Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 430
--> D Part 1: Barrier Methods Lourens J.D. Zaneveld, Ph.D., D.V.M. Department of Obstetrics and Gynecology, Rush University, Rush-Presbyterian-St. Luke's Medical Center Deborah J. Anderson, Ph.D. Fearing Research Laboratory, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School Kevin J. Whaley, Ph.D. Department of Biophysics, The Johns Hopkins University Introduction This chapter has two parts. The first describes approaches to development of novel vaginal agents and formulations with potential for preventing both conception and STD transmission. To facilitate understanding of these approaches, we present background information on the nature of chemical formulations, the functional activity of spermatozoa, and the infective mechanisms of sexually transmitted pathogens. The second part of the chapter presents some of the theoretical underpinnings of mucosal immunity, an area that offers hope of bridging the large and present gap between contraception and prevention of sexually transmitted disease. The need to focus on sexually transmitted diseases in connection with contraception reflects a growing, if reluctant, recognition of several large sociomedical facts: that the prevalence of these diseases is mounting in much of the world; that their transmission is not limited to small or distant populations engaging in aberrant sexual behavior; that their immediate and more remote sequelae can be dire; and that, biologically and behaviorally, contraception and disease prevention will be necessary partners, at least sometimes, for significant numbers of people and for the foreseeable future. While effective contraceptive technology for females has been available for several decades, very few contraceptive methods—the condom and some vaginal
OCR for page 431
--> formulations and devices—also protect against sexually transmitted diseases (STDs) (Claypool 1994). Of these, only the condom offers protection against the whole spectrum of these diseases, including HIV, and only the female condom and vaginal formulations and devices can be controlled directly by women. Attempts to limit the spread of HIV and other STDs through behavioral modification, encouraging condom use and fewer sexual partners, for example, have proved insufficient to the large task of stemming transmission of these diseases (Stein 1993). Furthermore, understanding about alternative, nonpenetrative sexual practices (''outercourse") that are both protective and satisfying would appear to be limited, although recent empirical data in large population samples are lacking (Greenwood and Margolis 1981; Norman and Cornett 1995; Norsigian 1994). Women experience particular difficulties owing to underlying gender power inequalities that constrain their ability—sometimes severely—to protect themselves from HIV infection, given the absence of a protective technology they could use, if necessary, without a partner's consent (Stein 1990). New emphasis on developing contraceptive agents that have the additional, critical characteristic of preventing STDs is also being driven by the realization that sexually transmitted diseases other than HIV elevate the risk of HIV transmission (Berkley 1991; Wasserheit 1992); by the increasing rates of heterosexual transmission of HIV infection; by realization of women's greater vulnerability to infection (Mann et al. 1992; Stein 1993); and by women's need to control their own protection against infection and/or conception. Globally, most women are at greatest risk of acquiring HIV through heterosexual vaginal intercourse with an infected man (Mayer and Anderson 1995). To avoid infection via this route, a preventive method must establish an effective barrier between the infectious elements in genital secretions and those cells of the female reproductive tract that are susceptible to infection. Such a barrier may be physical (such as that provided by condoms), chemical (such as that provided by an intravaginal microbicide), some combination of a physical and a chemical barrier (such as a condom and an intravaginal microbicide), or immunologic (such as topically applied monoclonal antibodies or mucosal immunogens). The ideal vaginal microbicide should be colorless, odorless, tasteless, stable at room temperature with a long shelf life, easy to use, fast-acting for an appropriate duration after insertion, effective pre- and postcoition, affordable, available without prescription, and safe for use at least once or twice daily. While it would be desirable to develop some microbicides that do not kill sperm, because women who only sometimes want to prevent pregnancy will always want to prevent STD infection, this paper focuses on chemical barriers that may be able to block both conception and STD transmission, that is, "prophylactic contraception" (Cone and Whaley 1994). In so doing, however, there is no intention to disparage the present and future value of physical barrier methods. The diaphragm and cervical cap can provide some protection against disease transmission (Rosenberg et al. 1992) and are
OCR for page 432
