It is hypothesized that OGF biotherapy may be safely administered in combination with gemcitabine to individuals with unresectable pancreatic cancer. The study includes two aims, the first is to evaluate the safety and toxicity of the combination of OGF and gemcitabine chemotherapy. The second aim of the trial is to study the efficacy of OGF and gemcitabine when used in combination.

开始日期2009-01-01

申办/合作机构

Hershey Medical Center

[+2]

NCT00706576

/ Completed临床1期IIT

Treatment of Unresectable Hepatocellular Cancer With Opioid Growth Factor: a Phase I Study

Hepatocellular cancer, one of the world's most deadly tumors, is associated with chronic liver injury and cirrhosis. With the increasing occurrence of viral hepatitis, the incidence of this cancer in the United States continues to rise. Surgical resection offers the only hope for cure; but sadly, few patients are candidates for surgery due to their liver disease. Liver transplant can be an effective treatment, but due to a scarcity of organs, most patients do not qualify for this therapy either. Patients who are not candidates for these procedures have very few therapeutic options as chemotherapy and radiation have little efficacy. New therapies are desperately needed.
Opioid Growth Factor (OGF) inhibits the growth of a number of cancer lines in vitro by a receptor-mediated mechanism. In pancreatic cancer this phenomenon has been well defined not only in vitro but in animal models. Based upon these findings, a phase I trial has been conducted demonstrating that OGF can be administered safely to patients with pancreatic cancer. The investigators hypothesize that administration of OGF will inhibit the course of cancer progression in human subjects with unresectable hepatocellular cancer and cirrhosis. As a first step in testing this hypothesis, the investigators propose a phase I trial to study the toxicity and pharmacokinetics of this therapy in patients suffering from inoperable hepatocellular cancer and cirrhosis.

开始日期2008-06-01

申办/合作机构

University of Missouri

[+1]

NCT00982696

/ Terminated临床2期IIT

Treatment of Advanced Head and Neck Cancer With Opioid Growth Factors: Phase II

This study will investigate the efficacy of opioid growth factor (OGF) on tumor size and survival in patients with head and neck cancer who have failed standard therapy.

开始日期2008-02-01

申办/合作机构

Hershey Medical Center

100 项与甲硫氨酸脑啡肽相关的临床结果

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100 项与甲硫氨酸脑啡肽相关的转化医学

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100 项与甲硫氨酸脑啡肽相关的专利（医药）

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5,546

项与甲硫氨酸脑啡肽相关的文献（医药）

2025-11-01·POULTRY SCIENCE

Research note: Peripheral administration of Met-enkephalin: Novel attenuation of the adrenal medullary and thyroidal stress responses in young female chickens

Article

作者: Scanes, Colin G ; Pierzchala-Koziec, Krystyna

Adrenal hormones play a critical response to stresses in poultry, livestock and other vertebrates. Moreover, there are stress effects on thyroid hormones. Plasma concentrations of epinephrine (EP), norepinephrine (NE), thyroxine (T₄) and triiodothyronine (T₃) were increased by restraint stress (placing pullets into a small cage in darkness) in 14-week-old pullets. There has been a complete dearth of publications on the effects of peripheral administered Met-enkephalin on endocrine systems in chickens. To remedy this, the effects of peripheral administration of Met-enkephalin per se was examined as was along with its ability to either potentiate or attenuate the responses to stress. Plasma concentrations of EP and NE were modestly increased in chickens receiving Met-enkephalin injection peripherally. The increase in plasma concentrations of EP, NE, T₃ and T₄ together with the decrease in reverse T₃ in chickens subjected to restraint stress were markedly attenuated in pullets receiving Met-enkephalin injection peripherally.

2025-03-16·CANCER INVESTIGATION

A Phase I Study of the Naturally Occurring Bioactive, Opioid Growth Factor, in Patients with Unresectable Hepatocellular Cancer

Article

作者: Waybill, Peter ; Li, Guangfu ; Staveley-O’Carroll, Kevin F. ; Smith, Jill P. ; Kaifi, Jussuf T. ; Kimchi, Eric T. ; Avella, Diego M. ; Gusani, Niraj J. ; Zagon, Ian S. ; Schreibman, Ian ; Jiang, Yixing ; McLaughlin, Patricia J.

