Hyaluronan as an innate ligand that induces inflammation after transplantation

描述（由申请人提供）：先天免疫系统的成分可能导致长期同种异体移植物耐受性的损害。然而，触发先天免疫系统启动同种异体移植排斥反应的分子激活因子是难以捉摸的。我们之前的工作表明，通过MyD88（一种天然免疫细胞上大多数Toll样受体下游的接头蛋白）传递的信号可阻止移植耐受。此外，我们有初步证据表明透明质酸（HA）是一种先天配体，可激活MyD88炎症通路，启动同种异体移植排斥和移植耐受抵抗。我们假设，不同组织中HA表达水平的差异可以解释为什么一些器官，如皮肤，表现出移植耐受性受损，而其他组织，如心脏异体移植，易受耐受性诱导。破译这些差异可以为在损伤部位（即同种异体移植物内）抑制先天免疫反应的新疗法的产生提供信息。在本提案的目的1中，我们将采用药理学方法阻断急性移植排斥和移植耐受实验模型中的HA活性，其中MyD88信号对移植排斥至关重要。在Aim 2中，我们将产生在同种异体皮肤移植物中诱导删除HA的小鼠。该小鼠模型将为未来确定HA是否介导MyD88依赖性同种异体皮肤移植排斥的实验提供有用的资源。我们将通过产生心脏组织内HA过度表达的小鼠来补充这种方法。这将使我们能够检查HA过度表达是否足以损害同种异体心脏移植的移植耐受性。因此，这一提议将产生新的试剂来检查HA在急性移植排斥和移植耐受诱导中的作用。此外，这些资源也会影响HA可能发挥主要作用的其他炎症模型。

DESCRIPTION (provided by applicant): Components of the innate immune system can contribute to impairment of long term allograft tolerance. However, the molecular activators that trigger the innate immune system to initiate allograft rejection are elusive. Our prior work demonstrates that signaling via MyD88 an adaptor protein downstream of most Toll like receptors on innate immune cells, prevents transplant tolerance. In addition, we have preliminary evidence to suggest that hyaluranan (HA) is an innate ligand that activates the MyD88 inflammatory pathway to initiate allograft rejection and transplant tolerance resistance. We hypothesize that differential HA expression levels in various tissues may explain why some organs, such as the skin, exhibit impaired transplant tolerance, while other tissues, e.g. cardiac allografts, are susceptible to tolerance induction. Deciphering such differences could inform on the generation of novel therapies to inhibit the innate immune response at the site of injury (i.e., within the allograft). In Aim 1 of this proposal, we will employ pharmacological approaches to block HA activity in experimental models of acute transplant rejection and transplantation tolerance for which MyD88 signaling is critical for graft rejection. In Aim 2, we will generate mice in which HA is inducibly deleted within skin allografts. This mouse model will be a useful resource for future experiments to determine if HA mediates MyD88 dependent rejection of skin allografts. We will complement this approach by generating mice in which HA is over-expressed within cardiac tissue. This will allow us to examine whether HA over-expression is sufficient to impair transplant tolerance of cardiac allografts. Hence, this proposal will generate novel reagents to examine the role of HA in acute graft rejection and transplant tolerance induction. Moreover, these resources would also impact other models of inflammation for which HA may play a major role. PUBLIC HEALTH RELEVANCE: Both experimental and clinical studies have revealed that the innate immune system contributes to acute rejection of organ allografts and transplant tolerance resistance. However, we do not know the nature of the substances that activate the innate system after organ transplantation. This proposal will examine whether a putative innate ligand, hyaluronan, is critical for acute allograft rejection and transplant tolerance resistance through pharmacological approaches and through generation of novel mice with modulated hyaluronan expression.