[转帖]免疫耐受和免疫排斥新机制

IC

美国Pennsylvania大学医学院科学家最近发现免疫细胞自我“决定”变得活跃或不活跃的机制，这有助于癌症，自身免疫疾病和器官移植排异的治疗。

??病理和药学教授Gary A. Koretzky在最新的一期《Nature Immunology》上描述了T细胞是怎样不对目标细胞或蛋白质发生反应的。他们发现，一种叫做甘油二酯（DAGs）的脂肪酸以及一种酶是这一过程的关键因素。

??免疫T淋巴细胞能识别身体的入侵者，如病毒，细菌，癌细胞或过敏原。正常情况下，T细胞会由一系列复杂信号激发，最后破坏外来物。但是有些T细胞处于未激发状态，这一过程保护免疫细胞自身和其它正常细胞不受攻击。

??Koretzky表示：“T淋巴细胞怎样被激发是免疫学的主要问题之一。我们的研究发现DAGs是这些细胞对入侵者反应的关键。但是当DAGs被甘油二酯酶（DGKs）作用后，T细胞不再对目标作出反应。”

??这一结果是通过研究去除了DGKs的小鼠后得出的。虽然这些小鼠的T细胞在大部分时候很正常，但DAGs无法得到DGKs的作用，所以T细胞会对外来抗原过度反应。

??一种本不该引发免疫反应的葡萄球菌毒素使小鼠T细胞发生了过度反应。这证明是DGK的缺乏造成的。而且T细胞制造了多于正常五倍的免疫因子。

??过度反应如果能被控制，就能对身体有好处，例如T细胞能消灭癌细胞。研究者正在继续研究这些小鼠，看看它们是否能将癌细胞识别为入侵者并消灭它们。

英文原文：

Penn researchers provide insights into how the immune system avoids attacking itself

A finding by University of Pennsylvania School of Medicine researchers about how immune cells “decide” to become active or inactive may have applications in fighting cancerous tumors, autoimmune diseases, and organ transplant rejection. Pathology and Laboratory Medicine Professor Gary A. Koretzky, MD, PhD, director of the Signal Transduction Program at Penn’s Abramson Family Cancer Research Institute describes, in the current issue of Nature Immunology, one way in which T cells may develop tolerance to host cells and proteins. Koretzky and colleagues found that small fatty acids called diacylglycerols (DAGs), and the enzymes that metabolize them, are critical players in the molecular pathway that leads to activity versus inactivity.

Immune cells called T lymphocytes recognize invaders in the body, such as viruses, bacteria, tumor cells, or allergens. Normally, T cells are activated by a complex series of signals that end with the destruction of the foreign substance. However, some T cells are not activated, in fact they are inactivated by a process called anergy or tolerance. This process helps prevent immune cells from attacking themselves and other normal cells and proteins.

“How T lymphocytes become activated or inactivated has been one of the major questions in the field of immunology,” says senior author Koretzky. “Our discovery shows that DAGs are critical for T-cell activation so these cells can respond to foreign invaders. However, when DAGs are chemically modified by enzymes called diacylglycerol kinases, T cells become tolerant or unresponsive to foreign substances and to self.”

The discovery was made by studying mice that had been engineered to lack diacylglycerol kinases (DGKs). Although T cells from these knock-out mice were normal in most respects the induction of tolerance was impaired. When DAGs could not be chemically altered because the DGKs were absent, the T cells were hyperreactive to foreign antigens and could not be made tolerant to host cells.

Hyperreactivity was shown when purified T cells from DGK knockout mice were stimulated by antigen in a culture dish. The failure of the T cells to become tolerant was demonstrated in experiments where mice were treated with a toxin from staphylococcal bacteria that should have induced unresponsiveness. Instead, the T cells produced about five times more of an immunity factor than did cells from normal mice.

The hyperreactive state, if controlled, might be beneficial to the body under some circumstances; for example, some T cells might be made more effective at eliminating tumors. The research team is continuing to study DGK knock-out mice to see if they are more resistant to tumors. If the hyper-reactive T cells in these mice recognize the tumor cell as a foreign invader, then the tumor might be eliminated or reduced. Conversely, if the tolerant state could be induced in a controlled manner, it might benefit individuals with autoimmune disease or help prevent rejection of transplants.
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