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效淋巴细胞清除抗体。最近，人们已经认识到，T细胞在淋巴细胞减少的环境中经历稳态扩增。此外，作为稳态增殖的结果，甚至先前的幼稚T细胞也可以获得记忆细胞的表型和功能特征，包括在不需要CD 28共刺激的情况下响应低浓度抗原的能力。使用小鼠系统的淋巴细胞耗竭程度的模型达到临床上，我们已经发现，残留的非耗尽的T细胞进行稳态扩张。我们还发现，稳态扩张通过阻断CD 28：B7和/或CD 154：CD 40途径诱导对耐受诱导的长期抗性，这两种途径都不能阻断稳态增殖。此外，耐受性抗性是显性的（即，它可以过继性转移到幼稚小鼠）。这些发现与记忆T细胞的已知行为以及记忆细胞通过阻断CD 28和/或CD 154抵抗耐受诱导的已知能力一致。 我们的工作模型是T细胞的稳态扩增诱导至少一个记忆样细胞亚群的发育，其随后干扰耐受诱导。我们的长期目标是识别这种细胞或细胞，并开发有针对性的方法来实现耐受性。虽然传统上已经证明耐受记忆细胞是相当困难的，但最近的数据表明，“新的”共刺激受体ICOS和OX 40（CD 134）是非常有前途的靶点。在目标#1中，我们将定义“稳态后”抗性细胞使用的表面表型和共刺激受体。特别是，我们假设ICOS和CD 134都将在稳态增殖T细胞的活化、增殖和存活中发挥重要作用。目的#2将检验推论假设，即阻断这些途径（和/或目的#1中鉴定的其他途径），沿着B7和/或CD 154，可抑制稳态增殖并克服对稳态增殖T细胞介导的移植耐受性的抗性。总的来说，这些研究将是开发补充淋巴细胞清除方法的重要步骤，并使其能够用于诱导耐受。这些方法也可能证明在建立T细胞记忆的环境中有价值，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.