Anti-polysaccharide antibody responses in humanized mice

人源化小鼠的抗多糖抗体反应

• 批准号: 8606392
• 负责人: TIMOTHY L MANSER
• 金额: $ 19.38万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-18 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606392
• 关键词: Adjuvant; Adult; Animals; Antibody Formation; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Cell Development; B-Lymphocytes; BLyS receptor; Bacteria; Blood; Borrelia; CD34 gene; Cell Lineage; Cell Maintenance; Cells; Communicable Diseases; Cytokine Receptors; Development; Diagnosis; Disease; Disease Progression; Dose; Engineering; Engraftment; Event; Generations; Hematopoietic; Hematopoietic stem cells; Human; Human Development; Immune response; Immune system; Immunity; Immunodeficient Mouse; Immunoglobulin M; Infection; Interleukin-7; Investigation; Knock-out; Laboratories; Lead; Life; Ligands; Lymphocyte; Malignant Neoplasms; Mature Lymphocyte; Mediating; Modification; Mouse Strains; Mus; Nature; Order Spirochaetales; Patients; Plasma Cells; Polysaccharides; Population; Prevention approach; Resolution; Rodent; Rodent Model; Role; Site; Solutions; Source; Spleen; Staging; Stem cells; Structure of germinal center of lymph node; Study models; Supplementation; Systems Development; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Toll-like receptors; Transplantation; Tropism; Umbilical Cord Blood; Xenograft procedure; bis(3-bis(4-chlorophenyl)methyl-4-dimethylaminophenyl)amine; cell type; cytokine; human disease; human tissue; improved; infected vector rodent; interest; knowledge translation; lymph nodes; model development; mouse model; neoplastic cell; pathogen; peripheral blood; public health relevance; receptor; response; tumor; tumor growth; vaccination strategy

DESCRIPTION (provided by applicant): The power of rodent models for the elucidation of basic immunological mechanisms is unquestioned. Unfortunately, particular aspects these mechanisms may be species specific. In addition, many human infectious pathogens are incapable of establishing productive infections in rodent hosts. These factors complicate the translation of knowledge gained from such experimental animals to better approaches for the prevention, diagnosis and treatment of human diseases. The development of new strains of immunodeficient mice that can be durably xenografted with human hematopoietic cells provides a potential solution to the problems mentioned above. We have utilized the NOD/SCID/common cytokine receptor g chain knockout (NSG) strain of mice and human umbilical cord blood (UCB) CD34+ hematopoietic stem cells (HSCs) to create hematopoietically humanized mice (HISmice). We have found that these mice are reproducibly and stably engrafted with human B lymphocytes in the blood, spleen and to some extent in the lymph nodes. However, major subpopulations of the B cell compartment in these mice appear phenotypically immature. Infection of these HISmice with the spirochete bacteria Borrelia hermsii results in a course of infection and resolution via an IgM response that is qualitatively similar, but is not as robust as those observed in infected humans and mouse models. While the protective immune response to B. hermsii in mice is a T cell independent (TI) response, this response is augmented by bacterial stimulation of Toll-like receptors (TLRs). HISmice also failed to make an antibody response to purified polysaccharide antigens unless TLR ligands were given as an adjuvant. Finally, HISmice mount antibody responses to T cell dependent antigens, but these responses are weak and IgM is the predominant isotype produced. These observations lead us to hypothesize that HISmice generated as describe above, fail or respond sub optimally to a variety of pathogens and antigens due to incomplete development of their lymphocyte compartments. We hypothesize that this is due, in part, to lack of efficient cross stimulation of human cytokine receptors on engrafting hematopoietic cells by host-produced murine cytokines. In this application, we propose to test this hypothesis by generating human IL-7 and human BLyS (BAFF) expressing NSG mice for use as recipients for UCB HSCs. We predict that both of these modifications will yield HISmice with more mature and diverse B cell compartments capable of mounting robust immune responses to a variety of antigens and pathogens. As such, we predict that the resulting HISmice will serve as far better models for the development of strategies for the diagnosis and treatment of human disease.

描述（由申请人提供）：毫无疑问，啮齿动物模型阐明基本免疫机制的力量。不幸的是，这些机制可能是特定于物种的。此外，许多人类感染性病原体无法在啮齿动物宿主中建立生产性感染。这些因素使从这种实验动物获得的知识转化为预防，诊断和治疗人类疾病的知识的转化变得复杂。 可以用人造血细胞持久地异种移植的免疫缺陷小鼠的新菌株的发展为上述问题提供了潜在的解决方案。我们已经利用了小鼠的点头/SCID/普通细胞因子受体G链敲除（NSG）菌株和人类脐带血（UCB）CD34+造血干细胞（HSCS）创建造血人性化的小鼠（HSC）。我们发现，这些小鼠在血液，脾脏和淋巴结中的血液，脾脏和某种程度上被人体B淋巴细胞植入。然而，这些小鼠中B细胞室的主要亚群似乎表型不成熟。 这些HIS虫感染这些Hermsii的螺旋体细菌会导致通过质量相似的IGM反应导致感染和分辨率的疗程，但不像强大 在感染的人类和小鼠模型中观察到的。虽然小鼠对HERMSII的保护性免疫反应是独立的T细胞（TI）反应，但通过细菌刺激Toll样受体（TLR）增强了这种反应。除非将TLR配体作为佐剂，否则Hismice也未能对纯化的多糖抗原做出抗体反应。最后，HISMICE对T细胞依赖性抗原的抗体反应持续，但是这些反应很弱，IgM是产生的主要同种异体。 这些观察结果使我们假设Hismice如上所述，由于其淋巴细胞室的不完整而产生了上述，失败或对各种病原体和抗原的反应。我们假设这部分是由于缺乏通过宿主产生的鼠类细胞因子在植入造血细胞上有效地刺激人类细胞因子受体的有效交叉刺激。在此应用中，我们建议通过产生人类IL-7和人类Blys（BAFF）来检验该假设，以表达NSG小鼠作为UCB HSC的接受者。我们预测，这两种修饰都将产生具有更成熟和多样化的B细胞室，能够安装对各种抗原和病原体的稳健免疫反应。因此，我们预测，由此产生的Hismice将为制定诊断和治疗人类疾病的策略提供更好的模型。