ROLE OF APPENDIX AND GALT IN DEVELOPMENT OF THE PRIMARY HUMAN IMMUNE REPERTOIRE

附录和 GALT 在人类初级免疫库发育中的作用

• 批准号: 6431670
• 负责人: rose G. mage
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6431670
• 关键词: B lymphocyte; antibody formation; autoimmunity; cell differentiation; child (0-11); developmental immunology; gut associated lymphoid tissue; human subject; ileocolonic region; immunocytochemistry; laboratory rabbit; polymerase chain reaction; tissue /cell culture

Our studies in the rabbit have shown that the young appendix is an important site of development of the cells destined to produce protective antibodies. The rabbit appendix has functions similar to those of the avian bursa of Fabricius. In the young rabbit, there is rapid growth and expansion of B lymphocytes in the appendix, and positive and negative selection events occur. We believe that the cells that survive selection in the appendix seed the peripheral lymphoid system and undergo self renewal to maintain the primary repertoire. The data on rabbit led us to study the role of human appendix and GALT in development of the human immune repertoire and mucosal immunity. We compared development of normal human appendix germinal centers (GC) with rabbit appendix GC development at different ages. In both human and rabbit appendix, we found that lymphoid follicles were just beginning to form at birth. Germinal centers became evident at about 1 month in human and at 1 week in rabbit appendix. Most lymphoid development occurred within the first year in the human and within the first 12 weeks in the rabbit appendix. Lymphoid tissue began to atrophy by adulthood in both human and rabbit appendix. The follicles became smaller and fewer in number whereas the connective tissue and smooth muscle increased. The appendix did not entirely involute; germinal centers were still present in 5 human samples from individuals 75 years or older and in 6- and 7 yr-old rabbit specimens. The human appendix shares some characteristics of a "mammalian bursa equivalent"; it is a B-cell rich organ in the young and the morphology of the follicles and GC changes with age. The human appendix is similar in many respects to the rabbit appendix, avian bursa and sheep ileal Peyer's patch, yet several differences exist. The GC structure and relative GC T-cell density of the human appendix throughout development differs from that of the rabbit appendix and chicken bursa which could indicate that human appendix is more similar to a peripheral than central lymphoid organ. However, it is possible that peripheral lymphoid organs share some central lymphoid function. Whether this is true for the human appendix and other GALT warrants further investigation. Molecular studies of sequences of genes encoding antibody heavy and light chain are in progress (see Z01 AI00226-19 LI) to further investigate whether the appendix of man plays any role as a primary lymphoid organ.(J. Dasso et al., 2000).A clinical research protocol (#OH99-I-N026) entitled, "Effect of Appendectomy on Mucosal Immunity in Children" was reviewed and approved by the IRBs of Children's National Medical Center, and NIAID, NIH. I terminated this study as of July 29, 2000 because of low numbers of patients accrued and our inability to carry through the arm of the study that would have analyzed responses to oral polio vaccine. A paper describing the methods developed to prepare and assay patient samples and some preliminary results is in preparation (J. Dasso et al., ms in preparation).

我们对兔子的研究表明，幼阑尾是产生保护性抗体的细胞发育的重要部位。家兔阑尾的功能与鸟类腔上囊相似。 在幼兔中，阑尾中B淋巴细胞快速生长和扩增，并发生阳性和阴性选择事件。我们相信，在阑尾选择中存活下来的细胞在外周淋巴系统中播种，并进行自我更新以维持初级库。兔的数据引导我们研究人阑尾和GALT在人免疫库和粘膜免疫发育中的作用。 我们比较了正常人阑尾生发中心（GC）和不同年龄兔阑尾GC的发育。 在人类和兔子的阑尾中，我们发现淋巴滤泡在出生时刚刚开始形成。在人类中大约1个月和在兔阑尾中1周时，Germination中心变得明显。大多数淋巴发育发生在人类的第一年内，兔阑尾的前12周内。人和兔阑尾的类阑尾组织在成年期开始萎缩。 滤泡变小、数量减少，结缔组织和平滑肌增多。 阑尾并不完全内卷;在来自75岁或以上个体的5个人类样本和6岁和7岁的兔子标本中仍然存在生发中心。 人类阑尾具有“哺乳动物囊等价物”的一些特征;它在年轻时是一个富含B细胞的器官，并且卵泡和GC的形态随着年龄的变化而变化。 人类阑尾在许多方面与兔阑尾、禽法氏囊和羊回肠派尔集合淋巴结相似，但也存在一些差异。 在整个发育过程中，人阑尾的GC结构和相对GC T细胞密度与兔阑尾和鸡法氏囊的GC结构和相对GC T细胞密度不同，这可能表明人阑尾更类似于外周淋巴器官而不是中枢淋巴器官。 然而，外周淋巴器官可能共享某些中枢淋巴功能。 人类阑尾和其他GALT是否如此，需要进一步研究。 编码抗体重链和轻链的基因序列的分子研究正在进行中（参见Z 01 AI 00226 -19 LI），以进一步研究人类阑尾是否作为初级淋巴器官发挥任何作用。(J. Dasso等人，标题为“Effect of Adipectomy on Mucocytes Immunity in Children”的临床研究方案（#0H99-I-N 026）由儿童国家医学中心的IRB和NIAID，NIH审查和批准。 我于2000年7月29日终止了这项研究，因为累积的患者数量很少，而且我们无法完成本应分析口服脊髓灰质炎疫苗反应的研究。 正在准备一篇描述开发用于制备和测定患者样品的方法以及一些初步结果的论文（J. Dasso等人，MS在准备中）。