--> appropriate for use by some women, although much is unknown about their efficacy, utilization, and protective power (Stein 1993; Stratton and Alexander 1993). Vaginal topical formulations had received very little research attention until recently. Advances have relied on serendipitous discovery or relatively minor changes in existing methods and, overall, have failed to solve the most critical problems associated with these formulations. Nevertheless, scientists have accumulated much new knowledge about sperm and genital tract physiology over the past three decades. Combined with recent progress in biochemistry, pharmaceutics, and engineering, such knowledge should make it possible now to compensate for previous lack of progress in this increasingly critical area. Mechanisms of Fertilization by Spermatozoa During ejaculation, spermatozoa are often placed near the cervix, trapped within the seminal coagulum. As the coagulum liquefies, the spermatozoa are released and enter cervical mucus, a process of penetration that can occur as rapidly as 1.5 to 3 minutes after ejaculation. The primary mechanism whereby spermatozoa pass through cervical mucus appears to be their motility, although other factors such as enzymatic digestion of the mucus may also play a role. The amount of time viable spermatozoa remain in the vagina is not well studied but appears to vary from two to six hours. Successful sperm penetration into and through cervical mucus occurs primarily during the mid-cycle of the menstrual period, at which time the cervical mucus may contain micelles that guide spermatozoa toward the uterus. At other times in the cycle, particularly the luteal phase, cervical mucus is "hostile" to spermatozoa and does not allow penetration. Even at the optimal period, only about 0.1 to 1 percent of ejaculated spermatozoa pass through the cervix. Still, many spermatozoa become trapped in the cervical crypts and can be released at a later date, potentially providing a constant source of spermatozoa for about four days. Passage of spermatozoa through the uterus and fallopian tubes (oviducts) relies on sperm motility, contractions of the tract, and the motion of cilia on the endothelial surface. Because the uterotubal junction and the fallopian tube isthmus also present a barrier to sperm transport, only about 5,000 spermatozoa actually reach the site of fertilization. At the time of fertilization, an oocyte is surrounded by three layers. These are, from the outside inwards, the cumulus oophorus, the corona radiata, and the zona pellucida. The fertilizing spermatozoon has to pass through all these layers to contact the oocyte itself. In addition, it must penetrate the vitelline (egg plasma) membrane and decondense inside the ooplasm. Penetration through the oocyte's protective layers requires the use of lytic enzymes, associated with the acrosome of the spermatozoon. Good evidence suggests that hyaluronidase helps sperm pass through the cumulus; acrosin, a serine proteinase, helps it penetrate
OCR for page 433
--> the zona pellucida. Sperm motility, ligand-receptor interactions, and other factors are also required for sperm penetration. Just before or just after it contacts the zona pellucida, the spermatozoon undergoes a morphologic change called the acrosome reaction. This extracellular or exocytotic event results in the disappearance of the sperm's outer acrosomal membrane and surrounding plasma membrane; dispersal of the acrosome proper; activation of proacrosin; and release of acrosomal contents, with acrosin being of particular importance. While sperm penetration through the cumulus oophorus can occur in the absence of the acrosome reaction—presumably because hyaluronidase is associated with the external membranes—sperm passage through the zona pellucida is not possible without this reaction. An early acrosome reaction, such as one that occurs in the vagina, will result in premature release of acrosomal contents and, most likely, in an inability of the spermatozoon to fertilize. Proper timing of the acrosome reaction is controlled by capacitation in the female genital tract, an activation process resulting in removal of inhibitory substances from the sperm surface; by possible modification of the sperm's plasma membrane; and by changes in motility patterns. Ejaculated spermatozoa cannot undergo the acrosome reaction unless they are capacitated. Capacitation can occur in all parts of the female genital tract, with the possible exception of the vagina, and requires at least four hours. However, it probably occurs as a continuous process while the spermatozoa are being transported through the cervix, uterus, and fallopian tubes, so that a spermatozoon is fully or mostly capacitated by the time it reaches the oocyte. Final steps in the capacitation process may occur during sperm passage through the cumulus oophorus. Recently, biochemical aspects of capacitation and the acrosome reaction have received significant attention as possible targets for intervention (Dunbar and O'Rand 1991; see also Appendixes B and C in this volume). The former appears to involve impeding maturation and the acrosome reaction by preventing changes in the sperm's plasma membrane or, in contrast, attempting to induce a premature acrosome reaction that would render sperm unable to meld with an egg. The acrosome reaction, like other exocytotic processes, requires certain physiological conditions such as ligand interaction with surface receptors, activation of second messenger systems, protein phosphorylation, ionic and osmotic changes, and, ultimately, membrane fusion, vesiculation, and disappearance. Mechanisms of Infection by Sexually Transmitted Pathogens Sexually transmitted diseases are caused by a variety of organisms, including bacteria (aerobic and anaerobic), chlamydia, mycoplasmas, ureaplasmas, spirochetes, fungi, flagellates, amoebae, worms, and viruses. Each of these organisms has different biologic properties, conferring widely diverse mechanisms of infection and pathogenesis (see Chapter 2 and Chapter 5).