Hepatocellular cancer (HCC), one of the world's most deadly tumors, and its incidence in the US continues to rise. Surgical resection/transplantation offers the only hope for cure; however, many patients are not candidates and have limited therapeutic options. Opioid growth factor (OGF) is a naturally occurring bioactive endogenous pentapeptide that inhibits growth of human HCC cell lines in vitro by a receptor-mediated mechanism and inhibits progression of tumors in nude mice. Based on these preclinical studies, we conducted a phase I clinical trial with dose escalation (standard 3 + 3 protocol) of OGF to determine the maximum tolerated dose in HCC patients with concomitant liver disease (NCT00706576). Fifteen doses were administered to 14 patients with a maximum 300 µg/kg dose. No Grade 3 toxicities were encountered in the study group. This dose exceeds the maximum tolerated dose reached in our previous phase I pancreatic cancer trial. We conclude that OGF can be safely administered to patients with HCC and concomitant liver disease without significant toxicities up to a dose of 300 µg/kg. The result of this trial provides data on toxicity and the pharmacokinetics of OGF in patients with HCC and liver disease and lays the groundwork for additional studies.

2024-09-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Modulation of endogenous opioid signaling by inhibitors of puromycin-sensitive aminopeptidase

Article

作者: Vince, Robert ; Singh, Rohit ; More, Swati S ; Dobariya, Prakashkumar ; Xie, Jiashu ; Williams, Jessica ; Rothwell, Patrick E ; Jiang, Rongrong ; Hanak, Filip

The endogenous opioid system regulates pain through local release of neuropeptides and modulation of their action on opioid receptors. However, the effect of opioid peptides, the enkephalins, is short-lived due to their rapid hydrolysis by enkephalin-degrading enzymes. In turn, an innovative approach to the management of pain would be to increase the local concentration and prolong the stability of enkephalins by preventing their inactivation by neural enkephalinases such as puromycin-sensitive aminopeptidase (PSA). Our previous structure-activity relationship studies offered the S-diphenylmethyl cysteinyl derivative of puromycin (20) as a nanomolar inhibitor of PSA. This chemical class, however, suffered from undesirable metabolism to nephrotoxic puromycin aminonucleoside (PAN). To prevent such toxicity, we designed and synthesized 5'-chloro substituted derivatives. The compounds retained the PSA inhibitory potency of the corresponding 5'-hydroxy analogs and had improved selectivity toward PSA. In vivo treatment with the lead compound 19 caused significantly reduced pain response in antinociception assays, alone and in combination with Met-enkephalin. The analgesic effect was reversed by the opioid antagonist naloxone, suggesting the involvement of opioid receptors. Further, PSA inhibition by compound 19 in brain slices caused local increase in endogenous enkephalin levels, corroborating our rationale. Pharmacokinetic assessment of compound 19 showed desirable plasma stability and identified the cysteinyl sulfur as the principal site of metabolic liability. We gained additional insight into inhibitor-PSA interactions by molecular modeling, which underscored the importance of bulky aromatic amino acid in puromycin scaffold. The results of this study strongly support our rationale for the development of PSA inhibitors for effective pain management.

