The basis of T-cell-mediated immunity to chronic myelogenous leukemia.
The basis of T-cell-mediated immunity to chronic myelogenous leukemia.
复制标题
T 细胞介导的慢性粒细胞性白血病免疫的基础。
DOI：
10.1038/sj.onc.1206093
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Lu,Sijie
中科院分区：
文献类型：
--
作者：
Molldrem,JeffreyJ;Kant,Shreya;Jiang,Weidong;Lu,Sijie
The most compelling evidence that lymphocytes meditate an anti-leukemia effect comes from studies where allogeneic donor lymphocyte infusions (DLI) have been used to treat relapse of myeloid leukemia after allogeneic BMT (Antin, 1993; Giralt and Kolb, 1996; Kolb and Holler, 1997; Kolb et al., 1995, 1996). Lymphocyte transfusion from the original bone marrow (BM) donor induces both hematological and cytogenetic responses in approximately 70–80% of patients with myelogenous leukemia in chronic phase (Kolb et al., 1996). A complete cytogenetic response is usually obtained between 1–4 months after DLI (van Rhee et al., 1994) and approximately 80% of responders will achieve reverse transcriptase-polymerase chain reaction (RT–PCR) negativity for the bcr–abl translocation (the fusion product of the t (9; 22) translocation found in chronic myelogenous leukemia (CML)) within a mean of 6 months (van Rhee et al., 1994). Acute myelogenous leukemia (AML) is also susceptible to the graft-versus-leukemia (GVL) effect, with 15–40% of patients obtaining remission with DLI alone (Collins et al., 1997). While significant graftversus-host disease (GVHD) occurs in 50% of patients treated with DLI, and disease response occurs in 90% of CML patients, 55% of patients who do not get GVHD also have disease response (Giralt and Kolb, 1996; Kolb and Holler, 1997). This demonstrates that GVL is separable from GVHD in some patients, although only a handful of antigens that drive the donor’s lymphocyte response preferentially against the leukemia have been identified. Remissions after DLI for AML are generally not as durable as those obtained in CML, which may reflect the rapid kinetics of tumor growth outpacing the kinetics of the developing immune response. However, if more antigens could be determined, and if large numbers of antigen-specific cytotoxic T-lymphocytes (CTLs) could be obtained, it would allow for development of leukemia-specific therapies using the antigens as a targets for generating specific T-cells for use in adoptive immunotherapy. To understand the nature of GVL and GVHD, we must review some of the principles of antigen recognition and highlight a recent discovery that has aided our ability to study T-cell interactions. T-cells recognize peptide antigens that are presented on the cell surface in combination with major histocompatibility complex (MHC) antigens. Peptides derived from cytoplasmic proteins that are 8 to 11 amino acids in length, bind in the groove of class I MHC molecules and are transported via the endoplasmic reticulum to the cell surface. Larger peptides, typically 12–18 amino acids in length, that are derived from cell processing of extracellular proteins, bind class II MHC molecules and are presented to T-cells on the cell surface. Both peptide/MHC-I and peptide/MHC-II are recognized by the heterodimeric T-cell receptor (TCR) on CD8 or CD4 T-lymphocytes, respectively, with rapid off rates and kD in the range of 1074 to 1075 M (Alam et al., 1996). Points of contact between the TCR and the peptide/MHC surface include surface amino acids contributed by the two alpha helical domains of the MHC molecule that flank the peptide antigen binding pocket, as well as amino acids from the peptide itself.Our understanding of the nature of antigen-specific T-cell responses has been greatly improved by the discovery that antigen-specific TCR can be reversibly labeled with soluble peptide/MHC tetramers (Altman et al., 1996). Peptide antigen, b2-microglobulin and the MHC-I heavy-chain are folded together, and, via a biotinylation signal sequence at the C-terminus of the MHC-I heavy-chain, are linked covalently to …