OCR for page 434
--> TABLE D-1 Susceptible Sites for Sexually Transmitted Disease Infection in the Lower Female Genital Tract Vulva Vagina Endocervix WBCs of Vascular Origin Treponema pallidum X X X Haemophilus ducreyi X X Neisseria gonorrhoeae X Candida albicans X Trichomonas vaginalis X Chlamydia trachomatis X Cytomegalovirus X Epstein Barr virus X Herpes simplex virus X X X Hepatitis B virus X X Human papillomavirus X X X Human immunodeficiency virus, type 1 ? ? X X Source: Derived from: P Stratton, NJ Alexander. Prevention of sexually transmitted infections. Infectious Disease Clinics of North America 7(4):841-859, December 1993; W Cates, KM Stone. HIV, other STDs, and barriers. IN Barrier Contraceptives: Current Status and Future Prospects, CK Mauck, M Cordero, HL Gabelnick, et al., eds. New York: Wiley-Liss. 1994. The most common human STD pathogens and their primary sites of infection are listed in Table D-1. Effective vaginal microbicides must block infection by directly and efficiently killing these organisms or by blocking or inactivating molecular mechanisms underlying infection. Current detergent vaginal formulations have broad-spectrum cytolytic properties that may be effective against several STD pathogens but may also damage epithelial and other genital tract cells and disrupt normal vaginal flora. Ligand/receptor molecules located on the surface of STD pathogens and their host cells—which are responsible for pathogen attachment and entry—are obvious targets for microbicide action. While these molecular structures have not been fully characterized for most STD pathogens, researchers are intensively seeking them today, importantly including HIV-AIDS. Human Immunodeficiency Virus (HIV) Type 1 The infectiousness of HIV is highly variable and there are still surprising gaps in understanding of its transmission, including the factors affecting amount and timing of virus shedding, the roles of vaginal and seminal antibodies, and the effects of exogenous or endogenous hormones (Mayer and Anderson 1995; Stratton and Alexander 1994). Partner studies have provided much of the information we do have. They indicate that the following factors affect rates of HIV
OCR for page 435
--> transmission: (1) mean numbers of sexual contacts and/or types of sexual practices; (2) differences in infectivity of partners depending on disease stage, symptomatology, and therapeutic drug status; (3) potential differences in infectivity of various clades of HIV-1; and (4) intrinsic biological differences between infecting or susceptible partners. Specific risk factors specific to heterosexual transmission of HIV-1 include: (1) sex during menstruation; (2) anal intercourse; (3) traumatic sex; (4) advanced HIV disease stage of infected partner; (5) zidovudine therapy (negative association); (6) age of the female partner; (7) choice of contraceptive method; and (8) concomitant STD infections (bacterial vaginosis, candidiasis, chancroid, chlamydia, gonorrhea, herpes simplex, human papilloma virus, syphilis, and trichomoniasis have all been associated with HIV transmission) (Mayer and Anderson 1995; Stratton and Alexander 1993). The cell biology and molecular mechanisms of HIV-1 sexual transmission are areas where much remains to be learned. It is known that HIV-1 is present in semen and cervicovaginal secretions, both in cell-free and cell-associated forms, and data from both in vitro and in vivo primate studies indicate that each of these forms may be capable of transmitting infection. Cell-free HIV-1 in genital-tract secretions may infect Langerhans cells, lymphocytes, and/or macrophages residing within the epithelial layer of mucosal surfaces in the vagina, foreskin, and penile urethra. Infection could occur via CD4, Fc, complement, or other receptors as yet unknown. If genital lesions or microabrasions are present, HIV-1-infected white blood cells (WBCs) in genital-tract secretions could infect by direct access to target cells in connective tissue (resident and extravasated WBCs). Furthermore, in vitro studies indicate that HIV-infected WBCs may have the capacity to adhere to mucosal epithelium