IN VIVO MODELS FOR HUMAN GENITAL TISSUES AND SEXUALLY TRANSMITTED DISEASES

大多数性传播疾病都没有疫苗，而且由于疫苗的开发和实施既昂贵又耗时，世界卫生组织和美国国立卫生研究院的官员已经认识到，控制和预防性传播疾病的一个切实可行的办法是开发局部杀微生物剂，这种杀微生物剂价格低廉，在环境温度下稳定，妇女可以谨慎使用。阴道杀微生物剂是阴道给药的产品，可用于预防人类免疫缺陷病毒（HIV）感染和/或其他性传播疾病感染。自该项目启动以来的三年中，在建立管状、阴道、人类上皮异种移植物方面取得了巨大成功，并证明了这些移植物对代表性性传播疾病（HPV和单纯疱疹病毒2型（HSV-2））的易感性。未感染的移植物再现了正常人类阴道的组织学和细胞化学特征，而感染的移植物产生了与患者病变相同的病理特征和病毒大分子合成。异种移植物也已成功地用于证明杀菌剂预防HPV感染（通过烷基硫酸盐化学家族的杀菌剂和杀菌剂C31G）以及HSV-2感染（通过C1G）。在拨款的下一阶段，我们会扩大使用这个模式。我们的具体目标将是：(1)继续在组织和细胞水平上对人类异种移植物进行表征：(a)优化移植物的生长参数，包括比较裸鼠、严重联合免疫缺陷（SCID）小鼠和用人淋巴网状细胞重组的SCID小鼠的生长；(b)描述黄体酮占优势（而不是雌激素占优势）状态下异种移植物的特征；(b)确定异种移植物中的非上皮细胞，特别是淋巴网状细胞的数量；(2)完成硫酸烷基杀菌剂在人类阴道异种移植物系统中的毒性和功效的表征；(3)确定未配制和配制的烷基硫酸盐在灭活或阻止从人、胎儿肛门上皮建立移植物方面的最低抑制浓度，其中杀微生物剂和目标组织感染的效果可能会被研究。

Vaccines do not exist for most STDs, and because vaccine development and implementation is costly and time-consuming, officials of the World Health Organization and the National Institutes of Health have recognized that on practical approach to control and prevention of STDs is development of topical microbicides which would be affordable, stable at ambient temperature and could be used discreetly by women. Vaginal microbicides are products for vaginal administration that can be used to prevent human immunodeficiency virus (HIV) infection and/or infections by other STDs. During the three years since this Program Project was initiated, great success has been achieved in establishing tubular, vaginal, human epithelial xenografts and susceptibility of these grafts to representative STDs [HPV and herpes simplex virus type 2 (HSV-2)] has been demonstrated. Uninfected grafts recapitulate the histological and cytochemical features of normal human vagina while infected grafts produce a profile of pathologic features and virus macromolecular synthesis identical to those in patient lesions. Xenografts have also been successfully used to demonstrate microbicidal prevention of HPV infection (by microbicides from the alkyl sulfate chemical family and by the microbicide C31G) as well as HSV-2 infection (by C1G). In the next phase of the grant, we will expand use of this model. Our Specific Aims will be to: (1) Continue characterization of human xenografts at the tissue and cellular level by: (a) Optimizing growth parameters for the grafts, including comparison of growth in nude mice, severe combined immunodeficient (SCID) mice, and SCID mice reconstituted with human lymphoreticular cells; (b) Characterizing the profile of xenografts in a progesterone-dominant (as opposed to an estrogen-dominant) state; (b) Determining the repertoire of non-epithelial cells, specifically lymphoreticular cells, in the xenografts: (2) Complete the characterizing of the toxicity and efficacy of alkyl sulfate microbicides in the human vaginal xenograft system: (3) Determine the minimal inhibitory concentrations of non-formulated and formulated alkyl sulfates in inactivating or interdicting establishing grafts from human, fetal anal epithelium, in which efficacy of microbicides and infections of this target tissue might be studied.