Thymic Influence on Ocular Immunoregulation

胸腺对眼免疫调节的影响

• 批准号: 7809475
• 负责人: Robert E. Cone
• 金额: $ 35.57万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-05 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7809475
• 关键词: Adoptive Transfer; Adult; Alteplase; Antibodies; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Blood Circulation; Bovine Serum Albumin; CD8B1 gene; Cattle; Cell Separation; Cells; Cellular Immunity; Ciliary Body; Complex; Delayed Hypersensitivity; Disease; Emigrations; Environment; Eye; Eye Neoplasms; Eye diseases; Fluorescein; Fluoresceins; Goals; Home environment; Hormones; Immune; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Inflammatory; Injection of therapeutic agent; Injury; Interferons; Interleukin-4; Intravenous; Investigation; Iris; Keratoplasty; Knock-out; Laboratories; Lead; Link; Major Histocompatibility Complex; Mediating; Mediator of activation protein; Mus; Myelin Basic Proteins; Ovalbumin; Pathway interactions; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Phycoerythrin; Picryl Chloride; Production; Reaction; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Role; Spleen; Suppressor-Effector T-Lymphocytes; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Transforming Growth Factors; Travel; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; anterior chamber; chemokine receptor; immunoregulation; killer T cell; neuronal cell body; peripheral blood; picric acid; prevent; thymocyte

DESCRIPTION (provided by applicant): The eye is protected from destructive innate and adaptive immune mechanisms by a local environment that is not conducive to immune-mediated reactions and by the ocular-induced regulation of systemic immunity. Active systemic regulation of destructive cell-mediated immunity is mediated by Anterior Chamber-Associated Immune Deviation (ACAID) imposed on the systemic immune system by complex cellular pathways in which circulating antigen presenting cells home to the thymus and to the spleen. In the thymus and spleen T lymphocytes that induce and effect the suppression of cell-mediated immunity are produced. Our laboratory has shown that after the intracameral injection of antigen (i) intracameral antigen but not intravenous antigen is found in the thymus;(ii) both iris monocytic cells and similar circulating monocytic cells activate immunoregulatory NK 1.1+ thymocytes that (i) enhance the production of lgG1 antibodies to the intracameral antigen and activate CD4+ and CD8+ splenic T cells that suppress cell-mediated immunity. To advance these studies we propose that the intracameral injection of antigen induces monocytic cells in the iris/ciliary body that activate thymic regulatory T cells and splenic immunoregulatory T cells that suppress systemic delayed-type hypersensitivity. To test this hypothesis we will (1) determine the mechanisms(s) by which intracameral antigen travels to the thymus and spleen, (2) determine the induction of regulatory thymocytes by monocytic cells derived from the iris. (3) Determine the mechanism(s) by which immunoregulatory thymocytes from donors receiving intracameral antigen activate splenic suppressor T cells. These studies are essential to a full definition of an oculo/thymic/splenic axis. This ocular-thymic link confirms an active role for the thymus and the eye in the regulation of systemic immunity that could impact on the management of inflammatory eye disease, corneal transplantation, ocular tumors and autoimmune disease.

描述（由申请人提供）：通过局部环境不利于免疫介导的反应以及眼部诱导的全身免疫调节，可以保护眼睛免受破坏性的先天和适应性免疫机制的保护。破坏性细胞介导的免疫的主动全身调节是由在全身免疫系统上通过复杂的细胞途径施加的前腔相关免疫偏差（ACAID）介导的，其中复杂的细胞途径循环循环抗原呈现给胸腔和脾脏的循环抗原细胞。在胸腺和脾淋巴细胞中，产生了诱导和作用抑制细胞介导的免疫力的淋巴细胞。我们的实验室表明，在胸腔内注射抗原（i）抗原内抗原（I）在胸骨中发现抗原抗原，但在胸腔内发现没有静脉内抗原；（ii）虹膜单核细胞和类似的循环单核细胞都激活了免疫调节的NK 1.1+胸膜均具有cd4+ cd的生产，并增强了LGG1的生产和活体的生产。 CD8+脾T细胞抑制细胞介导的免疫力。为了推进这些研究，我们提出抗原内注射抗原会在虹膜/睫状体中诱导单核细胞，从而激活胸腺调节性T细胞和脾脏免疫调节的T细胞，从而抑制全身性延迟延迟型超敏性。为了检验该假设，我们将（1）确定腔内抗原向胸腺和脾脏传播的机制，（2）确定源自虹膜的单核细胞诱导调节性胸腺细胞。 （3）确定从接受腔内抗原激活脾抑制T细胞的供体免疫调节性胸腺细胞的机制。这些研究对于Oculo/胸腺/脾轴的完整定义至关重要。这种眼部胸膜链接证实了胸腺的积极作用，而眼睛在调节系统性免疫方面可能会影响炎症性眼病的治疗，角膜移植，眼部肿瘤和自身免疫性疾病。

项目成果

Immune amplification of murine CD8 suppressor T cells induced via an immune-privileged site: quantifying suppressor T cells functionally.

• DOI: 10.1371/journal.pone.0022496
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sharafieh R;Lemire Y;Powell S;O'Rourke J;Cone RE
• 通讯作者: Cone RE

T cell sensitivity to TGF-beta is required for the effector function but not the generation of splenic CD8+ regulatory T cells induced via the injection of antigen into the anterior chamber.

• DOI: 10.1093/intimm/dxp023
• 发表时间: 2009-05
• 期刊: International immunology
• 影响因子: 4.4
• 作者: Cone RE;Chattopadhyay S;Sharafieh R;Lemire Y;O'Rourke J;Flavell RA;Clark RB
• 通讯作者: Clark RB

Paradoxical effect of pertussis toxin on the delayed hypersensitivity response to autoantigens in mice.

• DOI: 10.1371/journal.pone.0011983
• 发表时间: 2010-08-05
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Yadav R;Bhowmick S;Gorecki P;O'Rourke J;Cone RE
• 通讯作者: Cone RE

Anterior Chamber-Associated Immune Deviation (ACAID): An Acute Response to Ocular Insult Protects from Future Immune-Mediated Damage?

前房相关免疫偏差（ACAID）：对眼部损伤的急性反应可以防止未来免疫介导的损伤？

• DOI: 10.4137/oed.s2858
• 发表时间: 2009
• 期刊: Ophthalmology and eye diseases
• 作者: Cone,RobertE;Pais,Roshan
• 通讯作者: Pais,Roshan

An intracameral injection of antigen induces in situ chemokines and cytokines required for the generation of circulating immunoregulatory monocytes.

前房内注射抗原会诱导产生循环免疫调节单核细胞所需的原位趋化因子和细胞因子。

• DOI: 10.1371/journal.pone.0043182
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Pais,Roshan;Bhowmick,Sourojit;Chattopadhyay,Subhasis;Lemire,Yen;Sharafieh,Roshanak;Yadav,Rajwahrdan;O'Rourke,James;Cone,RobertE
• 通讯作者: Cone,RobertE