ORAL ADMINISTRATION OF ANTIGEN AND THE OCULAR IMMUNE RESPONSE

在视网膜S抗原(S-Ag)和视黄醇受体间结合蛋白(IRBP)诱导的实验性自身免疫性葡萄膜视网膜炎的动物模型上，观察了口服不同抗原对眼免疫反应的影响。反复灌胃S-Ag可诱导大鼠口服耐受性。随机对照试验评价眼内注射S-银制剂的有效性 炎症性疾病于1995年8月完成招募，试验于1997年初公布。这项研究的目的是评估口服视网膜抗原对眼部炎症各种参数的影响和安全性。这是一项I/II期随机、掩蔽试验。 将依赖免疫抑制剂治疗的内源性葡萄膜炎患者随机分为4组，每组10例，分别接受视网膜S抗原、视网膜S抗原和视网膜可溶性抗原混合物、视网膜可溶性抗原混合物和安慰剂治疗。然后，试图在八周的时间里完全减少患者的标准免疫抑制治疗。研究的主要终点是眼部炎症发作的时间。第二个研究终点是在8周内完全停止患者的免疫抑制或细胞毒性药物的能力。葡萄膜炎发生的时间是主要的研究终点，四个治疗组中的任何一个在统计学上都没有显著差异。然而，与安慰剂相比，单独接受纯化S抗原的组似乎更成功地逐渐减少免疫抑制药物(p=0.08)，而所有其他组似乎比接受安慰剂的组表现更差。没有观察到可归因于任何治疗的毒性反应。尽管没有统计学意义，但与其他受试组相比，服用S抗原的患者更有可能逐渐停止长期服用的全身免疫抑制治疗。 我们现在正在测试Optiquel(由Enzo公司提供的CRADA)作为一种潜在的葡萄膜炎口服耐受剂的使用。Optiquel是一种B27PD多肽序列，存在于几种HLA-B抗原中，在所有与葡萄膜炎相关的抗原中最为显著，如B27、B51和B44(与HLAA29有基因联系)。已经证明，当喂给实验性自身免疫性葡萄膜炎免疫的动物时，它可以诱导口服耐受。 这项正在进行的掩蔽随机研究的目的是在一项概念性临床试验中，评估在接受口服皮质类固醇治疗或与免疫抑制剂联合使用的参与者中，Optiquel作为一种非皮质类固醇非感染性葡萄膜炎非激素类药物的安全性和有效性。有效的假设是： (1)在大剂量口服皮质类固醇治疗逐渐减少的葡萄膜炎患者中，Optiquel将是安全的，并且比安慰剂有更大的疗效。 (2)两种不同剂量的Optiquel中的一种最有效。 符合条件的非感染性葡萄膜炎患者需要至少20毫克口服泼尼松来维持眼睛静止，将符合条件。该方案在IRB批准和IND的情况下执行。这也是美国国立卫生研究院人类免疫学中心批准的研究，如果看到显著的临床结果，将进行进一步的综合研究。这项研究正在进行中，目前还没有结果。 此外，正在进行平行的大鼠实验，以评估肠道佐剂的使用，试图增强耐受性效果。

The effect of the oral administration of various antigens on the ocular immune response has been tested in the animal model for severe intraocular inflammatory disease, experimental autoimmune uveoretinitis, that is induced by both retinal S-antigen (S-Ag) and interphotoreceptor retinoid-binding protein (IRBP). Oral tolerance could be induced by repeatedly feeding S-Ag to rats. A randomized masked trial to evaluate the usefulness of S-Ag feeding in patients with intraocular inflammatory diseases finished recruitment in August 1995, with publication of the trial in early 1997. That study was aimed to evaluate the effect and safety of the oral administration of retinal antigens on various parameters of ocular inflammation. It was a phase I/II randomized, masked trial. Patients with endogenous uveitis who were dependent on immunosuppressive agents were randomly assigned to receive either retinal S-antigen alone (n=10), retinal S-antigen and a mixture of soluble retinal antigens (n=10), retinal mixture of soluble antigens alone (n=10), or placebo (n-15). An attempt was then made to taper patients completely off their standard immunosuppressive therapy over an eight week period. The primary study endpoint was time to ocular inflammatory attack. The secondary study endpoint was the ability to taper patients completely off their immunosuppressive or cytotoxic medication within eight weeks. Time to development of uveitis was the main study endpoint and was not statistically significantly different for any of the four treatment groups. However, the group receiving the purified S-Antigen alone appeared to be tapered off their immunosuppressive medication more successfully as compared to placebo (p=0.08), while all the other groups appeared to do worse than those receiving placebo. No toxic effects attributable to any treatment were observed. Although not statistically significant, patients given S-antigen were more likely to be tapered off their chronically administered systemic immunosuppressive therapy than the other groups tested. We are now testing the use of Optiquel (provided under a CRADA by Enzo corporation) as a potential oral tolerance agent for uveitis. Optiquel is a B27PD peptide sequence found in several HLA-B-antigens, most remarkably in all those that are associated with uveitis, such as B27, B51 and B44 (genetically linked to HLA A29). It has been shown to induce oral tolerance when fed to animals immunized for experimental autoimmune uveitis. The objective of the ongoing masked randomized study is to evaluate the safety and efficacy of Optiquel as a corticosteroid-sparing agent for chronic non-infectious uveitis in participants receiving oral corticosteroid therapy alone or combined with an immunosuppressive agent in a proof-of-concept clinical trial. The working hypotheses are that: (1) Optiquel will be safe and have greater efficacy than placebo as a corticosteroid-sparing treatment in patients with uveitis tapered from high dose oral corticosteroid therapy. (2) One of two alternative doses of Optiquel will be most efficacious. Eligible patients with non-infectious uveitis requiring at least 20 mg of oral prednisone to maintain a quiescent eye will be eligible. The protocol is performed under IRB approval and an IND. It is also an NIH Center for Human Immunology approved study and further comprehensive studies will be performed if a signficant clincal result is seen. The study is ongoing with no results as of yet. In addition, parallel rat experiments are being performed to evaluate the use of gut adjuvants in an attempt to enhance the toleragenic effect.