and transmit HIV directly to these cells (Mayer and Anderson 1995). Numerous biologic variables can affect HIV levels in semen and cervicovaginal secretions and may also influence HIV transmission rates. Leukocytospermia (inflammation of the genital tract) in men has been associated with higher HIV-1 titres in semen. This phenomenon may be due to recruitment of HIV-1-infected cells to the genital tract; induction of edema and capillary dilation, both of which increase the potential for erosion and escape of blood lymphocytes and monocytes into the intravascular space and lumen; and/or activation of lymphocytes that could make them more capable of producing HIV- 1. In women, several variables can affect infectious HIV-1 titres in genital-tract secretions, including: (1) inflammation of the genital tract; (2) menstruation, which introduces infected peripheral blood cells into vaginal secretions; (3) factors elevating vaginal pH, which is normally acidic and confers protection against STDs, including HIV-1; (4) cervical ectopy; and (5) hormonal factors that influence the thickness of the epithelial layer and the production of protective mucus (Mayer and Anderson 1995). An open—and highly significant—question is whether HIV is carried solely by somatic cells in semen or whether it is carried by the sperm themselves. If the
OCR for page 436
--> former is the case, contraception is not necessary for prevention of sexually transmitted infection, so that a primary technologic need is for a virucide/microbicide; individuals can then decide whether they wish to contracept as well, but it is a separate decision. However, if the latter is the case, contraception becomes an essential concomitant of disease prevention (Stein 1993). The healthy human vagina has several natural defense mechanisms against STD pathogens. The stratified squamous epithelium lining of the vagina and ectocervix is generally several cell layers thick, conferring physical protection against most invading organisms. Copious amounts of mucins produced during certain stages of the menstrual cycle also provide a physical barrier to pathogens. In addition, the vagina and cervix are both capable of mounting antibody and cell-mediated immune responses to genital tract infections, and cervicovaginal secretions contain a number of nonspecific antibacterial and antiviral defense agents, including lysozymes, polyamines, zinc, H202, lactoferrin, and B-defensins (Cohen et al. 1990). Finally but quite importantly, the predominant normal vaginal microflora—lactobacillus organisms—help to maintain low pH conditions that are hostile to most viral and bacterial pathogens (Voeller et al. 1992b). Unfortunately, a number of situations perturb these natural protective mechanisms. Menopause and progestin-dominated hormonal therapies, for example, cause thinning of the squamous epithelial layer and reduction in cervical mucus production. Intercourse and vaginal infections, whose coincidence is not uncommon, can cause an elevation in vaginal pH, disarming this effective protective mechanism. And, although currently marketed vaginal topical contraceptives may, in fact, be buffered at acidic pH, the buffering capacity of semen itself elevates the vaginal pH substantially (Masters and Johnson 1980). Approaches to the Development of Novel Vaginal Formulations Pivotal Issues The Balance Between Protection and Perturbation The functional activity of both spermatozoa and pathogenic microbes can be prevented by killing or inactivating them. The former strategy employs spermicides and microbicides. The latter relies on agents that inhibit the functional activity of spermatozoa and microbes so that they are unable to enter, respectively, the oocyte or the vaginal/cervical epithelium and target cells. Although these inactivating agents are more appropriately called spermistats and microbistats, the terms spermicide or microbicide are still frequently used for all antifertility and antimicrobial agents. Candidate classes of these compounds include detergents and surfactants, iodophores, carbohydrates, antibodies, antiviral drugs, defensins, and pyocins.
