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切实可行的方法是开发局部杀微生物剂，这种杀微生物剂将是负担得起的，在环境温度下稳定，并且可以由妇女谨慎使用。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STD感染。在本计划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病[HPV和单纯疱疹病毒2型（HSV-2）]的易感性。未感染的移植物概括了正常人阴道的组织学和细胞化学特征，而感染的移植物产生与患者病变相同的病理特征和病毒大分子合成的概况。异种移植物也已成功地用于证明HPV感染的杀微生物预防（通过来自烷基硫酸盐化学家族的杀微生物剂和通过杀微生物剂C31 G）以及HSV-2感染（通过C1 G）。在下一阶段的赠款中，我们将扩大使用这种模式。我们的具体目标将是：（1）通过以下方式继续在组织和细胞水平上表征人异种移植物：（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建的SCID小鼠的生长;（B）表征甾酮显性免疫缺陷小鼠中异种移植物的特征。（与雌激素主导的相反）状态;（B）确定异种移植物中非上皮细胞，特别是淋巴网状细胞的库：（2）完成烷基硫酸盐杀微生物剂在人阴道异种移植物系统中的毒性和功效的表征：（3）测定未配制和配制的烷基硫酸盐在灭活或阻断从人胎儿肛门上皮建立的移植物中的最小抑制浓度，其中可以研究杀微生物剂的功效和该靶组织的感染。

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.