Recently the role of metabolic signaling pathways has emerged as playing a critical role in dictating the outcome of T cell responses. The uptake and metabolism of the amino acid glutamine is essential for effector T cell activation. Since the growth and expansion of tumor cells relies on similar anabolic and metabolic requirements, we hypothesized that glutamine blockage might represent a promising strategy to promote allograft survival while inhibit tumor growth. 6-Diazo-5-oxo-L-norleucine (DON) was used as a glutamine antagonist. First, an in vitro study of T cell proliferation was performed to examine the ability of glutamine antagonism to inhibit T cell proliferation. Then we investigated whether DON could prolong allograft survival and inhibit tumor growth by using a fully MHC-mismatched mice full thickness skin transplantation model and a mice TC-1 tumor-bearing model. The proliferation study demonstrated that DON inhibited effector T cells proliferation in a dose-dependent manner. We found a marked prolonged graft median survival time and significant tumor inhibition for mice that received DON compared to those that received no treatment.

These results highlight that targeting glutamine metabolism can promote allograft acceptance in a long tumor-free period.

最近，代谢信号通路的作用已在决定T细胞反应结果中起关键作用。氨基酸谷氨酰胺的摄取和代谢对于效应器T细胞活化至关重要。由于肿瘤细胞的生长和扩增依赖于相似的合成代谢和代谢要求，因此我们假设谷氨酰胺阻断可能代表了一种促进同种异体移植存活同时抑制肿瘤生长的有前途的策略。将6-重氮基5-氧代-L-正亮氨酸（DON）用作谷氨酰胺拮抗剂。首先，进行了T细胞增殖的体外研究，以检验谷氨酰胺拮抗作用抑制T细胞增殖的能力。然后，我们调查了DON是否可以通过使用完全不匹配的MHC小鼠全厚度皮肤移植模型和TC-1荷瘤小鼠模型来延长同种异体移植的存活并抑制肿瘤的生长。增殖研究表明，DON以剂量依赖性方式抑制效应T细胞增殖。我们发现接受DON的小鼠与未接受治疗的小鼠相比，移植物的中位存活时间显着延长，并且对肿瘤的抑制作用明显。

这些结果表明，靶向谷氨酰胺代谢可在较长的无肿瘤时期内促进同种异体移植的接受。