OCR for page 437
--> Many of the chemical formulations that are currently available for use as vaginal contraceptives, in addition to their contraceptive properties, can confer some protection against such STD infections as Neisseria gonorrhea , Trichomonas vaginalis, and Chlamydia trachomatis (Rosenberg et al. 1987, 1992). However, like microbicides, spermicides act as cytotoxins, often destroying vaginal and cervical cell membranes (Patton et al. 1992). As a consequence, the protective capacity of these formulations erodes under frequent and/or prolonged use, largely because their potential effects on normal vaginal flora and on the vaginal/cervical epithelium create perturbations that can actually promote the possibility of STD transmission (Kreiss et al. 1992; Niruthisard et al. 1991, 1992). This means that, if vaginal formulations are to be used more often for STD prevention, they will have to be nonirritating, nontoxic, and not upset the normal vaginal environment. In other words, such formulations must produce no lasting impact on the normal vaginal flora and their work in maintaining the vaginal milieu and its naturally acidic pH, nor should they compromise the vaginal or cervical epithelium. Each formulation will therefore need to be rigorously tested for any proinflammatory effects that could promote transmission of STD pathogens, notably HIV-1. Efficacy A topical formulation used for purposes of vaginal contraception consists of one or more active ingredients and a base (carrier) to deliver them. Both are important and each presents particular challenges to researchers and users. Typically, an active ingredient makes up only about 5-10 percent of an entire formulation; at least this is the case for those products that are on today's market, primarily surfactants or detergents such as nonoxynol-9, octoxynol-9, menfegol, and benzalkonium chloride (Haslett 1990; Hatcher and Warner 1992; Mauck et al. 1994). The activity of these products resides in their ability to dissolve lipid components in the cell membrane or viral envelope. Since these agents have approximately the same properties and potency, marketed formulations differ primarily in their base composition—either jellies, creams, foams, suppositories, tablets, films, or sponges. Because the active ingredients in these formulations all act by immobilizing or killing spermatozoa, they are usually referred to as "spermicides." The contraceptive use-effectiveness of existing formulations varies greatly from study to study (Trussell 1994). Reported failure rates range from 2 percent to over 40 percent, with typical rates falling between 15 and 20 percent (Sobrero 1989), much higher than desirable. The limited efficacy of these formulations, their brief longevity after vaginal placement and effects on coital spontaneity, together with leakage and consequent "messiness," surely constrain consumer interest in available vaginal contraceptives. Although the relatively poor efficacy of available vaginal contraceptive for-
OCR for page 438
--> mulations can be partly blamed on improper use, some animal experiments have shown that the efficacy of many current products may be low even with more reliable use (Homm et al. 1976; Zaneveld et al. 1977). This implies that either their active ingredients and/or their distribution/delivery systems are in some way ineffective; because good comparative studies are rare, it has been difficult to discern where, exactly, the primary limitations reside. Furthermore, because many pathogens—for instance, HIV, the herpes viruses, and chlamydial elementary bodies—are cell-associated, the margin between toxicity and efficacy is narrow. There is nothing unique about the membrane of an infected cell that permits a surfactant to distinguish it from the membrane of a healthy cell, though the cells of intact genital mucosa may be protected to some extent by a coating of mucus. Finally, in vitro spermicidal efficacy does not necessarily translate into in vivo contraceptive efficacy (Quigg et al. 1988). Thus, without in vivo studies, it is not possible to state with certainty whether an agent with spermicidal properties is also contraceptive (Zaneveld 1994a, 1994b), nor are in vitro spermicidal comparisons adequate to the task of assessing the relative contraceptive activity of different formulations. The Base Because an active ingredient is only as effective as its delivery system allows, the formulation's base requires careful attention. Not only can the nature of a given base "make or break" the active ingredients, but can, in itself contribute to prevention of STD infections and conception, an attribute that should enhance the overall acceptability of vaginal topicals to women. The following characteristics of a good base are particularly important: A good base should spread rapidly and evenly over the vaginal and cervical surface, forming a slightly adhesive film. Optimally, this film should be impenetrable to microbes and, if possible, spermatozoa. The film should remain in place for prolonged periods of time, including during intercourse, providing long-acting protection. Leakage and consequent "messiness" should be minimal. Finally, the formulation should be somehow buffered at an acidic pH so as to retain a pH below 4.5 even in the presence of semen. New Technologies Many complicated biochemical processes are required for successful fertilization. Inhibition of any of these processes can lead to infertility, providing a