项与甲硫氨酸脑啡肽相关的新闻（医药）

2025-10-06

·BioArt

2025诺奖深度观察 | Science杂志系统总结T细胞耐受最新进展

编者按：2025年10月6日，诺贝尔生理或医学奖颁发给了外周免疫耐受。获奖者为Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi “for their discoveries concerning peripheral immune tolerance.” 在漫长地时间中，生命体，尤其是脊椎动物 (Vertebrate)，进化出强大精妙的免疫系统构筑起生命的屏障。固有免疫系统(Innate immune system) 非特异性识别入侵者并做出快速的反应，守护机体的第一道防线。适应性免疫系统(Adaptive immune system) 则特异性地识别入侵者并制造“精准导弹”靶向清除异物。自从18世纪Edward Jenner使用牛痘治疗天花开始，人们就对适应性免疫应答展开一系列的研究。现在，我们知道T细胞和B细胞依赖于种类庞大的TCR和BCR识别入侵者，更伟大的是，这套系统可以应对几乎所有的大自然病原体以及随时发生变异的病原体并做出有效的应答。这无疑是大自然赋予的神奇力量。幸运的是，这套强大的武器系统在日常生活中并没有伤害机体自身。要知道的是，作为细胞本身，T细胞和B细胞并不能决定自己的TCR或BCR如何组装。但是，聪明的机体使用阴性选择去除大量针对自身抗原的T细胞和B细胞，这就是中枢耐受(Central tolerance)。然而，研究者发现阴性选择并不是完美的，在健康人群中依然存在针对自身抗原的T细胞或B细胞。但是，机体并没有受损，这说明存在一个外周的耐受(Peripheral tolerance) 机制调节可能泄漏的自身反应性免疫应答。但是目前我们对于这种外周耐受还知之甚少，例如何时(when)，何地(where)，如何(how) 产生外周免疫耐受？这些问题仍有待于研究。近日，来自美国纽约纪念斯隆-凯特林癌症中心的Alexander Y. Rudensky教授和Chrysothemis C. Brown教授在Science杂志上在线发表题为Spatiotemporal regulation of peripheral T cell tolerance的综述文章。该论文总结了T细胞耐受的最新研究进展，尤其关注肠道菌群耐受的建立机制，包括最新的耐受性抗原提成细胞和免疫调节淋巴细胞及这些细胞的分层发育(layered ontogeny)以及相应的耐受发育窗口期。另外，作者也强调肠道作为研究外周T细胞耐受的模型组织。 T细胞介导的免疫应答的基础是TCR识别抗原递呈细胞 (Antigen-presentation cells，APC) 上的MHC-抗原肽复合物，继而完成激活，增殖和分化。但TCR的组装是基因重排后随机产生的，因此，一个巨大的挑战是TCR如何区分自身抗原和外来抗原。一个重要的机制是中枢耐受，其可以通过阴性选择或产生免疫调节细胞初步完成耐受的建立。然而，中枢耐受并不是完美的，在健康人体或实验动物的外周依然存在自身反应性的T细胞，这就迫使外周具备其他的耐受机制防止自身免疫病的发生。不仅如此，T细胞也会遇到来自共生菌和食物来源的无害抗原，一旦这些抗原的耐受被打破，会引起异常的炎症性疾病，例如肠炎和食物过敏等。机制的研究离不开合适的模型，肠道提供了一个合适的研究免疫耐受的组织平台 (图一)。肠道存在大量的肠道菌群并时刻面临食物来源的抗原，因此，肠道必然存在合理的外周耐受机制。目前，通过无菌小鼠和基因工程菌等技术已经发现肠道特异的耐受性APC和Treg介导的免疫耐受，但是这种现象是否具有普适性仍有待于研究。另外，在肠道内，断奶期肠道菌群定植的顺序以及食物抗原进入的窗口期对于耐受建立的影响也值得研究，这可能帮助肠道耐受打破之后重新辅助建立肠道耐受以治疗相应的疾病。图一 T细胞反应性的外周调节传统观点认为外周T细胞耐受涉及细胞内源和外源机制。内源性的机制包括静息(quiescence)，忽视(ignorance)，无能(anergy)，耗竭(exhaustion)，衰老(senescence)和细胞死亡(cell death)。外源性的机制来自于免疫调节细胞，例如耐受性的APC和Treg。内源性和外源性机制之间存在相互交叉，例如T细胞抑制性信号造成T细胞对于外源性信号更加敏感。调控T细胞的反应性可能是抑制外周自身反应性T细胞的主要方式。健康的人外周中分离的自身反应性CD8+T细胞在体外对同源抗原保持低反应性【1】，小鼠中也存在类似的现象，即针对自身抗原的CD4+T细胞高表达anergy标记FR4 (folate receptor 4) 和CD73【2, 3】。