Division of Hematologic Malignancies, Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Clin Cancer Res. 2010 Mar 1;16(5):1642-51. doi: 10.1158/1078-0432.CCR-09-2701. Epub 2010 Feb 16.
Donor T cells respond to minor histocompatibility antigens (mHA), resulting in both graft-versus-host disease and graft versus leukemia after allogeneic hematopoietic stem cell transplantation. Because relatively few mHAs are known, we developed a new approach to predict and subsequently validate candidate mHA.
We developed an algorithm based on genetic disparities between Y chromosome-encoded and X chromosome-encoded proteins and known requirements for binding to HLA class I molecules to predict Y chromosome-derived, HLA A0201-restricted peptides (HY) and ranked peptides based on potential immunogenicity. We evaluated T-cell responses to 41 candidate peptides in 28 male recipients with female donors (FM), 22 male recipients with male donors (MM), and 26 normal individuals. All patients and donors were HLA A0201 positive.
Thirteen peptides derived from five proteins elicited significantly greater T-cell responses in FM patients compared with MM patients and in normal females compared with normal males. Six peptides were more immunogenic than the only previously known HLA A0201-restricted Y-encoded mHA. Twenty-seven of 28 FM patients responded to at least one HY peptide, but despite a common Y chromosome mismatch and expression of HLA A0201, each patient responded to a unique set of peptides.
Novel HLA A*0201-restricted HY epitopes can be predicted and validated in patients after allogeneic hematopoietic stem cell transplantation. Highly diverse patterns of T-cell response against these epitopes have been identified. Prospective monitoring of responses to large panels of immunogenic peptides can facilitate the identification of clinically relevant targets of graft-versus-host disease and graft versus leukemia.
供体细胞对次要组织相容性抗原（mHA）产生反应，导致异基因造血干细胞移植后移植物抗宿主病和移植物抗白血病。由于已知的 mHA 相对较少，我们开发了一种新的方法来预测和随后验证候选 mHA。
我们开发了一种基于 Y 染色体编码蛋白和 X 染色体编码蛋白之间的遗传差异以及与 HLA Ⅰ类分子结合的已知要求的算法，以预测 Y 染色体衍生的、HLA A0201 限制性肽（HY），并根据潜在的免疫原性对肽进行排序。我们评估了 28 名女性供体的男性受者（FM）、22 名男性供体的男性受者（MM）和 26 名正常个体的 41 种候选肽的 T 细胞反应。所有患者和供者均为 HLA A0201 阳性。
从五个蛋白中衍生的 13 个肽在 FM 患者中比 MM 患者和正常女性中比正常男性引起了显著更大的 T 细胞反应。六个肽比唯一已知的 HLA A0201 限制性 Y 编码 mHA 更具免疫原性。28 名 FM 患者中有 27 名至少对一种 HY 肽产生反应，但尽管存在共同的 Y 染色体错配和 HLA A0201 的表达，每个患者都对一组独特的肽产生反应。
可在异基因造血干细胞移植后患者中预测和验证新的 HLA A*0201 限制性 HY 表位。已经鉴定出针对这些表位的高度多样化的 T 细胞反应模式。对大panel 的免疫肽的反应的前瞻性监测可以促进识别移植物抗宿主病和移植物抗白血病的临床相关靶标。
