Thesis (Ph. D.)--University of Wisconsin--Madison, 1964. / Typescript. Vita. Description based on print version record. Includes bibliographical references (leaves 129-136).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1966. / Typescript. Vita. Description based on print version record. Includes bibliographical references.

Techn. Universiẗat, Diss., 2003--Dresden.

Universiẗat, Diss., 2004--Bielefeld.

Os linfócitos T sofrem rígida regulação homeostática desde seu desenvolvimento até sua maturação, expansão clonal e morte celular. Compostos endógenos ou exógenos que alterem as funções fisiológicas dos linfócitos T podem modular passos importantes da resposta imune. Triptofano tem um papel importante na manutenção da homeostasia dos linfócitos T e é o precursor da síntese de melatonina. Neste estudo, avaliamos os efeitos de triptofano, melatonina e seus produtos de oxidação sobre os principais processos de ativação e desativação dos linfócitos T. Inicialmente, investigamos os efeitos biológicos de L-quinurenina (KYN, composto formado na via de metabolização do triptofano), melatonina e seus produtos de oxidação N1-acetil-N2-formil-5-metoxiquinuramina (AFMK) e N1-acetil-5- metoxiquinuramina (AMK) sobre a proliferação dos linfócitos T humanos e na produção de interferon-gamma (IFN-γ) e das interleucinas IL-2, IL-10 e IL-12. Observamos que KYN, melatonina, AFMK e AMK inibem a linfoproliferação e a liberação de IL-2 e de IFN-γ . O efeito inibitório destes compostos na síntese de IFN-γ não está associado às variações na produção das duas citocinas mais importantes na regulação de IFN-γ , ou seja, IL-10 e IL-12. Na seqüência, descrevemos a ação da melatonina e seus produtos de oxidação, sobre a morte celular induzida por ativação (AICD) de hibridomas de linfócitos T e os possíveis mecanismos de ação. Os resultados deste estudo mostram que tanto melatonina quanto AFMK e AMK são potentes inibidores da apoptose dos linfócitos T. Estes compostos inibem a ativação do Fator de Transcrição Nuclear de Células T ativadas (NFAT) e suprimem a expressão da molécula Fas Ligante (FasL), que é o evento imprescindível para a indução da AICD. Como conclusões, verificamos que os produtos formados tanto a partir da oxidação de triptofano quanto de melatonina são potenciais reguladores da resposta imune e podem participar dos efeitos imunossupressores, nos quais a depleção de triptofano tem sido sugerida como principal mecanismo de regulação dos linfócitos T. Adicionalmente, nossos achados podem ter utilidade na avaliação de possíveis efeitos indesejáveis durante a utilização terapêutica de melatonina. / T Lymphocytes are exposed to severe homeostatic regulation from development stage up to their maturation, clonal expansion and cell death. Endogenous or exogenous compounds altering the physiological functions of T lymphocytes can modulate important steps of the immune response. Tryptophan plays an important role for maintaining the homeostasis of T lymphocytes and is the precursor of the melatonin synthesis. In this study we evaluated the effects of tryptophan, melatonin and their oxidation products concerning the main activation and deactivation processes of T lymphocytes. Firstly, we analyzed the biological effects of L-kynurenine (KYN, a compound formed at the tryptophan metabolization pathway), melatonin and its oxidation products, N-acetyl-N-formyl-5-methoxykynuramine (AFMK) and N-acetyl-5- methoxykynuramine (AMK), concerning the proliferation of human T lymphocytes and the production of interferon-gamma (IFN-γ) as well as of interleukins IL-2, IL-10 and IL-12. It was observed that KYN, melatonin, AFMK and AMK inhibit the lymphocytes proliferation and the release of IL-2 and IFN-γ. The inhibitory effect of these compounds in the IFN-γ synthesis is not related to the variations on the production of the two most important cytokines for the IFN-γ regulation, that is, IL-10 and IL-12. After that, we reported the melatonin action as well as of its oxidation products, in what concerns activation-induced cell death (AICD) of T lymphocytes hybridomas and probable activation mechanisms. The results of this study have shown that melatonin as well as AFMK and AMK are powerful inhibitors of the T lymphocytes apoptosis. These compounds inhibit the activation of the nuclear transcription factor of activated T cells (NFAT) and suppress the expression of the Fas-Ligand molecule (FasL), which is the essential event to the AICD induction. We concluded that products formed by the oxidation of either tryptophan or melatonin are potential regulators of the immune response and may participate on immunosuppression effects, in which the tryptophan depletion is believed to be the main mechanism for T lymphocytes regulation. Added to that, our results may be helpful for evaluating possible unwanted effects during the therapeutical use of melatonin.

M.Tech. (Homoeopathy) / Please refer to full text to view abstract

Serotonin (5-HT) containing neuroepithelial cells (NECs) are O2 sensitive chemoreceptors found throughout the skin of larval zebrafish (Danio rerio). Zebrafish larvae are sensitive to changes in ambient PO2 as early as 2 days post fertilisation (dpf) and hyperventilate in response to hypoxia beginning at 3 dpf. Tryptophan hydroxylase (tph) is the rate-limiting enzyme in 5-HT synthesis; three tph paralogs are present in zebrafish (tph1a, tph1b and tph2). Although 5-HT has been implicated as a key neurotransmitter mediating hypoxic hyperventilation, it has not been possible to discern the role of 5-HT specifically contained within the NECs in promoting hypoxic hyperventilation. The purpose of this study was to determine the role of NEC 5-HT in regulating the hypoxic ventilatory response in larval zebrafish. It was hypothesised that 5-HT is a key neurotransmitter released from NECs which contributes to hypoxic hyperventilation. Immunohistochemistry was used to determine the distribution of tph paralogs and their role in 5-HT production in NECs. Tph1a was present in NECs and nerves innervating NECs. Exposure to the non-selective tph inhibitor, para-chlorophenylalanine (pCPA), or translational gene knockdown of tph1a, diminished 5-HT expression within NECs. Exposure to acute hypoxia (PO2 = 30 mmHg) revealed a blunted hypoxic ventilatory response (reduced breathing frequency) in fish exhibiting depleted 5-HT in NECs. The hypoxic hyperventilatory response was rescued with application of 5-HT. The results of these experiments demonstrate that tph1a is responsible for 5-HT production in NECs of larval zebrafish, and that 5-HT released from NECs is involved in establishing their hypoxic hyperventilatory response.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19887号 / 医博第4136号 / 新制||医||1016(附属図書館) / 32964 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 横出 正之, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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