此外，这些T细胞在遭遇同源抗原时更容易分化为Treg。但是，这种自身反应性T细胞的anergy是在胸腺还是外周形成，是否需要持续的信号维持仍不清楚。我们都知道T细胞的活化需要APC上CD80/86等共刺激信号，相应地，也存在CTLA4和PD-L1等共抑制信号进行调节，其背后的机制是T细胞免疫激活基序或免疫抑制基序传递的信号，这些共同协调控制机体对抗原的时空应答过程。一个典型的例子莫过于目前火热的肿瘤免疫疗法-免疫检查点阻断疗法 (immune checkpoint therapy，ICB therapy)。在接受PD-1或CTLA4阻断抗体的患者中常发生累及粘膜屏障组织和其他器官的严重免疫相关不良反应 (immune-related adverse events，iRAEs)，表现为外周耐受的打破引起的炎症性疾病，例如肠炎和心肌炎【4, 5】。 T细胞耗竭指的是在持续抗原刺激下发生的终末分化状态，表现为高表达抑制性受体PD-1等，代谢改变和效应响应功能进行性丢失【6】。由于常出现在肿瘤和慢性病毒感染中，耗竭似乎被认为是贬义词，是T细胞功能的丢失而非一种有益的适应。但其也参与到对外周自身抗原的耐受维持。一项研究表明，耗竭性T细胞除了缺失效应功能，也具有类似Treg的转录和代谢特征，可以通过CD39介导的腺苷抑制CD8+T细胞的免疫应答【7】。胸腺来源Treg和外周来源Treg的分工从上世纪60年代开启对Treg的研究以来，我们对于Treg介导的免疫调节有了深刻的理解。Treg缺失的小鼠会发生致死性的自身免疫，可以推测Treg在建立和维持耐受中发挥的重要作用。Treg通过多种方式行使功能，包括抑制性细胞因子产生和IL2竞争等非接触依赖的方式和诱导死亡，调节APCs等接触依赖性的方式。研究显示Treg在转录和功能层面表现出显著的异质性，研究人员将Treg分为胸腺来源 (thymus derived Treg，tTreg) 和外周来源 (peripheral derived Treg，pTreg)。pTreg对自身和外来抗原的调节，而tTreg更倾向于对自身抗原的调节。在胸腺中，AIRE表达的mTEC驱动tTreg的发育，AIRE或mTEC缺陷的小鼠胸腺中tTreg数量降低且伴随tTreg TCR库的转变，即部分原本属于tTreg的TCR出现在conventional CD4+T(Tcon) 细胞中，由此导致严重的自身免疫性疾病。事实上，很多证据支持tTreg的关联抑制 (linked suppression) 模型，即tTreg抑制抗原和组织相匹配的的Tcon【8】。现在，我们知道naïve T细胞可以在外周经过合适的刺激分化为pTreg，尤其在遭遇共生菌和饮食抗原刺激时。有趣的是，在结肠，共生菌诱导分化的pTreg具有独特的转录特征，其高表达RORγt。无菌饲养的小鼠肠道缺少这一群Treg则说明了肠道菌群在诱导pTreg的重要性。另外，研究报道这些肠道菌群依赖的pTreg可以进入肠道上皮间定居，并丢失foxp3表达但仍然具有免疫调节作用，称之为CD4IELs (intraepithelial CD4+ T cells)，这进一步说明了组织环境在决定免疫调节模式的重要性。实验证据表明肠道pTreg缺陷会引起肠道菌群依赖的肠炎，具体来说，Th1，Th17，中性粒细胞等炎症细胞和肥大细胞以及IgA+浆细胞浸润增多。另外，肠道pTreg缺陷的小鼠也会易感口服抗原引起的过敏和炎症。这些表型均证明肠道pTreg对于肠道稳态的重要调节作用。值得注意的是，最近一篇发表在Immunuty的文章指出肠道RORγt+pTreg可以从肠道迁出至远端器官，包括心肌，肝脏和骨骼肌等，以抑制局部炎症并促进稳态的维持 (Immunity | 肠道菌群通过调节性T细胞促进肌肉组织再生)【9】。考虑到Treg空间定位和功能的TCR依赖性，这种肠道pTreg迁移可能有交叉抗原，肠道APCs携带肠道菌群迁移和低水平的共生菌转位等机制解释。虽然我们现在知道肠道pTreg的产生依赖于肠道菌群，但具体机制仍然不清楚，有报道认为TGFβ，短链脂肪酸，胆汁酸和视黄酸等促进pTreg的产生 (Nature | 胆汁酸次级代谢产物促进结肠组织Treg细胞产生)【10, 11】。另外，foxp3蛋白在pTreg和tTreg中也有不同的作用【12】。总之，肠道pTreg参与外周耐受的形成，且肠道可以作为研究外周耐受的模型组织。图二耐受性APCs APCs开启适应性免疫应答。寻找诱导T细胞耐受的独特APCs类型或状态是免疫学家的追逐的圣杯。虽然目前知道这些细胞的存在，但其具体身份依然不清楚。