Homeostatic T Cell Expansion As A Barrier To Tolerance

描述(由申请人提供)：移植的临床和临床研究方案越来越多地在植入时使用强大的淋巴消耗抗体。最近，人们认识到T细胞在淋巴细胞减少的环境中经历内稳态扩增。此外，由于动态平衡的增殖，即使是以前的原始T细胞也可能获得记忆细胞的表型和功能特征，包括对低浓度抗原的反应能力，而不需要CD28共刺激。利用小鼠系统模拟临床上达到的淋巴耗竭程度，我们发现剩余的未耗尽的T细胞经历了动态平衡扩张。我们还发现，动态平衡的扩张通过阻断CD28：B7和/或CD154：CD40通路来诱导对耐受诱导的长期抵抗，但这两个通路都不能阻止动态平衡的增殖。此外，耐受性占主导地位(即，它可以过继地转移到幼小鼠身上)。这些发现与记忆T细胞的已知行为以及记忆细胞抵抗CD28和/或CD154阻断诱导耐受的已知能力是一致的。 我们的工作模型是，T细胞的稳态扩张诱导至少一个记忆样细胞子集的发展，这随后干扰了耐受诱导。我们的长期目标是识别这种细胞，并开发有针对性的方法来实现耐受性。虽然传统上对记忆细胞的耐受性被证明是相当困难的，但最近的数据表明，“新的”共刺激受体ICOS和OX40(CD134)是非常有希望的靶标。在目标1中，我们将定义“动态平衡后”耐药细胞所使用的表面表型和共刺激受体。特别是，我们假设ICOS和CD134都将在稳态增殖的T细胞的激活、增殖和生存中发挥重要作用。AIM#2将验证推论假设，即阻断这些途径(和/或AIM#1中确定的其他通路)以及B7和/或CD154可能会导致抑制稳态增殖，并克服由稳态增殖的T细胞介导的移植耐受。总的来说，这些研究将是开发补充淋巴枯竭的方法的重要步骤，并使其能够用于耐受诱导。这些方法在已建立的T细胞记忆的设置中也可能被证明是有价值的，例如可能发生在致敏受体中。

DESCRIPTION (provided by applicant): Clinical and clinical research protocols in transplantation are increasingly employing potent lymphodepleting antibodies at the time of engraftment. Recently it has been appreciated that T cells in a lymphopenic environment undergo homeostatic expansion. Moreover, as a result of homeostatic proliferation, even previously naive T cells may acquire phenotypic and functional characteristics of memory cells, including the ability to respond to low concentrations of antigen without a need for CD28 costimulation. Using mouse systems which model the degree of lymphodepletion achieved clinically, we have found that residual non-depleted T cells undergo homeostatic expansion. We also find that homeostatic expansion induces long-lived resistance to tolerance induction by blockade of the CD28:B7 and/or CD154:CD40 pathways, neither of which are able to block homeostatic proliferation. Moreover, tolerance resistance is dominant (i.e., it can be adoptively transferred to naive mice). These findings are consistent with known behavior of memory T cells, and the known ability of memory cells to resist tolerance induction by blockade of CD28 and/or CD154. Our working model is that homeostatic expansion of T cells induces the development of at least a subset of memory-like cells, which subsequently interfere with tolerance induction. Our long-term goals are to identify this cell or cells and develop targeted approaches to enable tolerance. While tolerizing memory cells has traditionally proven quite difficult, recent data suggests that the "new" costimulatory receptors ICOS and OX40 (CD134) are extremely promising targets. In aim #1, we will define surface phenotype and costimulatory receptors used by "post-homeostatic" resistant cells. In particular, we hypothesize that both ICOS and CD134 will play an important role in activation, proliferation and survival of homeostatically proliferating T cells. Aim #2 will test the corollary hypothesis, that blockade of these pathways (and/or others identified in aim #1), along with B7 and/or CD154 may result in inhibition of homeostatic proliferation and overcome the resistance to transplantation tolerance mediated by homeostatically proliferating T cells. Collectively these studies will be important steps towards the development of approaches that complement lymphodepletion, and enable it to be used for tolerance induction. These approaches may also prove valuable in the setting of established T cell memory, such as may occur in sensitized recipients.