OCR for page 439
--> large number of potential attack sites for new contraceptive agents, both chemical and immunologic. Yet, to date, only a few researchers have taken advantage of advances in knowledge to develop novel vaginal contraceptives. New information can also be utilized to identify agents that can prevent both conception and STD infection. Tissue and/or cell invasion is required for both spermatozoa and pathogenic microbes to reach their target sites. Such invasion requires the activity of lytic enzymes, binding proteins, receptor-ligand interactions, fusion, endo- and exocytotic events, and a myriad of other processes. Each of these events is susceptible to inhibition, which would in turn prevent invasion. It is possible, if not likely, that spermatozoa and certain pathogenic microbes use some identical mechanisms of invasion. If so, the same agent could be used to prevent both occurrences (see Table D-2). Detergents and Surfactants Several detergents are already licensed in one country or another for intravaginal use as contraceptive agents. These include nonoxynol-9, the most commonly used, as well as menfegol, octoxynol, and benzalkonium chloride. Like the phospholipids that constitute cell membranes, detergents have hydrophobic and hydrophilic domains and exhibit activity that derives from their ability to dissolve lipid components in the cell membrane or viral envelope. Improvements on nonoxynol-9 may come from removing low molecular weight toxic components from the polydispersed N9 mixture (Klebanoff 1992; Walter et al. 1991a, 1991b), from improving dispersion/distribution, by providing for triggered release (Quigg 1991), or by lowering the detergent dose. In order to extend the spectrum of activity or longevity of action, low concentrations of nonoxynol-9 could be combined with other agents, for example, other detergents (Psychoyos 1994), beta-lactoglobulin (Neurath et al. 1996), antivirals (De Clercq 1993; Tsai et al. 1995), or zinc (Krieger and Rein 1992; Mardh et al. 1980; Williams 1980). Milk Fatty Acids Lipids found in human milk and epidermis display antibacterial and antiviral activity (Isaacs et al. 1990). Microbial killing by milk lipids is primarily due to the free fatty acids and monoglycerides that are released from milk triglycerides by lipases. At high concentrations, lipophilic molecules may be expected to have activity on sperm membranes that is similar to their activity on the membranes of other cells (Thormar et al. 1987). Chlorhexidine Chlorhexidine is a broad-spectrum antiseptic used in a prescription oral rinse. It is a positively charged molecule at physiological pH and binds to negative sites
OCR for page 440
--> TABLE D-2 Potential Targets and Mechanisms for Agents that Prevent Pregnancy and/or Sexually Transmitted Diseases Target Mechanism Intended Effect Sperm Nonoxynol-9 Surfactant Spermicidal C31G Surfactant Spermicidal Chlorhexidine Surfactant Spermicidal Peroxides Membrane active Spermicidal Antibody (MAb) Agglutination Decreased forward motility Shaking phenomenon Decreased forward motility Magainin Pore formation Spermicidal Decapacitation factor Blocks capacitation No acrosome reaction Progesterone Activates calcium channels Premature acrosome reaction AGB Acrosin inhibitor Fertilization blocked Sulfonated polystyrene Acrosin inhibitor Fertilization blocked Agglutination Decreased forward motility ZP mimics Blocks ZP binding Fertilization blocked Acidic buffer Maintains low pH Spermicidal Zinc Blocks capacitation Blocked fertilization Neem Membrane-active Spermicidal Squalamine Membrane-active Microbicidal Pathogen Nonoxynol-9 Disrupts membrane/envelope Microbicidal C31G Disrupts membrane/envelope Microbicidal Chlorhexidine Disrupts membrane/envelope Microbicidal Milk fatty acids Disrupt membrane/envelope Microbicidal Peroxides Membrane-active Microbicidal Antibody Agglutination Immune exclusion Docosanol Disrupts membrane/envelope Microbicidal (enveloped viruses) CAM mimic Decoy Adhesion blocked Sulfated polymer Coats cells Adhesion blocked Coats virus Fusion blocked AGB Protease inhibition Adhesion blocked Protegrins Pore-formation Microbicidal Acidic buffer Maintains low pH Microbicidal Zinc Binds proteins Microbicidal Neem Membrane-active Microbicidal Squalamine Membrane-active Microbicidal PMPA Reverse transcriptase inhibition Anti-HIV Cervicovaginal Environment 1. Mucus Acidic buffer Lowers or maintains pH Microbicidal Lactoferrin Fe binding Inhibits Fe dependent pathogens Lysozyme Enzymatic bacteriolysis Bactericidal Zinc Protein binding Microbicidal Sulfonated polystyrene Increases viscosity Decreased sperm migration Chlorhexidine Increases viscosity Decreased sperm migration