既往默认诱导耐受的APC是经典树突状细胞 (classical dendritic cells，cDCs)，其辅助建立针对饮食，共生菌和自身抗原的外周耐受。但最近的研究发现肠道内的pTreg由RORγt+APCs诱导而非肠道DCs【13】，提示不同的APCs负责训练针对不同抗原的独特T细胞耐受。 DCs DCs是典型的专职APCs，具有高效的抗原摄取，加工和提呈抗原以启始T细胞免疫。不同于T细胞中存在Foxp3+Treg，目前没有鉴定到诱导耐受的独特DCs。科学家提出成熟DC诱导免疫，非成熟的DC诱导耐受的模型。成熟DC显示活化表型，高表达趋化因子CCR7，共刺激分子CD40，CD80和CD86，并向引流淋巴结迁移【14】。但也存在例外，CCR7+DCs除了表达共刺激分子也会表达抑制性分子，例如PD-L1，PD-L2和CD200【15】。是否CCR7+DC在炎症环境下变换身份导致其免疫激活或耐受？但测序分析表明TLR刺激和非刺激的CCR7+DC无显著差别。因此，CCR7+DC在机体诱导耐受和免疫的具体作用仍有待于进一步研究。 RORgt+ APCs: A recently recognized lineage of tolerogenic APCs 去年，Nature背靠背3篇文章鉴定独特的RORγt+APCs诱导肠道pTreg维持耐受(背靠背Nature | 吕梦泽等揭示ILC3在肠道微生物免疫耐受中的关键作用)【13, 16, 17】，打破了长期认为的DC作为唯一的APCs诱导Treg分化。实验证实，RORγt+APCs表达的MHC-II和ITGAV或ITGB8对于pTreg诱导发挥重要作用(图二)。其中，一项研究将RORγt+APCs命名为Thetis cells (TC)，其转录普类似于胸腺的mTECs和DCs，并将其分为四种亚群，分别为TC-I，TC-II，TC-III和TC-IV。然而，这种现象是肠道特有还是其他黏膜组织存在类似的APCs仍有待于确证。总之，这项发现丰富了我们对于耐受性APCs诱导Treg的认识。免疫耐受的发育窗口期在一生中，我们遭遇自身和外来抗原的过程并不是一成不变的。试想一下，出生，断奶，性成熟和怀孕等事件必然伴随新的抗原出现。对于早期免疫发育的研究也揭示在胸腺或外周出现的独特的耐受性免疫细胞的发育潮【18, 19】。除了数量的变化，新生tTreg具有独特的功能且不能被成人tTreg取代【18】，提示不仅存在分层发育 (layered ontogeny) 也存在阶段特异性。遗传示踪实验发现围产期产生的tTreg在出生后长期存在，但其是否在成年发挥作用不得而知。在婴幼儿发育时期从进食母乳到摄入固体食物，肠道中的共生菌也发生深远影响。如果在断奶期未能成功建立肠道耐受则会增加过敏反应和炎症疾病的风险[19]。新生儿和婴儿的免疫系统高度适应建立免疫耐受，说明这个阶段是耐受性APCs和Treg形成的关键时期。这也在实验中得到验证，将TCR修饰的初始T细胞过继到断奶前的小鼠中倾向于分化为Treg【20, 21】。巧合得是，诱导pTreg的RORγt+APCs中TC-IV也在断奶期的肠系膜淋巴结中出现发育潮【13】，这可能表明在这个短暂的时间窗口内决定pTreg的分化和丰度 (图二)。一个有趣的支持证据是成年pTreg的丰度受到母体的影响，比如母乳中的IgA【22】。皮肤中也有类似的机制【23】。因此，免疫耐受的建立也有明显的发育阶段，这种耐受性免疫细胞群体的动态变化可能反应机体的发育需求。结语综上所述，这篇综述从T细胞内源性到外源性机制，从胸腺Treg到外周Treg，从耐受性DCs到最新的RORγt+APCs，从位点特异的耐受建立到发育阶段的耐受建立，为我们总结了近几年关于外周耐受有关的最新进展。过去已成过去，新的研究与发现仍在路上，整装待发，披荆斩棘，期待攻克免疫耐受人为建立和打破并运用于炎症性疾病和癌症治疗的那天。原文链接： https://www.science.org/doi/10.1126/sciimmunol.add1153 制版人：十一参考文献 1. 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M Cabeza-Cabrerizo, Cardoso A, Minutti CM, Pereira da Costa M and Reis e Sousa C. Dendritic Cells Revisited. Annual review of immunology. 2021;39:131-166. 