Role of Innate Immunity in Transplantation Tolerance

通过Toll样受体(TLRs)的先天免疫是抵御微生物入侵的第一道防线，是 对于病原体检测是必不可少的。我们的初步数据，使用实验小鼠系统，也 表明TLR依赖免疫对同种异体免疫反应很重要，因为它允许 树突状细胞(DC)的最大功能，特别是产生促炎症细胞因子 随后启动TH1同种异体免疫。尽管这些影响对于拒绝未成年人是至关重要的 不匹配的同种异体皮肤移植对于完全同种异体皮肤和心脏的排斥反应不是必需的 异体移植。然而，先天免疫在移植耐受中的作用尚不清楚。因为一个 先前的报道，使用非移植的体外模型，证明了T调节细胞(T Reg)的功能 TLR刺激的DC的存在变化，我们的初步数据调查了先天的影响 移植耐受的免疫性，并表明重要的TLR信号MyD88的缺失 转接器是耐受性诱导的关键。我们提供的证据表明，这是通过监管机构 与CD4+CD25+T细胞数量增加和减少有关的机制 促炎环境。因此，这项建议将采用小鼠实验性移植模型， 将研究先天免疫缺陷促进移植耐受的机制。目标 本提案的第1部分将检查MyD88的缺失是否与耐受性协同工作 协议(共刺激封锁)，使平衡倾向于容忍，而不是免疫，由 增加T调节子的生成和功能。目标2将调查MyD88缺陷，通过 减少促炎细胞因子环境，增加T效应分子对调节的敏感性 导致耐受性诱导。因此，这项提案将批判性地解决是否缺少 与生俱来的MyD88信号促进移植耐受，这是一个以前在 移植。所产生的信息将支持移植和研究领域的新范式 有可能提供可移植到人类同种异体移植的未来疗法，并 自身免疫(例如，在耐受诱导时MyD88被阻断)。

Innate immunity via Toll Like Receptors (TLRs) is the first line of defense against microbial invasion and is essential for pathogen detection. Our preliminary data, using experimental murine systems, also demonstrates that TLR dependent immunity is important for alloimmune responses by allowing the maximal function of dendritic cells (DCs), specifically the production of proinflammatory cytokines that subsequently initiate TH1 alloimmunity. Although these effects are critical for the rejection of minor mismatched skin allografts they are not essential for the rejection of fully allogeneic skin and cardiac allografts. However, the role of innate immunity in transplantation tolerance remains unexplored. Since a prior report, using non-transplant in vitro models, demonstrated that T regulatory cell (T reg) function changes in the presence of TLR stimulated DCs, our preliminary data investigate the impact of innate immunity on transplantation tolerance and show that absence of MyD88, an important TLR signal adaptor, is critical for tolerance induction. We provide evidence that this occurs via a regulatory mechanism that is associated with increased numbers of CD4+CD25+ T cells and a reduced proinflammatory milieu. Therefore, this proposal will employ a murine experimental transplant model and will examine the mechanisms by which defective innate immunity facilitates transplantation tolerance. Aim 1 of this proposal will examine whether the absence of MyD88 operates in synergy with the tolerance protocol (costimulatory blockade), tipping the balance towards tolerance rather than immunity, by increasing the generation and function of T regs. Aim 2 will investigate whether MyD88 deficiency, by reducing the proinflammatory cytokine environment, increases T effector susceptibility to regulation leading to tolerance induction. Therefore, this proposal will critically address whether an absence of innate MyD88 signaling promotes transplantation tolerance, a previously unexplored concept in the field of transplantation. The information generated will support a new paradigm in the field of transplantation and has the potential to provide future therapeutics translatable to human allograft transplantation and autoimmunity (e.g., MyD88 blockade at the time of tolerance induction).