PDF(Pubmed)
Abstract：
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.
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.
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.
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.
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.
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.
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.
摘要：
目的：FOXP3缺乏导致小鼠和人类严重的多系统自身免疫，由缺乏功能性调节性T细胞驱动。患者通常表现为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，浪费,未能茁壮成长。如果没有成功的治疗，缺乏FOXP3的患者通常在生命的头2年内死亡。造血干细胞移植提供了治疗选择，但首先需要对炎症状况进行充分控制。由于这种情况的罕见，尚未进行任何临床试验，具有广泛的不标准化的治疗方法。我们试图比较先导治疗候选药物雷帕霉素的疗效，抗CD4抗体，和CTLA4-Ig在控制小鼠Foxp3缺陷的生理和免疫学表现中的作用。
方法：我们产生了Foxp3缺陷小鼠和适当的临床评分系统，能够直接比较先导治疗候选药物雷帕霉素，非消耗性抗CD4抗体，和CTLA4-Ig.
结果：我们发现了每种治疗方法诱导的不同的免疫抑制谱，导致独特的保护性组合在不同的临床表现。CTLA4-Ig提供了更广泛的保护性结果，包括移植过程中的高效保护。
结论：这些结果强调了由调节性T细胞丢失引发的致病途径的机制多样性，并表明CTLA4-Ig是FOXP3缺陷患者的潜在优越治疗选择。
方法：我们产生了Foxp3缺陷小鼠和适当的临床评分系统，能够直接比较先导治疗候选药物雷帕霉素，非消耗性抗CD4抗体，和CTLA4-Ig.
结果：我们发现了每种治疗方法诱导的不同的免疫抑制谱，导致独特的保护性组合在不同的临床表现。CTLA4-Ig提供了更广泛的保护性结果，包括移植过程中的高效保护。
结论：这些结果强调了由调节性T细胞丢失引发的致病途径的机制多样性，并表明CTLA4-Ig是FOXP3缺陷患者的潜在优越治疗选择。