15. JC Miller, Brown BD, Shay T, Gautier EL, Jojic V, Cohain A, Pandey G, Leboeuf M, Elpek KG, Helft J, Hashimoto D, Chow A, Price J, Greter M, Bogunovic M, Bellemare-Pelletier A, Frenette PS, Randolph GJ, Turley SJ and Merad M. Deciphering the transcriptional network of the dendritic cell lineage. Nature immunology. 2012;13:888-99. 16. M Lyu, Suzuki H, Kang L, Gaspal F, Zhou W, Goc J, Zhou L, Zhou J, Zhang W, Shen Z, Fox JG, Sockolow RE, Laufer TM, Fan Y, Eberl G, Withers DR and Sonnenberg GF. ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut. Nature. 2022;610:744-751. 17. R Kedmi, Najar TA, Mesa KR, Grayson A, Kroehling L, Hao Y, Hao S, Pokrovskii M, Xu M, Talbot J, Wang J, Germino J, Lareau CA, Satpathy AT, Anderson MS, Laufer TM, Aifantis I, Bartleson JM, Allen PM, Paidassi H, Gardner JM, Stoeckius M and Littman DR. A RORγt cell instructs gut microbiota-specific T cell differentiation. Nature. 2022;610:737-743. 18. S Yang, Fujikado N, Kolodin D, Benoist C and Mathis D. Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science (New York, NY). 2015;348:589-94. 19. P Brodin. Immune-microbe interactions early in life: A determinant of health and disease long term. Science (New York, NY). 2022;376:945-950. 20. KA Knoop, Gustafsson JK, McDonald KG, Kulkarni DH, Coughlin PE, McCrate S, Kim D, Hsieh CS, Hogan SP, Elson CO, Tarr PI and Newberry RD. Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria. Science immunology. 2017;2. 21. K Nutsch, Chai JN, Ai TL, Russler-Germain E, Feehley T, Nagler CR and Hsieh CS. Rapid and Efficient Generation of Regulatory T Cells to Commensal Antigens in the Periphery. Cell reports. 2016;17:206-220. 22. J Zimmermann and Macpherson AJ. Breast Milk Modulates Transgenerational Immune Inheritance. Cell. 2020;181:1202-1204. 23. Y Xing and Naik S. Baby's First Bacteria: Discriminating Colonizing Commensals from Pathogens. Cell host & microbe. 2019;26:705-707. （可上下滑动阅览）转载须知【原创文章】BioArt原创文章，欢迎个人转发分享，未经允许禁止转载，所刊登的所有作品的著作权均为BioArt所拥有。BioArt保留所有法定权利，违者必究。

