Genomic Biomarkers Correlate with HLA-Identical Renal Transplant Tolerance
Genomic Biomarkers Correlate with HLA-Identical Renal Transplant Tolerance
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DOI：
10.1681/asn.2013010068
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发表时间：
2013-09-01
影响因子：
13.6
通讯作者：
Miller, Joshua
中科院分区：
文献类型：
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作者：
Leventhal, Joseph R.;Mathew, James M.;Miller, Joshua
移植后获得免疫耐受的能力是一个治疗目标。在这里，我们报告了一项正在进行的hla同源同胞肾移植耐受性试验的中期结果。免疫抑制方案包括阿仑单抗诱导，供体造血干细胞，他克莫司/麦考酚酸酯免疫抑制转化为西罗莫司，移植后24个月完全停药。如果接受者在12个月无免疫抑制后活检和肾功能正常，则被认为耐受。在入选的20名受者中，10名在移植后至少随访了36个月。这10名受者中有5名免疫抑制成功解除16-36个月（耐受），2名疾病复发，3名在方案活检中出现亚临床排斥反应（不耐受）。微嵌合现象在1年后消失，在移植后5年内，耐受和不耐受受体的CD4(+)CD25（高）CD127(-)FOXP3（+）调节性T细胞和CD19(+)IgD/M(+)CD27(-) B细胞均有所增加。然而，外周血和尿液中的免疫/炎症基因表达途径在耐受和不耐受受体之间存在差异下调。总之，这项试验的中期结果表明，预测的基因组生物标志物，而不是免疫调节表型，可能能够区分耐受和不耐受的患者。
The ability to achieve immunologic tolerance after transplantation is a therapeutic goal. Here, we report interim results from an ongoing trial of tolerance in HLA-identical sibling renal transplantation. The immunosuppressive regimen included alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converted to sirolimus, and complete drug withdrawal by 24 months post-transplantation. Recipients were considered tolerant if they had normal biopsies and renal function after an additional 12 months without immunosuppression. Of the 20 recipients enrolled, 10 had at least 36 months of follow-up after transplantation. Five of these 10 recipients had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence, and 3 had subclinical rejection in protocol biopsies (nontolerant). Microchimerism disappeared after 1 year, and CD4(+)CD25(high)CD127(-)FOXP3(+) regulatory T cells and CD19(+)IgD/M(+)CD27(-) B cells were increased through 5 years post-transplantation in both tolerant and nontolerant recipients. Immune/inflammatory gene expression pathways in the peripheral blood and urine, however, were differentially downregulated between tolerant and nontolerant recipients. In summary, interim results from this trial of tolerance in HLA-identical renal transplantation suggest that predictive genomic biomarkers, but not immunoregulatory phenotyping, may be able to discriminate tolerant from nontolerant patients.