IN VIVO MODELS FOR HUMAN GENITAL TISSUES AND SEXUALLY TRANSMITTED DISEASES

大多数性传播疾病不存在疫苗，由于疫苗的开发和实施既昂贵又耗时，世界卫生组织和国家卫生研究院的官员认识到，在控制和预防性传播疾病的实际方法上，有必要开发负担得起的、在常温下稳定的局部杀微生物剂，并可供妇女谨慎使用。阴道杀菌剂是用于阴道给药的产品，可用于预防人类免疫缺陷病毒(HIV)感染和/或其他性传播疾病的感染。自该计划项目启动以来的三年中，在建立输卵管、阴道和人上皮异种移植方面取得了巨大的成功，并证明了这些移植物对典型的性传播疾病[HPV和单纯疱疹病毒2型(HSV-2)]的易感性。未感染的移植物概括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皮损相同的病理特征和病毒大分子合成。异种移植物也被成功地用于证明杀菌预防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)。在下一阶段的赠款中，我们将扩大这一模式的使用。我们的具体目标将是：(1)继续在组织和细胞水平上描述人类异种移植的特征：(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)小鼠和由人淋巴网状细胞重组的SCID小鼠的生长；(B)描述异种移植的黄体酮占优势(而不是雌激素占优势)状态的特征；(2)完成烷基硫酸盐在人阴道异种移植系统中的毒性和有效性的表征：(3)确定非配方和配方烷基硫酸盐灭活或阻断人胎儿肛门上皮建立移植物的最低抑菌浓度，其中可研究杀菌剂的有效性和对该靶组织的感染。

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.