BIOCHEMICAL MODULATION OF IMMUNE RESPONSE IN VIVO AND IN VITRO

免疫细胞的正常发育和功能 需要腺苷脱氨酶（ADA）活性。缺席或低水平 ADA在人类中的浓度导致严重的联合免疫缺陷 （SCID），其特征是胸腺发育不全，T 淋巴细胞耗竭和自身免疫。ADA SCID目前 只能用细胞内积累的 腺苷。 我们对腺苷受体的研究结果 表明T细胞表面的A2 a受体可能向 阻断胸腺细胞分化和 存活的成熟T细胞的条件下，导致积累 细胞外腺苷我们最近和正在进行的实验是 旨在检验免疫病理学 腺苷浓度增加的影响 ADA缺乏至少可以部分解释为细胞外 腺苷触发信号。我们证明了在一定条件下 ADA缺乏时，细胞外腺苷拮抗 TCR触发的信号传导，并阻断 活化标志物和胸腺细胞中的早期活化事件。在 ADA缺乏的条件下，长期（长达4天）生存的 TCR触发的胸腺细胞在体外是通过阻断 腺苷转运蛋白介导的毒性蓄积 胞内腺苷然而，存活的胸腺细胞 非活化表型是由于外泌素介导的， TCR拮抗信号传导。因此，实验数据是 与模型一致，其中细胞内毒性 腺苷主要负责淋巴细胞耗竭，而 细胞外腺苷干扰正常分化， 这些20-30%的T细胞在体内存活， ADA缺乏症。我们认为T细胞耗竭， 免疫缺陷和自身免疫也可能是由于 细胞外腺苷（extAdo）诱导的信号传导，其抑制 抗原受体（TCR）信号传导，因此影响 TCR驱动的胸腺细胞的阳性和阴性选择。而这 反过来，可能导致抗原受体库的变化， 免疫缺陷，腺苷受体的这种特性表明 对ADA SCID发病机制的深入了解， 由于两种独立的（细胞内和细胞外）机制 腺苷的作用。此外，已证实的细胞外 腺苷介导的信号转导在ADA SCID的机制中将 指出腺苷受体作为新的免疫药理学 治疗这种疾病的目标。

Normal development and functions of immune cells require adenosine deaminase (ADA) activity. Absence or low levels of ADA in humans result in severe combined immunodeficiency (SCID), which is characterized by hypoplastic thymus, T lymphocyte depletion, and autoimmunity. ADA SCID is currently explained only by intracellular lymphotoxicity of accumulated adenosine. The results of our studies of adenosine receptors indicated that A2a receptors on the T cell surface may signal to block both thymocyte differentiation and effector functions of surviving mature T cells in conditions that lead to accumulation of extracellular adenosine. Our recent and ongoing experiments are designed to test the hypothesis whether the immunopathological effects of increased concentrations of adenosine in conditions of ADA deficiency can be at least partially explained by extracellular adenosine- triggered signaling. We demonstrated that in conditions of ADA deficiency, extracellular adenosine antagonizes TCR-triggered signaling and blocks the upregulation both of activation markers and of early activation events in thymocytes. In conditions of ADA deficiency, long-term (up to 4 days) survival of TCR-triggered thymocytes in vitro was accomplished by blocking the adenosine transporter-mediated accumulation of toxic intracellular adenosine. However, the surviving thymocytes had nonactivated phenotype because of extAdo-mediated, TCR-antagonizing signaling. Thus, the experimental data are consistent with the model where the intracellular toxicity of adenosine is mostly responsible for lymphocyte depletion, whereas extracellular adenosine interferes with normal differentiation and functioning of those 20-30% of T cells which do survive in conditions of ADA deficiency. We propose that T cell depletion, immunodeficiency, and autoimmunity could also be due to extracellular adenosine (extAdo)-induced signaling, which inhibits the antigen receptor (TCR) signaling and therefore affects the TCR-driven positive and negative selection of thymocytes. This, in turn, may lead to changes in antigen receptor repertoires and to immunodeficiency, such properties of adenosine receptors suggest an expanded understanding of pathogenesis of ADA SCID as being due to two independent (intracellular and extracellular) mechanisms of adenosine action. In addition, a proven role of extracellular adenosine-mediated signaling in mechanisms of ADA SCID will point to adenosine receptors as novel immunopharmacological target in treatment of this disease.