OCR for page 463
--> administered suppositories and a boosting effect might also be produced by reproductive processes themselves. Relatively little is known about cell-mediated immune (CMI) responses within the male or female genital tracts and their potential effects on fertility. Although chronic CMI responses may be associated with undesirable side effects such as delayed-type hypersensitivity and irreversibility, CMI responses to infrequent or low antigen exposures could provide a powerful adjunct mechanism for mucosally targeted immunization. More needs to be known about how secreted antibodies function in mucus to protect the human mucosal surfaces. Despite evidence that antibodies can be highly effective at blocking mucosal transmission of both infectious agents and sperm, both sperm and STD pathogens have evolved mechanisms for successful exchange between sexual partners—mechanisms that evade immune defenses in mucosal secretions—of which one of the most challenging is the common evasion mechanism of antigenic variability, which enables pathogens to stay a step ahead of host immune responses. A potential, though surely challenging, research direction would be to seek combinations of pathogen-specific monoclonal antibodies and pan-semen or other anti-human surface antigenic monoclonal antibodies that could defeat these evasive actions and ultimately provide effective broad-spectrum protection against STDs and pregnancy (Cone and Whaley 1994). References Abraham E, S Shah. Intranasal immunization with liposomes containing IL-2 enhances polysaccharide antigen-specific pulmonary secretory antibody response. Journal of Immunology 149:3719-3726, 1992. Ada GL. The induction of immunity at mucosal surfaces. IN Local Immunity in Reproductive Tract Tissues. PD Griffin, PM Johnson, eds. Oxford, UK: Oxford University Press. 1993. Alving CR, RL Richards. Liposomes containing lipid A: A potent nontoxic adjuvant for a human malaria sporozoite vaccine. Immunology Letters 25:275-279, 1990. Anderson DJ. Mechanisms of HIV-1 transmission via semen. Journal of NIH Research 4:104-108, 1992. Anderson DJ. Cell mediated immunity and inflammatory processes in male infertility. Archives of Immunology and Therapeutic Experiments 38:79-86, 1990. Anderson DJ, JA Hill. Cytokines in the reproductive tract that affect fertility. Mucosal Immunology Update 2:6-15, 1995. Anderson DJ, J Pudney. Mucosal immune defense against HIV-1 in the male urogenital tract. Vaccine Research 1:143, 1992. Anderson DJ, EJ Yunis. "Trojan Horse" leukocytes in AIDS. New England Journal of Medicine 309:984-985, 1983. Araujo FG, B Morein. Immunization with Trypanosoma cruzi epimastigote antigens incorporated into ISCOMS protects against lethal challenge in mice. Infectious Immunology 59:2909-2914, 1991. Beagley KW, JH Eldridge, F Lee, et al. Interleukins and IgA synthesis: Human and mouse IL-6 induce high rate of IgA secretion in IgA committed B cells . Journal of Experimental Medicine 169:2133-2148, 1989.
OCR for page 464
--> Berkley S. The public health significance of sexually transmitted diseases in HIV infection in Africa. IN AIDS and Women's Health: Science for Policy and Action. L Chen, et al., eds. New York: Plenum Press. 1991. Berlin C, EL Berg, MJ Briskin, et al. a4ß7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM- . Cell 74:185-195, 1993. Besredka A. De la vaccination contre les états typhoides par la voie buccale. Annales de l'Institute Pasteur 33:882-903, 1919. Besredka A. Local Immunization. Baltimore: Williams and Wilkins. 1927. Best CL, JA Hill. Natural infertility due to immunological factors. IN Birth Control Vaccines. R Raghupathy, GP Talwar, eds. Austin, TX: RG Landes. 1995. Bienenstock J, AD Befus. Mucosal immunology. Immunology 41:249-270, 1980. Bjercke S, H Scott, LR Braathen, et al. HLA-DR expressing Langerhans-like cells in vaginal and cervical epithelium. Acta Obstetrica Gynecologica Scandinavica 585-589, 1983. Bloom LD, D Rowley. Local immune response in mice to Vibrio cholerae. Australian Journal of Experimental Biology and Medical Science 57:313-323, 1979. Bockman DE, MD Cooper. Pinocytosis by epithelium associated with lymphoid follicles in the bursa of Fabricus, appendix, and Peyer's patches: An electron microscopic study. American Journal of Anatomy 136: 455-478, 1973. Bond MW, B Strader, TR Mosmann, et al. A mouse T cell product that preferentially enhances IgA production. 