Immunoglobulin light chain, Blimp-1 and cytochrome P4501B1 peptides as potential vaccines for AL amyloidosis.
Immunoglobulin light chain, Blimp-1 and cytochrome P4501B1 peptides as potential vaccines for AL amyloidosis.
复制标题
免疫球蛋白轻链、Blimp-1 和细胞色素 P4501B1 肽作为 AL 淀粉样变性的潜在疫苗。
DOI：
10.1038/icb.2011.73
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发表时间：
2012
影响因子：
4
通讯作者：
Sherr,DavidH
中科院分区：
文献类型：
--
作者：
Flies,Amanda;Ahmadi,Tahamtan;Parks,AshleyJ;Prokaeva,Tatiana;Weng,Liangping;Rolfe,SandraSolomon;Seldin,DavidC;Sherr,DavidH
淀粉样轻链（AL）淀粉样变性是一种致死性疾病，其特征为重要器官中克隆浆细胞衍生的纤维形成免疫球蛋白轻链的病理性沉积。目前的化疗方案在器官功能受损的患者中存在问题，并且对所有患者都无效。在此，基于计算机的预测和临床前小鼠建模平台用于开始开发AL淀粉样变性的互补免疫方法。三种肽/MHC I结合算法鉴定了来自三种AL浆细胞相关蛋白的免疫原性肽：（1）淀粉样蛋白λ6轻链，（2）CYP 1B 1，一种在AL浆细胞中超表达的通用肿瘤抗原，和（3）B淋巴细胞诱导成熟蛋白1（Blimp-1），一种浆细胞分化所需的转录因子。该算法正确预测了HLA-A β 0201结合的天然肽和异型肽。在HLA-A2转基因小鼠中，这些肽单独或联合给药，可诱导强效CTL，杀伤负载肽的人淋巴瘤细胞和/或产生靶蛋白的淋巴瘤细胞。Blimp-1肽免疫小鼠的脾、淋巴结和骨髓浆细胞百分比降低，脾浆细胞绝对数量减少，表明（1）内源性浆细胞呈递靶肽，以及（2）适当的CTL归巢至淋巴器官，随后杀死靶浆细胞。这些研究表明，AL淀粉样变性具有相对较低的肿瘤细胞负荷，可能是基于肽的多价疫苗的有吸引力的靶点。
Amyloid light chain (AL) amyloidosis is a lethal disorder characterized by the pathologic deposition of clonal plasma cell‐derived, fibrillogenic immunoglobulin light chains in vital organs. Current chemotherapeutic regimens are problematic in patients with compromised organ function and are not effective for all patients. Here, a platform of computer‐based prediction and preclinical mouse modeling was used to begin development of a complementary, immunotherapeutic approach for AL amyloidosis. Three peptide/MHC I‐binding algorithms identified immunogenic peptides from three AL plasma cell‐associated proteins: (1) amyloidogenic λ6 light chains, (2) CYP1B1, a universal tumor antigen hyper‐expressed in AL plasma cells and (3) B lymphocyte‐induced maturation protein 1 (Blimp‐1), a transcription factor required for plasma cell differentiation. The algorithms correctly predicted HLA‐A∗0201‐binding native and heteroclitic peptides. In HLA‐A2 transgenic mice, these peptides, given individually or in combination, induced potent CTL which kill peptide‐loaded human lymphoma cells and/or lymphoma cells producing target protein. Blimp‐1 peptide‐immunized mice exhibited a reduced percentage of splenic, lymph node and bone marrow plasma cells and a decrease in the absolute number of splenic plasma cells demonstrating (1) presentation of target peptide by endogenous plasma cells and (2) appropriate CTL homing to lymphoid organs followed by killing of target plasma cells. These studies suggest that AL amyloidosis, with its relatively low tumor cell burden, may be an attractive target for peptide‐based multivalent vaccines.