Hoffmann F, Zhang E P, Pohl T, Kunzendorf U, Wachtlin J, Bulfone-Paus S
Department of Ophthalmology, Benjamin Franklin Medical Center, Free University of Berlin, Germany.
Graefes Arch Clin Exp Ophthalmol. 1997 Aug;235(8):535-40. doi: 10.1007/BF00947013.
Activation of T cells requires both the interaction of T-cell receptor with major histocompatibility complex on the antigen-presenting cell and costimulatory signals, for instance the B7 antigens expressed on antigen-presenting cells and the CD28 molecule expressed on T cells. A recombinant fusion protein, CTLA4-Ig, has been produced that contains the extracellular domain of human CTLA4 fused to IgG1 constant region and that binds the B7 molecule with high affinity. Blocking the CD28/B7 interaction with CTLA4-Ig inhibits T cell activation in vitro and in vivo.
We used CTLA4-Ig in a fully MHC-mismatched mouse keratoplasty model. The animals were divided into four groups: (1) no treatment, (2) intraperitoneal treatment with 130 micrograms CTLA4-Ig, (3) intraperitoneal treatment with 300 micrograms CTLA4-Ig, (4) subconjunctival treatment with 290 micrograms CTLA4-Ig.
The allograft reaction occurred in untreated animals between days 12 and 16 (mean 13.5). While topical application of CTLA4-Ig seemed to shorten the graft survival (mean 11.6 days) and systemic application of 130 micrograms had no influence (mean 14.0), only intraperitoneal injection of 300 micrograms of CTLA4-Ig prolonged the survival of allografts (mean > 20 days) (P < 0.01).
CTLA4-Ig prolonged significantly the survival of corneal allografts in a fully MHC-mismatched mouse keratoplasty model, but the small antigen load of the corneal transplant and the anterior chamber-associated immune deviation (ACAID) may have a disadvantage to induce tolerance in this model of CTLA4-Ig therapy.
T细胞的激活需要T细胞受体与抗原呈递细胞上的主要组织相容性复合体相互作用以及共刺激信号，例如抗原呈递细胞上表达的B7抗原和T细胞上表达的CD28分子。已产生一种重组融合蛋白CTLA4-Ig，其包含与人IgG1恒定区融合的人CTLA4胞外结构域，并且能以高亲和力结合B7分子。用CTLA4-Ig阻断CD28/B7相互作用可在体外和体内抑制T细胞激活。
我们在完全MHC不匹配的小鼠角膜移植模型中使用CTLA4-Ig。动物被分为四组：（1）不治疗，（2）腹腔注射130微克CTLA4-Ig，（3）腹腔注射300微克CTLA4-Ig，（4）结膜下注射290微克CTLA4-Ig。
未治疗的动物在第12至16天（平均13.5天）发生同种异体移植反应。虽然局部应用CTLA4-Ig似乎缩短了移植物存活时间（平均11.6天），而全身应用130微克没有影响（平均14.0天），但只有腹腔注射300微克CTLA4-Ig延长了同种异体移植物的存活时间（平均>20天）（P<0.01）。
在完全MHC不匹配的小鼠角膜移植模型中，CTLA4-Ig显著延长了角膜同种异体移植物的存活时间，但角膜移植的小抗原负荷和前房相关免疫偏离（ACAID）可能不利于在该CTLA4-Ig治疗模型中诱导耐受性。