细胞疗法免疫疗法

2025-09-19

·BioArt

Immunity | 端粒不稳，T细胞“早衰”：癌症免疫治疗的新靶点

撰文 | Qi 肿瘤微环境（TME）是一个极具挑战性的“战场”，在抗原持续存在以及存在代谢障碍（如低氧张力）的环境中，T细胞会逐渐失去功能，进入耗竭状态，但促使T细胞功能失调并导致终末耗竭T细胞积累的生物学机制仍不完全清楚。越来越多的研究表明，氧化应激在T细胞功能障碍中扮演关键角色，尤其是线粒体功能异常导致的活性氧（ROS）积累，已被证实能通过影响NFAT信号通路和表观遗传状态，促进T细胞衰竭【1, 2】，但ROS是否直接损伤T细胞的DNA，比如端粒呢？由于端粒是染色体末端的“保护帽”，其富含鸟嘌呤（G-rich）的序列极易受到氧化损伤。以往在衰老和慢性病毒感染中观察到端粒缩短与T细胞功能下降相关【3】，但在肿瘤浸润T细胞（TILs）中，端粒的状态和功能影响尚不明确。近日，来自美国匹兹堡大学的Greg M. Delgoffe团队在Immunity杂志上发表了文章Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer，他们通过化学光遗传学工具，在T细胞中实现线粒体或端粒特异性ROS诱导，并揭示端粒损伤而非缩短是驱动T细胞功能障碍的关键机制。更重要的是，该团队还开发了一种端粒靶向的抗氧化策略（端粒靶向的抗氧化酶GPX1-TRF1），显著增强T细胞功能与抗肿瘤疗效。该团队利用荧光激活肽（FAP）系统，构建了可在T细胞中特异性表达在线粒体上的光敏蛋白（MitoFAP）。当与染料MG-2I结合并经660nm光激发后，可在线粒体局部产生单线态氧，模拟TME中的氧化应激。MitoFAP+T细胞经光激发后，线粒体ROS显著上升，膜电位下降，氧消耗率（OCR）降低，伴随T细胞增殖受阻，抑制性受体（PD-1、Tim-3）表达上升，细胞因子（IFN-γ、TNF-α、IL-2）分泌减少，T细胞呈现终末分化和衰老表型（CD39上调、CD27下调）。随后，该团队通过端粒荧光原位杂交（Telo-FISH）技术分析处于中期的染色体，来探究氧化应激对端粒完整性的影响，观察到在ROS诱导后，DNA损伤应答蛋白（γ-H2AX、53BP1）在端粒处显著聚集，但端粒并未显示出任何丢失或缩短的情况，提示复制压力导致的端粒不稳定。随后，该团队从小鼠B16和MC38肿瘤模型中分选T细胞，相比脾脏T细胞，肿瘤中的T细胞（尤其是终末耗竭型Texh）端粒处γ-H2AX和53BP1显著增多，且在人的黑色素瘤和头颈癌样本中，肿瘤CD8+T细胞也显示更高水平的端粒损伤，强调了肿瘤浸润性CD8+ T细胞中出现端粒损伤的保守性。接下来，该团队构建了端粒靶向的FAP系统（TRF1-FAP），可在端粒处特异性产生ROS。诱导后，T细胞增殖受阻，耗竭标志物上升，衰老相关蛋白p21和β-gal表达增加，而细胞因子分泌能力下降，杀伤功能减弱。RNA-seq分析进一步显示，p53通路、细胞周期调控、DNA修复通路激活，而糖代谢和TCR相关基因下调。基于上述发现，他们设计了端粒靶向的抗氧化融合蛋白GPX1-TRF1，将其导入治疗性T细胞（如Pmel-1或CAR-T）中。在肿瘤中，GPX1-TRF1+T细胞的端粒损伤显著减少，细胞因子分泌能力增强，抗肿瘤效果提升，且转录组分析显示线粒体功能、DNA修复相关基因富集，耗竭相关基因（如SOX4）下调。综上，这项工作证明端粒氧化损伤而非端粒缩短是T细胞功能障碍的直接驱动因素，而端粒靶向抗氧化策略具有显著的治疗潜力，有望应用于CAR-T、TIL疗法等领域，尤其针对实体瘤治疗中的T细胞功能障碍问题。原文链接： https://doi.org/10.1016/j.immuni.2025.08.008 制版人：十一参考文献 1. Ford, B.R., Vignali, P.D.A., Rittenhouse, N.L., Scharping, N.E., Peralta, R., Lontos, K., Frisch, A.T., Delgoffe, G.M., and Poholek, A.C. (2022). Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells. Sci. Immunol. 7, eabj9123. https://doi.org/10.1126/sciimmunol.abj9123. 2. Vignali, P.D.A., DePeaux, K., Watson, M.J., Ye, C., Ford, B.R., Lontos, K., McGaa, N.K., Scharping, N.E., Menk, A.V., Robson, S.C., et al. (2023). Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity. Nat. Immunol. 24, 267–279. https:// doi.org/10.1038/s41590-022-01379-9. 3. Scharping, N.E., Rivadeneira, D.B., Menk, A.V., Vignali, P.D.A., Ford, B.R., Rittenhouse, N.L., Peralta, R., Wang, Y., Wang, Y., DePeaux, K., et al. (2021). Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 22, 205–215. https:// doi.org/10.1038/s41590-020-00834-9. 学术合作组织（*排名不分先后）战略合作伙伴（*排名不分先后） · 转载须知【原创文章】BioArt原创文章，欢迎个人转发分享，未经允许禁止转载，所刊登的所有作品的著作权均为BioArt所拥有。BioArt保留所有法定权利，违者必究。 BioArt Med Plants 人才招聘近期直播推荐点击主页推荐活动关注更多最新活动！

