IV IG MODULATION OF ALLOIMMUNE RESPONSES IN VIVO

IV IG 体内同种免疫反应的调节

• 批准号: 2517277
• 负责人: STANLEY C JORDAN
• 金额: $ 36.07万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2517277
• 关键词: MHC class I antigen; antiidiotype antibody; child (0-11); dosage; enzyme linked immunosorbent assay; gamma globulin; histocompatibility; human subject; immunoglobulin G; immunoglobulin M; immunotherapy; intravenous administration; transplantation immunology; vascular endothelium

Renal transplantation has emerged as the treatment of choiCe for pediatric patients with end-stage renal disease (ESRD). This therapy offers the best hope for a near normal life for these Children, including the prospects for normal growth and development. Unfortunately, nearly 30% of pediatric ESRD patients awaiting renal transplantation are considered highly-HLA- sensitized. This results in a significant prolongation of waiting time for transplantation, and often precludes transplantation altogether. Even after transplantation, the highly-HLA-sensitized state results in a higher risk for allograft rejection and loss. There are currently no proven therapies to lower anti-HLA antibody reactivity and enhanced alloimmune responses in these patients. Our hypothesis is that IVIG can modulate humoral and cellular immune reactivity' toward alloantigenic targets, and could be useful in the down regulation of anti-HLA antibody levels and alloimmune responses. Data from our lab and others has established that IVIG inhibits lymphocytotoxicity of anti-HLA class l antibodies in vitro, and lowers levels of anti-HLA antibody in highly-HLA-sensitized individuals. IVIG also strongly inhibits the mixed lymphocyte reaction (MLR) suggesting a possible role for this reagent in inhibition of alloreactivity. Based on these preliminary observations, we propose to conduct a double blinded, block randomized, placebo-controlled trial of IVIG infusion in highly-HLA-sensitized pediatric patients to assess its effectiveness in lowering cytotoxic antibody titers and alloreactivity. The specific objectives of this proposal are: A). To determine if IVIG is more effective than placebo for reduction of cytotoxic anti-HLA antibodies and anti- endothelial cell antibodies (AECA) in highly-HLA-sensitized pediatric ESRD patients. B). To determine if IVIG treatment is more effective than placebo in conferring a long-lasting suppression of anti-HLA antibody levels, AECA levels, and alloreactivity measured by the ability of IgG/lgM isolated from patients' sera to suppress 3rd party MLRs. In addition, we will study the patients MLR reactivity over time toward a constant allogeneically dissimilar target to determine if cellular reactivity is also reduced in IVIG treated vs placebo treated patients. C). To determine if IVIG treated patients, through inhibition of anti-HLA antibody levels receive renal allografts more rapidly than would be anticipated when compared to the placebo treated patients. Data obtained from this study will help us better understand the immunoregulatory mechanisms of IVIG on allospecific immune responses in pediatric ESRD patients, and could result in the establishment of protocols to reduce humoral and cellular alloimmunity with subsequent improvements in transplantation rates and reduced rates of graft rejection. A secondary benefit would be the development of tests that would identify specific antibodies involved in blocking cytotoxicity and reactions. Thus, reagent lots with high-titer blocking antibodies could be identified for use in these patients.

肾移植已成为儿科治疗的首选 患有终末期肾病（ESRD）的患者。这种疗法提供了最好的 希望这些孩子能过上接近正常的生活，包括 正常生长发育。不幸的是，近 30% 的儿科 ESRD 等待肾移植的患者被认为是高度HLA- 敏感了。这导致等待时间显着延长 移植，并且经常完全排除移植。即使之后 移植时，HLA 高度敏感状态会导致更高的风险 用于同种异体移植排斥和损失。目前尚无经过证实的治疗方法 降低抗 HLA 抗体反应性并增强同种免疫反应 这些病人。 我们的假设是 IVIG 可以调节体液和细胞免疫 对同种异体抗原靶标的反应性，并且可能在羽绒中有用 抗 HLA 抗体水平和同种免疫反应的调节。数据来自 我们的实验室和其他人已经确定 IVIG 可以抑制淋巴细胞毒性 体外抗 HLA I 类抗体，并降低抗 HLA 水平 HLA 高度敏感个体中的抗体。 IVIG 也强烈抑制 混合淋巴细胞反应（MLR）表明这可能发挥作用 抑制同种异体反应性的试剂。 基于这些初步观察，我们建议进行双 IVIG 输注的盲法、分组随机、安慰剂对照试验 HLA 高度敏感的儿科患者评估其有效性 降低细胞毒性抗体滴度和同种异体反应性。具体的 该提案的目标是：A).确定 IVIG 是否更有效 与安慰剂相比，细胞毒性抗 HLA 抗体和抗 内皮细胞抗体 (AECA) 在高度 HLA 敏感性儿科 ESRD 中的应用 患者。 B）。确定 IVIG 治疗是否比安慰剂更有效 赋予抗 HLA 抗体水平的长期抑制，AECA 水平，以及通过分离的 IgG/IgM 的能力测量的同种反应性 患者血清抑制第 3 方 MLR。此外，我们还将研究 患者 MLR 反应性随着时间的推移趋于恒定的同种异体 不同的目标以确定细胞反应性是否也降低 IVIG 治疗患者与安慰剂治疗患者对比。 C）。确定 IVIG 是否已接受治疗 患者通过抑制抗 HLA 抗体水平接受肾 与同种异体移植相比，同种异体移植的速度比预期的要快 安慰剂治疗的患者。 这项研究获得的数据将帮助我们更好地了解 IVIG对同种异体特异性免疫反应的免疫调节机制 儿科 ESRD 患者，并可能导致方案的建立 减少体液和细胞同种免疫并随后改善 移植率和移植物排斥率降低。二级 好处是开发测试来识别特定的 参与阻断细胞毒性和反应的抗体。因此，试剂 可以鉴定出具有高滴度封闭抗体的批次用于 这些病人。