COMBINATION ANTIRETROVIRAL THERAPY & THYMUS TRANSPLANTATION IN HIV INFECTION

联合抗逆转录病毒治疗

• 批准号: 6415270
• 负责人: CHARLES B HICKS
• 金额: $ 29.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6415270
• 关键词: AIDS therapy; CD4 molecule; HIV infections; T lymphocyte; antiAIDS agent; biopsy; clinical research; clinical trials; combination therapy; flow cytometry; human subject; human therapy evaluation; lamivudine; protease inhibitor; thymus transplantation; zidovudine

Purpose: The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) would lead to restoration of T cell function in HIV infection. Methods: Eight treatment-naive HIV-infected patients were enrolled who had CD4+ T cell counts between 200 and 500/mm3. After 3 weeks of HAART, the patients were randomized into two groups: 4 patients received cultured allogeneic postnatal thymic tissue at day 42 of HAART and the other 4 were controls. Following 1 week of HAART, patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). Results: HIV plasma RNA levels of 16,625 copies /ml (median) decreased to <100 copies/ml within 12 weeks of therapy in all but one patient. The median increase in CD4+ T cell count over the first 399 days of HAART was 175/mm3. The T cell proliferative responses to Candida antigen and TT normalized in all patients. T cell proliferative responses to KLH developed in 3 of 4 transplant recipients and in 1 of 2 controls (the 2 other controls dropped out) after the secondary immunization. All 4 thymic grafts were rejected. Summary: Four of 6 patients developed T cell proliferative responses to neoantigens over the first 600 days of HAART. Transplanted thymus tissue was rejected. There was with no clear difference in restoration of T cell function in the transplant recipients compared to the controls. Novel immune reconstitution strategies may be needed in those patients on HAART with suboptimal immune restoration. Future plans: We have begun a substudy to evaluate whether rejection of thymus grafts can be prevented by use of a course of immunosuppression prior to thymic transplantation in patients with very low CD4 T cell counts despite over one year of HAART. Significance: It is important to determine how to restore immune function in patients with low T cell counts despite HAART. HIV-infected patients in this category remain at risk for life threatening infections.

目的：本研究的目的是确定胸腺移植，除了高效抗逆转录病毒治疗（HAART）将导致T细胞功能的HIV感染的恢复。方法：入组了8例未经治疗的HIV感染患者，他们的CD 4 + T细胞计数在200和500/mm 3之间。HAART治疗3周后，将患者随机分为两组：HAART治疗第42天，4例患者接受同种异体胸腺组织培养，另4例为对照组。HAART治疗1周后，患者每6个月接种一次新抗原匙孔血蓝蛋白（KLH）和回忆抗原破伤风类毒素（TT）。结果：除1例患者外，所有患者的HIV血浆RNA水平均在治疗12周内从16，625拷贝/ml（中位数）降至<100拷贝/ml。在HAART的前399天，CD 4 + T细胞计数的中位数增加为175/mm 3。所有患者对念珠菌抗原和TT的T细胞增殖反应均正常化。在二次免疫后，4名移植受者中有3名和2名对照中有1名（其他2名对照脱落）出现了对KLH的T细胞增殖反应。4例胸腺移植均发生排斥反应。总结：6例患者中有4例在HAART的前600天内对新抗原产生了T细胞增殖反应。移植的胸腺组织被排斥。与对照组相比，移植受者的T细胞功能恢复没有明显差异。在HAART中免疫恢复不佳的患者中可能需要新的免疫重建策略。未来计划：我们已经开始了一项亚组研究，以评估是否可以通过使用免疫抑制过程中的非常低的CD 4 T细胞计数的患者，尽管超过一年的HAART胸腺移植前胸腺移植物的排斥反应可以预防。重要性：重要的是要确定如何恢复低T细胞计数患者的免疫功能，尽管HAART。这类艾滋病毒感染者仍有感染危及生命的危险。