INDUCTION OF ANTIGEN SPECIFIC TOLERANCE OF T CELL COSTIMULATION

T细胞对MHC结合抗原的激活依赖于辅助性T细胞 来自抗原提呈细胞的刺激信号 T细胞受体与MHC抗原复合体的相互作用。在体外， 阻断B7/CD28或GP/CD40共刺激通路 会导致抗原特异性的无反应。虽然有能力 在体内诱导抗原特异性耐受将具有广泛的治疗作用 对人类的影响，试图通过以下方式诱导长期耐受 在体内阻断这些通路产生了好坏参半的结果。我们有 最近观察到，虽然封锁B7/CD28或 Gp39/CD40共刺激通路导致初级免疫抑制 体内反应，同时阻断两条途径导致 对一种可溶性蛋白抗原的持续抗原特异性耐受 正常的小鼠。根据这些观察，拟议的研究将 阐明这种效应背后的机制。具体来说，我们将 确定特定分子对信号的干扰是否 耐受性诱导的必要性，耐受性诱导是否 伴随着T细胞细胞因子产生的变化，以及这是否 这种影响也适用于其他有效的免疫原，包括单抗 抗体。我们还将确定是否中断共刺激 在初级抗原暴露期间是必要的诱导 耐受性，或者抗原特异性耐受性是否也可以在 抗原启动已经发生了。最后，拟议的研究将确定 阻断B7/CD28和gp39/CD40共刺激是否会导致 NZB/NZW狼疮易感小鼠的抗原特异性无反应性 这对耐受性诱导尤其具有抵抗力。这些研究将 为未来旨在鼓励宽容的提案提供基础 自身免疫小鼠的自身抗原。

T cell activation in response to MHC-bound antigen is dependent upon co- stimulatory signals from antigen presenting cells in addition to the interaction of the T cell receptor with the MHC-antigen complex. In vitro, interruption of either the B7/CD28 or the gp/CD40 co-stimulation pathway can result in antigen-specific unresponsiveness. While the ability to induce antigen-specific tolerance in vivo would have broad therapeutic implications in humans, attempts to induce long-term tolerance by interruption of these pathways in vivo has produced mixed results. We have recently observed that while blockade of either the B7/CD28 or the gp39/CD40 co-stimulatory pathways result in suppression of primary immune responses in vivo, simultaneous blockade of both pathways results in sustained antigen-specific tolerance to a soluble protein antigen in normal mice. Based on these observations, the proposed studies will clarify the mechanism underlying this effect. Specifically, we will determine whether interruption of signaling by specific BY molecules is necessary for tolerance induction, whether tolerance induction is accompanied by changes in T cell cytokine production, and whether this effect applies to other potent immunogens, including monoclonal antibodies. We will also determine whether interruption of co-stimulation during primary antigen exposure is necessary for the induction of tolerance, or whether antigen-specific tolerance can also be induced after antigen priming has occurred. Finally, the proposed studies will determine whether interruption of B7/CD28 and gp39/CD40 co-stimulation can result in antigen-specific unresponsiveness in NZB/NZW lupus-prone mice, a strain that is particularly resistant to tolerance induction. These studies will provide the basis for future proposals aimed at inducing tolerance to auto-antigens in autoimmune mice.