Myelodysplasia

本年度报告因主要负责该领域工作的Sloand博士意外去世而缩短。 在脊髓发育不良的努力是在三个方面：1。临床试验，主要针对低风险骨髓增生异常综合征的免疫调节治疗; 2。采用体外方法研究免疫抑制治疗的血液学反应机制; 3.炎症在诱导染色体不稳定性（如非整倍体）中作用的实验室研究。 此外，分支还在选定的高危MDS患者中开展了细胞周期蛋白D抑制剂ON 1910的临床研究。 在临床研究中，我们完成了检查alumtuzimab（Campath;一种针对CD 52的单克隆抗体）在选择的免疫抑制应答概率高的患者中的效用的方案。 概率算法是基于我们在MDS患者中使用马ATG加环孢菌素的丰富经验。 在我们最近发表的研究中，22例主要为年轻和HLADR 15的患者中，近80%对Alemtuzimab表现出有临床意义的血液学应答。 除了实现输血独立性和足够的白色血细胞计数外，一些患者还令人惊讶地显示异常细胞遗传学恢复正常，原因不明。 根据我们的ATG经验和其他人的经验，加上这项新的Alemtuzimab试验，免疫抑制治疗似乎适用于选定的MDS患者，可以诱导血液学应答和延长生存期。 在其他临床研究中，ON 1910在患有更晚期疾病的MDS患者中进行了测试。 这种药物也在淋巴瘤中进行了研究，确实在一些患者中导致了短暂的血液学改善，而没有明显的毒性作用。 辅助研究表明，ON 1910在体内实现了对细胞的预期分子效应。 在实验室中，针对MDS的8三体形式中的造血的免疫细胞抑制机制的广泛工作随着实验的发表而完成，所述实验显示在该综合征中的细胞毒性淋巴细胞的至少一个靶标是WT 1雄激素。 WT 1是已知的肿瘤抗原，在正常干细胞中表达，并且在一些白血病细胞中以更高水平表达。 我们的实验表明，在三体8 WT 1过度表达的机制，可能继发于基因剂量效应的c-myc（位于三体8），导致免疫细胞识别，无辜的旁观者杀死正常造血细胞，和进化的三体8克隆抗凋亡。 通过生物制剂如ATG和Campath减轻免疫介导的细胞杀伤可以减轻正常的造血作用并改善血细胞计数。 在单独的实验室实验中，我们更广泛地探讨了炎症与染色体不稳定性之间的关系。 在这些实验中，将总淋巴细胞或淋巴细胞亚群（分离的CD 4和CD 8细胞）添加到自体或HLA错配的靶骨髓细胞中。 暴露几天后，使用原位杂交评估骨髓细胞染色体不稳定性的证据。 这些实验表明，暴露于HLA错配效应细胞导致非整倍体细胞的增加，主要是单体7，但也有三体8。 这种效应由CD 8细胞而不是CD 4细胞介导，并由细胞因子如γ-干扰素增强。 目前的实验是针对获得更强大的和验证性的数据和辨别的机制，特别是加速端粒磨损发生的可能性，由于淋巴细胞攻击下的T细胞增殖增加。

This annual report is abbreviated due the unexpected death of Dr. Sloand, who is largely responsible for work in this area. Efforts in myelodysplasia were in three areas: 1. Clinical trials, directed mainly towards immunomodulatory therapy of low risk myelodysplastic syndrome; 2. Investigation of the mechanism for hematologic response to immunosuppressive therapy, using in vitro methods; 3. Laboratory studies of the role of inflammation in inducing chromosome instability, such as aneuploidy. Additionally, the Branch has performed clinical studies of an inhibitor of cyclin D, ON1910, in selected patients with high risk MDS. In clinical studies, we completed protocols examining the utility of alumtuzimab (Campath; a monoclonal antibody directed to CD52) in patients selected for a high probability of response to immunosuppression. The probability algorithm was based on our extensive experience with horse ATG plus cyclosporine in patients with MDS. In our recently published study, almost 80% of 22 patients who were mainly younger and HLADR15 showed a clinically meaningful hematologic response to alemtuzimab. In addition to achieving transfusion-independence and adequate white blood cell counts, several patients also surprisingly showed reversion of abnormal cytogenetics to normal, for unexplained reasons. Based on our ATG experience and that of others plus this new trial of alemtuzimab, immunosuppressive therapy would appear appropriate for selected patients with MDS, in whom it can induce hematologic response and prolonged survival. In other clinical studies, ON1910 was tested in MDS patients with more advanced disease. The drug, which has also been studied in lymphoma, did lead to transient hematologic improvement in some patients without pronounced toxic effects. Ancillary studies showed that ON1910 achieved the expected molecular effects on cells in vivo. In the laboratory, extensive work directed to the mechanism of immune cell suppression of hematopoiesis in the trisomy 8 form of MDS were completed with the publication of experiments showing that at least one target of cytotoxic lymphocytes in this syndrome is a WT1 androgen. WT1 is known tumor antigen, expressed in both normal stem cells and at higher levels in some leukemic cells. Our experiments suggest a mechanism in trisomy 8 of WT1 over expression, probably secondary to a gene dosage effect of c-myc (located on trisomy 8), leading to immune cell recognition, innocent bystander killing of normal hematopoietic cells, and evolution of a trisomy 8 clone resistant to apoptosis. Relief of immune-mediated cell killing by biological agents such as ATG and Campath can relieve normal hematopoiesis and improve blood counts. In separate laboratory experiments, we have pursued more generally the relationship between inflammation and chromosome instability. In these experiments, the total lymphocytes or lymphocyte subpopulations (separated CD4 and CD8 cells) were added to autologous or HLA-mismatched target bone marrow cells. After several days of exposure, the bone marrow cells were assessed for evidence of chromosome instability, using in situ hybridization. These experiments have suggested that exposure to HLA-mismatched effector cells leads to an increase in aneuploid cells, mainly monosomy 7 but also trisomy 8. This effect is mediated by CD8 rather than CD4 cells and enhanced by a cytokine such as gamma-interferon. Current experiments are directed towards obtaining more robust and confirmatory data and discerning a mechanism, especially the possibility that accelerated telomere attrition occurs as a result of increased T cell proliferation under lymphocyte attack.