The NK cell response to prenatal allotransplantation

NK 细胞对产前同种异体移植的反应

• 批准号: 8875729
• 负责人: AIMEN F SHAABAN
• 金额: $ 37.11万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875729
• 关键词: Adult; Affect; Allogenic; Antigens; Apoptosis; Autoimmunity; Cell Maturation; Cell Transplants; Cells; Child; Childhood; Chimerism; Clinical; Development; Disease; Donor Selection; Dose; Education; Engraftment; Ensure; Environment; Excision; Failure; Fetus; Frequencies; Future; Goals; Graft Rejection; Hematopoietic; Hereditary Disease; Hypersensitivity; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunology; Infant; Knowledge; Laboratories; Ligands; Link; MHC Class I Genes; Memory; Modeling; Mus; Natural Killer Cells; Outcome; Phenotype; Pregnancy; Principal Investigator; Reporting; Repression; Research; Surveys; Testing; Transplantation; cytotoxicity; fetal; in utero; prenatal; programs; receptor; research study; response; stem; success; therapeutic target; tool

DESCRIPTION (provided by applicant): A primary assumption that guides current approaches to in utero hematopoietic cellular transplantation (IUHCT) is that the early-gestation fetus has an immature immune system that is incapable of rejecting a donor cell transplant. For this reason, transplanting the cells prior to the maturation of the adaptive immune system leads to recognition of the donor cells as "self" rather than "foreign". However, repeated failures in clinical cases of IUHCT that do not involve an immunodeficiency disease force a re-examination of this model of the fetal immune system. A survey of both clinical and laboratory reports of IUHCT reveal enhanced success when the immunodeficient host is also natural killer (NK) cell deficient. Preliminary studies in mice reveal that NK cells act as an early immune barrier to IUHCT. In order to establish NK cell tolerance and ensure successful engraftment, a minimum level of hematopoietic chimerism must be achieved prior to NK cell maturation. Below this "chimerism threshold", the host NK cells predictably reject the graft. In this way, the chimerism threshold offers a logical explanation for past failures of clinical IUHCT. Fortunately, the identification of the chimerism threshold greatly facilitates study of the mechanisms linking the chimerism level to the emergence of NK cell tolerance following IUHCT. This concept drives the central hypothesis that the chimerism threshold provides the minimum amount of donor ligand recognition necessary for the selection of "friendly" NK cell phenotypes and repression of "hostile" ones. To challenge this hypothesis, the experiment in this proposal will determine the impact of the chimerism threshold on alloreactive NK cell: 1) selection; 2) cytotoxicity; and 3) memory. The expected outcome for the experiments in this proposal is the delineation of the mechanisms linking the chimerism level to the emergence of NK cell tolerance following IUHCT. This knowledge will have a dramatic impact on the field of IUHCT as it establishes a new paradigm for the early fetal immune response to allotransplantation. This directly affects the development of strategies to enhance the success of IUHCT such as donor cell dose, donor selection, booster transplants and therapeutic targeting of the host immune response. On a broader scale, these findings will guide further mechanistic study of fetal NK cell education.

描述(由申请人提供)：指导当前宫内造血细胞移植(IUHCT)方法的一个主要假设是，怀孕早期的胎儿具有不成熟的免疫系统，不能排斥供体细胞移植。出于这个原因，在适应性免疫系统成熟之前移植细胞会导致捐赠者细胞被识别为“自我”而不是“异体”。然而，在不涉及免疫缺陷疾病的IUHCT临床病例中，反复失败迫使人们重新检查这种胎儿免疫系统模型。对IUHCT的临床和实验室报告的调查显示，当免疫缺陷宿主也是自然杀伤(NK)细胞缺陷时，成功率更高。对小鼠的初步研究表明，NK细胞是IUHCT的早期免疫屏障。为了建立NK细胞耐受性并确保成功植入，必须在NK细胞成熟之前达到最低水平的造血细胞嵌合体。在这个“嵌合体阈值”以下，宿主NK细胞可以预见地排斥移植物。通过这种方式，嵌合阈值为过去临床IUHCT的失败提供了一个合乎逻辑的解释。幸运的是，嵌合体阈值的确定极大地促进了嵌合体水平与IUHCT后NK细胞耐受的机制的研究。这一概念推动了一个中心假设，即嵌合体阈值提供了选择“友好的”NK细胞表型和抑制“敌对的”NK细胞表型所需的最少量的供体配体识别。为了挑战这一假设，本方案中的实验将确定嵌合体阈值对同种异体反应性NK细胞的影响：1)选择；2)细胞毒性；3)记忆。这项提议中的实验的预期结果是描绘出嵌合体水平与IUHCT后NK细胞耐受出现之间的联系机制。这一知识将对IUHCT领域产生重大影响，因为它为同种异体移植的早期胎儿免疫反应建立了一个新的范式。这直接影响到促进IUHCT成功的战略的制定，如供体细胞剂量、供体选择、助推器移植和宿主免疫反应的治疗性靶向。在更广泛的范围内，这些发现将指导对胎儿NK细胞教育的进一步机械化研究。

项目成果

Prenatal Allogeneic Tolerance in Mice Remains Stable Despite Potent Viral Immune Activation.

尽管病毒免疫激活有效，但小鼠的产前同种异体耐受性仍保持稳定。

• DOI: 10.4049/jimmunol.1500844
• 发表时间: 2015
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Strong,BeverlySI;Ryken,KatherineO;Lee,AmandaE;Turner,LucasE;Wadhwani,RamK;Newkold,TessJ;Alhajjat,AmirM;Heusel,JonathanW;Shaaban,AimenF
• 通讯作者: Shaaban,AimenF

Tolerance to noninherited maternal antigens, reproductive microchimerism and regulatory T cell memory: 60 years after 'Evidence for actively acquired tolerance to Rh antigens'.

对非遗传性母体抗原、生殖微嵌合和调节性 T 细胞记忆的耐受性：“主动获得对 Rh 抗原耐受性的证据”60 年后。

• DOI: 10.1080/19381956.2015.1107253
• 发表时间: 2015
• 期刊: Chimerism
• 作者: Kinder,JeremyM;Jiang,TonyT;Ertelt,JamesM;Xin,Lijun;Strong,BeverlyS;Shaaban,AimenF;Way,SingSing
• 通讯作者: Way,SingSing

Maternal and Fetal Immune Response to in Utero Stem Cell Transplantation.

母体和胎儿对子宫内干细胞移植的免疫反应。

• DOI: 10.1007/s40778-018-0129-5
• 发表时间: 2018
• 期刊: Current stem cell reports
• 影响因子: 1.4
• 作者: Alhajjat,Amir;Shaaban,Aimen
• 通讯作者: Shaaban,Aimen

Extrinsic allospecific signals of hematopoietic origin dictate iNKT cell lineage-fate decisions during development.

• DOI: 10.1038/srep28837
• 发表时间: 2016-06-29
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Strong BSI;Newkold TJ;Lee AE;Turner LE;Alhajjat AM;Heusel JW;Shaaban AF
• 通讯作者: Shaaban AF

Trogocytosis as a mechanistic link between chimerism and prenatal tolerance.

• DOI: 10.4161/chim.26666
• 发表时间: 2013-10-01
• 期刊: Chimerism
• 作者: Alhajjat, Amir M;Strong, Beverly S;Shaaban, Aimen F
• 通讯作者: Shaaban, Aimen F