Aplastic anemia: Pathophysiology and treatment

我们的数据现已得到多个小组的证实，表明至少有两类造血干细胞(HSC)：原始或高质量干细胞，能够产生终生植入所有血液学谱系的干细胞；承诺或低质量干细胞，仅产生短期血液学重建。我们发现，高质量的HSC在直接培养时不能产生可分析的前体细胞，并且不能在移植后快速植入；然而，高质量的HSC能够在体外显著地扩增细胞，产生大量的前体细胞。我们推测，重型再生障碍性贫血(SAA)的免疫攻击是针对低质量的HSC，而不是高质量的HSC。高质量的HSC在SAA中的持续存在解释了大剂量环磷酰胺在不需要血液或骨髓移植的情况下在SAA中的成功。我们的初步数据表明，可以从SAA患者体内分离和体外扩增高质量的HSC。这项建议的总体目标是研究SAA的生物学，并计划开发这种疾病的新临床治疗方法。具体地说，我们计划：1)继续研究干细胞在SAA中的生物学，特别是允许其在体外扩增的方法； 2)研究SAA的免疫病理生理机制；3)开发新的临床试验，特别是针对SAA和急性白血病患者的自体HSC移植。

Our data, now confirmed by many groups, show that there are at least two classes of hematopoietic stem cells (HSC): primitive or high quality stem cells that are capable of producing life-ling engraftment of all hematologic lineages and committed or low quality stem cells that produce only short-term hematologic reconstitution. We found that high quality HSC do not produce assayable progenitors upon direct culture and are unable to produce rapid engraftment after transplantation; however, high quality HSC are capable of marked cellular expansion in vitro with the production of large numbers of progenitors. We hypothesize that the immune attack in severe aplastic anemia (SAA) is against low quality HSC, but spares high quality HSC. The persistence of high quality HSC in SAA would explain the success of high-dose cyclophosphamide without blood or marrow transplantation in this disease. Our preliminary data suggest that high quality HSC can be isolated, and expanded in vitro, from patients with SAA. The overall objective of this proposal is to study the biology of SAA with the plan to develop novel clinical treatments for the disease. Specifically, we plan to: 1) continue to study the biology of HSC in SAA, especially approaches that will allow their expansion in vitro; 2) investigate the immuno-pathophysiology of SAA; and 3) develop novel clinical trials, especially autologous HSC transplantation, for the patients with SAA and acute leukemia.