ORAL ADMINISTRATION OF ANTIGEN AND THE OCULAR IMMUNE RESPONSE

口服抗原和眼部免疫反应

• 批准号: 8339751
• 负责人: Robert Nussenblatt
• 金额: $ 22.94万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8339751
• 关键词: Adjuvant; Adrenal Cortex Hormones; Animal Model; Animals; Antigens; Arrestins; Autoimmune Process; Blood group antigen S; Chronic; Clinical Trials; Cooperative Research and Development Agreement; Development; Disease; Dose; Eye; HLA-B Antigens; Human; Immune response; Immunology; Immunosuppressive Agents; Inflammation; Inflammatory; Institutional Review Boards; Link; Masks; Oral; Oral Administration; Participant; Patients; Peptides; Pharmaceutical Preparations; Phase; Placebos; Prednisone; Protocols documentation; Publications; Randomized; Rattus; Retinal; Safety; Testing; Therapeutic immunosuppression; Time; Toxic effect; United States National Institutes of Health; Uveitis; Work; autoimmune uveitis; cytotoxic; feeding; gastrointestinal; interstitial retinol-binding protein; oral tolerance; protein aminoacid sequence; research study; uveoretinitis

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.

在视网膜s抗原（S-Ag）和光感受器间类维甲酸结合蛋白（IRBP）诱导的严重眼内炎性疾病——实验性自身免疫性葡萄膜视网膜炎的动物模型中，研究了口服各种抗原对眼部免疫反应的影响。大鼠可通过多次喂食S-Ag诱导其口服耐受。一项评估S-Ag喂养在眼内直视患者中的有效性的随机隐蔽性试验