新型疗法或可改变慢性感染中力量平衡

tonychant

当你遭受急性感染例如说流感时，机体通常会做出反应，协调免疫细胞增殖，发动攻击快速清除病原体。在完成任务后，免疫系统解除战备状态，留下一群记忆细胞充当哨兵，万一再度发生感染这些细胞则可快速调动免疫系统。

这就是接种疫苗起作用的原因，也是理论上曾得过一次水痘的人将永远不会再得这种疾病的原因。

那么慢性感染的情况又如何？在丙型肝炎、HIV和疟疾等情况下，身体和病原体基本上会长期对抗处于一种僵持状态，任一方都无法获得优势。然而，随着时间的推移，免疫细胞被“耗尽”，免疫系统崩溃，最终病原体会占据优势。

现在，来自宾夕法尼亚大学Perelman医学院的研究人员在一项新研究揭示了慢性感染过程中发生的事件。研究结果还表明一种新型的治疗方法或许可用于改变慢性感染中的力量平衡。该研究发表在11月30日的《科学》（Science）杂志上。

免疫学研究所主任及微生物学副教授E. John Wherry博士说：“慢性感染时存在一种平衡状态，使得你能够维持对感染的控制，但又不足以让你完全清除感染。”

由Wherry领导的研究小组利用一种慢性病毒感染小鼠模型描绘了当免疫系统处于扩展战备状态时出现的T细胞反应。他们发现了两种不同类型的病毒特异性CD8+ T细胞：一种表达高水平的T-bet蛋白，另一种表达高水平的Eomes蛋白。这两种细胞协同作用控制了感染。

具体来说，他们发现两种细胞群似乎是一种祖细胞与成熟（progenitor-mature）细胞的关系。T-bet表达细胞似乎具有祖细胞功能，也就是干细胞。这些细胞既可再生并维持病毒特异性T细胞库。也能分裂并分化形成成熟的、终末分化的Eomes表达细胞。Eomes表达细胞能够更有效对抗病毒，但却无法增殖。

研究人员发现这两种细胞亚群往往将自身局限在感染动物的不同解剖部位。T-bet阳性细胞存在于血液和脾脏中，而Eomes细胞存在于肝脏、骨髓和肠道中。

研究人员通过敲除一种或另一种蛋白导致任一细胞亚群缺失，发现均可以引起免疫系统对抗感染的能力下降，转而有利于病原体。

根据Wherry所说，这些数据可以帮助解释在丙型肝炎等慢性感染中观察到病毒特异性T细胞逐渐丧失。

“我们的数据表明在一些慢性感染过程中免疫控制丧失的原因在于：长期对这种祖细胞-成熟细胞关系施加压力导致了祖细胞库耗竭，”他说。

更为重要的是，研究揭示了可用于对抗，或至少能更好控制慢性感染的新治疗途径。例如，他说：“如果我们能够更长时间维持这些祖细胞，或诱导终末子细胞进一步分裂，我们或许能够改变平衡，维持对感染的控制，”他说。

Wherry实验室正在对候选分子信号通路展开研究，以确定它们控制及或许调节两种T细胞群的效力。

StephenW

•                 Penn Team Identifies Molecular Root of "Exhausted" T Cells in Chronic Viral Infection                             
  • News Release
    
  
  

                                                    PHILADELPHIA — When you get an acute infection, such as  influenza, the body generally responds with a coordinated response of immune-cell  proliferation and attack that rapidly clears the pathogen. Then, their mission  done, the immune system stands down, leaving a population of sentinel memory  cells to rapidly redeploy the immune system in the event of reinfection.
                                                            Related Links
               

• Perelman School of Medicine at the University of Pennsylvania
• University of Pennsylvania Health System
  

              
                                 This is why vaccination works, and it’s why, in theory at  least, people who have had the chicken pox once will never get it again.
But what about chronic infection? In the case of such  pathogens as hepatitis C, HIV, and malaria, the body and the pathogen  essentially fight to a prolonged stalemate, neither able to gain an advantage.  Over time, however, the cells become “exhausted” and the immune system can  collapse, giving the pathogen the edge.
Now, a new study by researchers at the Perelman  School of Medicine,  University of Pennsylvania, is showing just  how that happens. The findings also suggest a novel therapeutical approach that  might be used to shift the balance of power in chronic infections. The study  appears in the November 30 issue of Science.
The team, led by E. John Wherry, PhD,  associate professor of Microbiology and Director of the Institute for  Immunology, used a mouse model of chronic viral infection to map the T-cell  response that arises when the immune system is on an extended war footing. They  found that two distinct classes of virus-specific CD8+ T cells – one expressing  high levels of the protein T-bet, the other expressing high levels of the  protein Eomes, work together to keep the infection in check.
Specifically, they found that the two cell populations  appear to have a progenitor-mature cell relationship. The T-bet-expressing  cells appear to function as the progenitor cells – that is, stem cells. These  cells divide both to regenerate and maintain the pool of virus-specific T cells.  But they also divide and differentiate to form mature, terminally differentiated  Eomes-expressing cells. These cells are more effective at fighting the virus  itself, but cannot replicate.
“There’s a balance, an equilibrium, which allows you to  maintain control over the infection but is insufficient to give you complete  clearance,” Wherry explains.
These two cell subpopulations tend to confine themselves to  different anatomic regions in the infected animals, the researchers found.  T-bet-positive cells were found in the blood and spleen, whereas Eomes cells  were found in the liver, bone marrow, and gut.
Loss of either subpopulation, which the researchers modeled  by deleting one or the other protein, reduces the immune system’s ability to  fight the infection, leading to a shift in favor of the pathogen.
According to Wherry, these data can help explain the gradual  loss of virus-specific T cells observed in such chronic infections as hepatitis  C.
“Our data suggest the reason for loss of immune control  during some chronic infections is that the long-term pressure on this  progenitor-mature cell relationship depletes the progenitor pool,” he says.
What’s more, the study suggests new therapeutic avenues that  can be used to fight, or at least better control, chronic infections. For  instance, he says, “If we can maintain these progenitor cells longer, or coax  the terminal progeny to divide further, we may be able to  shift the balance and maintain control of the infection,” he says.
Wherry’s lab is now studying candidate molecular pathways to  determine their efficacy in controlling, and perhaps modulating, these two T-cell  populations.

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