Targeted proteinase inhibitors in the study of antigen processing

脊椎动物对病毒、细菌或其他微生物的感染作出非常特殊的免疫反应，以防止入侵的生物体繁殖和引起疾病。这些反应是所有疫苗发挥作用的基础。这种反应是由一种叫做淋巴细胞的细胞进行的，它约占所有白细胞的20%。最著名的淋巴细胞类型是B细胞，它们产生抗体，这种分子紧密地附着在单个病毒或细菌成分的表面，阻止它们工作，或者将它们定位为吞噬细胞的目标。然而，另一种类型的淋巴细胞，CD4 T淋巴细胞，对大多数免疫反应也是必不可少的，因为它在组织不同白细胞之间的合作中起着重要作用。这种细胞类型的极端重要性在艾滋病中得到了强调，艾滋病是一种艾滋病毒导致CD4淋巴细胞破坏的疾病，使身体容易受到各种感染。CD4 T淋巴细胞能够识别数量惊人的不同感染。然而，它们的识别系统是这样的，它只能识别病毒或细菌蛋白质的片段，如果这些蛋白质首先被称为蛋白酶的酶切成小块。本研究的目的是找出哪一种蛋白酶在这一过程中起重要作用，以及如何抑制它们的活性来改变免疫反应。为此，我们将使用已知能抑制各种类型蛋白酶（抑制剂）的化学物质，并测试它们对各种免疫反应的影响，包括对寄生虫疟疾的免疫反应。我们现有的抑制剂对分离的蛋白酶效果很好，但它们通常不溶于水或血液，不能很好地到达免疫系统的正确细胞或渗透到正确的细胞室。因此，我们将制造出更好的抑制剂，把它们附着在更大的“载体”分子上，这样就能有效地、有选择地将它们运送到体内正确的细胞上。这些研究的结果将增加我们对免疫系统如何工作的理解，从而最终有助于开发更好的方法来预防感染。

Vertebrates respond to infections with viruses, bacteria or other microorganisms by very specific immunological responses, which act to prevent the invading organisms from multiplying and causing disease. These responses are the basis on which all vaccines work. The responses are carried out by cells called lymphocytes, which represent about 20% of all white blood cells. The most well known type of lymphocyte are called B cells and make antibody, molecules which attach tightly to the surface of individual viral or bacterial components, and stop them working, or target them for destruction by phagocytes. Another type of lymphocyte, however, the CD4 T lymphocyte, is also essential for most immune responses, because of its role in organising the co-operation between different white blood cells. The vital importance of this cell type has been highlighted by AIDS, a disease in which HIV virus leads to the destruction of the CD4 lymphocyte, leaving the body susceptible to all sorts of infections. CD4 T lymphocytes are able to recognise a bewildering number of different infections. However, their recognition system is such that it can only recognise pieces of viral or bacterial proteins if the proteins are first cut up into small sections by enzymes called proteinases. The aim of this study is to find out which type of proteinase is important in this process, and how inhibiting their activity may be used to change the immunological response. For this purpose, we will use chemicals which are known to inhibit various types of proteinases (inhibitors) and test them on various immunological responses, including the immune response to the parasite malaria. The inhibitors we have available work well with isolated proteinases, but they are often insoluble in water or blood and not good at reaching the right cells of the immune system or penetrating into the right cellular compartment. We will therefore make better versions of these inhibitors, by attaching them to larger 'carrier' molecules which will be able to carry them efficiently and selectively to the right cell within the body. The results of these studies will add to our understanding of how the immune system works, and thus ultimately help to develop better ways to prevent infection.