1007/s10875-023-01462-2
Margaux Gerbaux _{1,

2} , Evelyne Roos _{1,

3} , Mathijs Willemsen _{1,

3} , Frederik Staels _{1,

3} , Julika Neumann _{1,

3} , Leoni Bücken ₁ , Jeason Haughton ₁ , Lidia Yshii , James Dooley _{1,

3,

4} , Susan Schlenner ₁ , Stephanie Humblet-Baron ₁ , Adrian Liston _{1,

3,

4}

Affiliation

Purpose

FOXP3 deficiency results in severe multisystem autoimmunity in both mice and humans, driven by the absence of functional regulatory T cells. Patients typically present with early and severe autoimmune polyendocrinopathy, dermatitis, and severe inflammation of the gut, leading to villous atrophy and ultimately malabsorption, wasting, and failure to thrive. In the absence of successful treatment, FOXP3-deficient patients usually die within the first 2 years of life. Hematopoietic stem cell transplantation provides a curative option but first requires adequate control over the inflammatory condition. Due to the rarity of the condition, no clinical trials have been conducted, with widely unstandardized therapeutic approaches. We sought to compare the efficacy of lead therapeutic candidates rapamycin, anti-CD4 antibody, and CTLA4-Ig in controlling the physiological and immunological manifestations of Foxp3 deficiency in mice.

Method

We generated Foxp3-deficient mice and an appropriate clinical scoring system to enable direct comparison of lead therapeutic candidates rapamycin, nondepleting anti-CD4 antibody, and CTLA4-Ig.

Results

We found distinct immunosuppressive profiles induced by each treatment, leading to unique protective combinations over distinct clinical manifestations. CTLA4-Ig provided superior breadth of protective outcomes, including highly efficient protection during the transplantation process.

Conclusion

These results highlight the mechanistic diversity of pathogenic pathways initiated by regulatory T cell loss and suggest CTLA4-Ig as a potentially superior therapeutic option for FOXP3-deficient patients.

中文翻译：

CTLA4-Ig 有效控制 Foxp3 缺陷小鼠模型的临床恶化和免疫状况

目的

由于功能性调节性 T 细胞的缺失，FOXP3缺陷会导致小鼠和人类出现严重的多系统自身免疫。患者通常会出现早期和严重的自身免疫性多内分泌病、皮炎和严重的肠道炎症，导致绒毛萎缩，最终导致吸收不良、消耗和生长障碍。如果没有成功的治疗，FOXP3 缺陷的患者通常会在生命的最初 2 年内死亡。造血干细胞移植提供了一种治疗选择，但首先需要充分控制炎症状况。由于这种情况罕见，尚未进行任何临床试验，治疗方法也普遍不标准化。我们试图比较主要候选治疗药物雷帕霉素、抗 CD4 抗体和 CTLA4-Ig 在控制小鼠 Foxp3 缺陷的生理和免疫学表现方面的功效。