Gonzalez-Rey Elena, Fernandez-Martin Amelia, Chorny Alejo, Delgado Mario
Institute of Parasitology and Biomedicine, CSIC, Granada, Spain.
Arthritis Rheum. 2006 Mar;54(3):864-76. doi: 10.1002/art.21652.
CD4+,CD25+ T regulatory cells (Treg) control the immune response to a variety of antigens, including self antigens, and may offer opportunities to intervene in the course of autoimmune diseases. Several models support the idea of the peripheral generation of CD4+,CD25+ Treg from CD4+,CD25- T cells, but little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+,CD25+ Treg. We undertook this study to investigate the capacity of the vasoactive intestinal peptide (VIP), an immunosuppressive antiarthritic neuropeptide, to induce functional Treg in vivo during the development of collagen-induced arthritis (CIA).
We measured the number of CD4+,CD25+ Treg following VIP administration to CIA mice, and we characterized their phenotype and their ability to suppress activation of autoreactive T cells. We determined the capacity of VIP to induce Treg in vitro as well as the use of Treg in the treatment of CIA, measuring the clinical evolution and the inflammatory and autoimmune components of the disease.
The administration of VIP to arthritic mice resulted in the expansion of CD4+,CD25+,Foxp3+ Treg in the periphery and joints, which inhibited autoreactive T cell activation/expansion. VIP induced more efficient suppressors on a per-cell basis. The VIP-generated CD4+,CD25+ Treg transfer suppressed and significantly ameliorated the progression of the disease.
These results demonstrate the involvement of the generation of Treg in the therapeutic effect of VIP on CIA. The generation of highly efficient Treg by VIP ex vivo could be used as an attractive therapeutic tool in the future, avoiding the administration of the peptide to patients with rheumatoid arthritis.
CD4⁺、CD25⁺调节性T细胞（Treg）可控制机体对多种抗原（包括自身抗原）的免疫反应，这可能为干预自身免疫性疾病进程提供契机。多种模型支持CD4⁺、CD25⁺Treg可由CD4⁺、CD25⁻T细胞在外周生成的观点，但对于控制CD4⁺、CD25⁺Treg外周扩增的内源性因素及机制却知之甚少。我们开展本研究，旨在探究血管活性肠肽（VIP）这一具有免疫抑制作用的抗关节炎神经肽，在胶原诱导性关节炎（CIA）发病过程中体内诱导功能性Treg的能力。
我们测定了向CIA小鼠给予VIP后CD4⁺、CD25⁺Treg的数量，并对其表型及抑制自身反应性T细胞活化的能力进行了表征。我们确定了VIP体外诱导Treg的能力以及Treg在CIA治疗中的作用，同时测量了疾病的临床进展以及疾病的炎症和自身免疫成分。
向患关节炎小鼠给予VIP可导致外周及关节中CD4⁺、CD25⁺、Foxp3⁺Treg扩增，这抑制了自身反应性T细胞的活化/扩增。VIP在单个细胞基础上诱导出更高效的抑制细胞。VIP产生的CD4⁺、CD25⁺Treg转移可抑制并显著改善疾病进展。
这些结果表明Treg的生成参与了VIP对CIA的治疗作用。VIP体外高效生成Treg未来可作为一种有吸引力的治疗工具，避免向类风湿关节炎患者给药该肽。
