Anti-polysaccharide antibody responses in humanized mice

人源化小鼠的抗多糖抗体反应

• 批准号: 8448919
• 负责人: TIMOTHY L MANSER
• 金额: $ 23.25万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448919
• 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）：啮齿动物模型阐明基本免疫学机制的能力是毫无疑问的。不幸的是，这些机制的特定方面可能是物种特异性的。此外，许多人类传染性病原体无法在啮齿动物宿主中产生有效感染。这些因素使得从实验动物获得的知识转化为预防、诊断和治疗人类疾病的更好方法变得更加复杂。 能够持久异种移植人类造血细胞的免疫缺陷小鼠新品系的开发为上述问题提供了潜在的解决方案。我们利用 NOD/SCID/共同细胞因子受体 g 链敲除 (NSG) 品系小鼠和人脐带血 (UCB) CD34+ 造血干细胞 (HSC) 来创建造血人源化小鼠 (HISmice)。我们发现这些小鼠的血液、脾脏以及一定程度的淋巴结中可重复且稳定地植入人类 B 淋巴细胞。然而，这些小鼠 B 细胞区室的主要亚群表现出不成熟的表型。 这些 HIS 小鼠被螺旋体细菌赫氏疏螺旋体感染，会导致感染过程并通过 IgM 反应消退，这种反应在性质上相似，但不如赫氏疏螺旋体那么强大。 在受感染的人类和小鼠模型中观察到的结果。虽然小鼠体内针对赫氏芽孢杆菌的保护性免疫反应是一种 T 细胞独立 (TI) 反应，但这种反应会通过 Toll 样受体 (TLR) 的细菌刺激而增强。 HISmice 也无法对纯化的多糖抗原产生抗体反应，除非给予 TLR 配体作为佐剂。最后，HISmice 对 T 细胞依赖性抗原产生抗体反应，但这些反应很弱，并且 IgM 是产生的主要同种型。 这些观察结果使我们推测，如上所述产生的 HISmice 由于其淋巴细胞区室的不完全发育，对多种病原体和抗原失败或反应不佳。我们推测，这部分是由于宿主产生的鼠细胞因子对移植造血细胞的人类细胞因子受体缺乏有效的交叉刺激。在本申请中，我们建议通过生成表达人 IL-7 和人 BLyS (BAFF) 的 NSG 小鼠作为 UCB HSC 的受体来测试这一假设。我们预测，这两种修饰将产生具有更成熟和多样化的 B 细胞区室的 HISmice，能够对各种抗原和病原体产生强大的免疫反应。因此，我们预测由此产生的 HISmice 将成为开发人类疾病诊断和治疗策略的更好模型。