免疫疗法

2024-12-20

·生物制药小编

T细胞：活化与代谢

免疫代谢（Immunometabolism）描述了免疫功能和代谢调节之间相互关系。T细胞在活化周期（初始T细胞-效应T细胞-效应后T细胞）不同阶段，对能量需求不同，需要通过代谢重编程来实现。免疫代谢免疫细胞通过改变代谢酶的活性和营养摄取，以支持免疫激活的代谢需求，这一过程被称为代谢重新编程。 1. 初始T细胞（Naive T 细胞）阶段胸腺发育成熟的T细胞，转移至淋巴结和脾脏等外周淋巴组织，在没有抗原刺激的晴情况下，处于相对静止的状态，称之为初始T细胞。静止的状态下，代谢也处于代谢静息状态；使用更多是氧化磷酸化而非糖酵解。 2. 早期效应阶段初始T细胞接受抗原刺激之后，启动活化，活化一系列相关基因，表达功能相关蛋白，发挥生物效应。此阶段细胞生物活动活跃，因此需要较多能量来支持。因此生物合成功能活跃，糖酵解、氧化磷酸化、三羧酸循环活跃。 TCR信号通过丙酮酸脱氢酶激酶1(PDHK1)与糖酵解直接相关联,PDHK1启动的需氧糖酵解，是细胞因子产生所必需的,细胞因子的合成通过抑制乳酸脱氢mRNA结合来控制. Cell Rep. 22(6):1509–21 3. 后期阶段（效应、记忆或者耗竭状态） T细胞有很强的可塑性。受到所处环境中各类细胞及其分泌的细胞因子等的影响，会发生表型和功能的改变。 Cell . 2017 Oct 5;171(2):385-397. 活化的T细胞成为效应细胞，发挥相应功能。此时糖酵解能力下降，生物能学能力增强。活化的T细胞健康的过度到记忆性T细胞；此时代谢以氧化磷酸化为主，线粒体增大，生物合成能力增强。在持续抗原暴露情况下（慢性感染，肿瘤）抑制细胞的诱导下过度到耗竭表型的T细胞。T细胞耗竭是一个长时间重编程形成的结果，相应内容可以阅读：T细胞耗竭（Exhaustion）和T细胞耗竭四阶段。 PD-1交联减弱PI3K、Akt和mTOR信号，直接影响代谢途径，包括抑制糖酵解。在体内，发育中的Tex细胞表现出代谢紊乱，包括抑制细胞呼吸、降低葡萄糖摄取和线粒体能量失调。主要参考文献 Menk AV, Scharping NE, Moreci RS, Zeng X, Guy C, et al. 2018a. Early TCR signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep. 22(6):1509–21 Ramon I Klein Geltink et al，Mitochondrial Priming by CD28，Cell . 2017 Oct 5;171(2):385-397.e11. Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, et al. 2016. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45(2):358–73

细胞疗法信使RNA

100 项与甲硫氨酸脑啡肽相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	甲硫氨酸脑啡肽	-	DB12668

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
胰腺癌	临床2期	美国	Biostax Corp.	2014-03-25
卵巢癌	临床2期	美国	Biostax Corp.	2012-01-23
肝细胞癌	临床2期	-	LadRx Corp.	-
肝细胞癌	临床2期	-	Immune Pharmaceuticals, Inc.	-
肝细胞癌	临床2期	-	TNI BioTech Ltd.	-
HIV感染	临床2期	-	Immune Pharmaceuticals, Inc.	-
HIV感染	临床2期	-	LadRx Corp.	-
HIV感染	临床2期	-	TNI BioTech Ltd.	-
晚期恶性实体瘤	临床1期	美国	Innovive Pharmaceuticals, Inc.	2005-11-01
流感病毒感染	临床前	美国	-	-

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适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00109941 (Pubmed)	临床2期	胰腺癌	24	OGF 250 µg/kg	選艱顧蓋鹽簾膚築鏇膚(鏇範廠艱積鏇衊廠襯壓) = No adverse effects on hematologic or chemistry parameters were noted 觸餘壓襯蓋顧繭餘範鏇 (願構鏇製遞鑰襯簾遞構 ) 更多	积极	2010-03-01