2. Physicochemical characterization. Journal of Immunology 139:3691-3696, 1987. Bourinbaiar AS, S Lee-Huang. Comparative in vitro study of contraceptive agents with anti-HIV activity: Gramicidin, nonoxynol-9 and gossypol. Contraception 49:131-137, 1994a. Bourinbaiar AS, S Lee-Huang. Acrosin inhibitor, 4'-acetamidophenyl 4-guanidinobenzoate, an experimental vaginal contraceptive with anti-HIV activity. Contraception 51:319-322, 1994b. Bourinbaiar AS, R Nagorny. Effect of serine proteinase inhibitor, N-a-tosyl-L-lysyl-chloromethylketone (TLCK) on cell-mediated and cell-free HIV-1 spread. Cellular Immunology 155:230-236, 1994. Brandtzaeg P. Human secretory immunoglobulin M: An immunochemical and immunohistochemical study. Immunology 29: 559-570, 1975. Brandtzaeg P. Two types of IgA immunocytes in man. Nature/New Biology 243:142-143, 1973. Brandtzaeg P, V Bosnes, TS Halstensen, et al. T lymphocytes in human gut epithelium express preferentially the alpha/beta antigen receptor and are CD45/UCHL-I positive. Scandinavian Journal of Immunology 30:23-128, 1989. Brandtzaeg P, E Christiansen, F Muller, et al. Humoral immune response patterns of human mucosae, including the reproductive tracts: The induction of immunity at mucosal surfaces. IN Local Immunity in Reproductive Tract Tissues. PD Griffin, PM Johnson, eds. Oxford, UK: Oxford University Press. 1993. Brandtzaeg P, I Fjellanger, ST Gjeruldsen. Human secretory immunoglobulins. I. Salivary secretions from individuals with normal or low levels of serum immunoglobulins. Scandinavian Journal of Haematology, Supplement 12: 1-83, 1970. Brandtzaeg P, I Fjellanger, ST Gjeruldsen. Immunoglobulin M: Local synthesis and selective secretion in patients with Immunoglobulin A deficiency. Science 160:789-791, 1968. Buiting AMJ, N van Rooijen, E Claasen. Liposomes as antigen carriers and adjuvants in vivo. Research in Immunology 143:541-548, 1992. Bulmer JN, DP Lunny, SV Hagin. Immunohistochemical characterization of stromal leukocytes in nonpregnant human endometrium. American Journal of Reproductive Immunology 17: 83-90, 1988. Burstein HJ, CM Shea, AK Abbas. Aqueous antigens induce in vivo tolerance selectively in IL-2 and IFN-gamma-producing (Thl) cells. Journal of Immunology 148:3687, 1992.
OCR for page 465
--> Cerf-Benussan N, B Begue, J Gagnon, et al. The human intraepithelial lymphocyte marker HML-1 is an integrin consisting of a ß7 subunit associated with a distinctive a chain. European Journal of Immunology 22:73-277, 1992. Challacombe SJ, T Lehner. Salivary antibody responses in rhesus monkeys immunized with Streptococcus mutans by the oral, submucosal or subcutaneous routes . Archives of Oral Biology 24:917-925, 1979. Challacombe SJ, TB Tomasi. Systemic tolerance and secretory immunity after oral immunization. Journal of Experimental Medicine 152:1459-1472, 1980. Chantler E, R Sharma, D Sharman. Changes in cervical mucus that prevent penetration by spermatozoa. Society for Experimental Biology 43:325-336, 1989. Chipperfield EJ, BA Evans. The influence of local infection on immunoglobulin formation in the human endocervix. Clinical Experiments in Immunology 11:219-223, 1972. Claasen I, A Osterhaus. The ISCOM structure as an immune-enhancing moiety: Experience with viral systems. Research in Immunology 143:531-541, 1993. Claypool LE. The challenges ahead: Implications of STDs/AIDS for contraceptive research. IN Contraceptive Research and Development, 1984 to 1994: The Road from Mexico City to Cairo and Beyond. PFA Van Look, G Pérez-Palacios, eds. Delhi: Oxford University Press. 1994. Cohen MS, RD Weber, PA Mardh. Genitourinary mucosal defenses. IN Sexually Transmitted Diseases (2nd ed.). KK Holmes, P-A Mardh, PF Sparling et al. eds. New York: McGraw-Hill. 1990. Cone RA, KJ Whaley. Monoclonal antibodies for reproductive health: Part I, Preventing sexual transmission of disease and pregnancy with topically applied antibodies. American Journal of Reproductive Immunology 32:114-131, 1994. Cook RF, T O'Neill, E Strachan, et al. Protection against lethal equine herpes virus type 1 (subtype 1) infection in hamsters by immune stimulating complexes (ISCOM) containing the major viral glycoproteins. Vaccine 8:491-496, 1990. Corner A-M, MM Dolan, SL Yankell, et al. C31G, a new agent for oral use with potent antimicrobial and antiadherence properties. Antimicrobiological Agents and Chemotherapy 32:350-353, 1988. Cornes JS. Number, size and distribution of Peyer's patches in human small intestine. Gut 6:225-233, 1965. Crabbe PA, AO Carbonara, JF Heremans. The normal human intestinal mucosa a major source of plasma cells containing A-immunoglobulin. Laboratory Investigation 14:235-248, 1965. Craig SW, JJ Cebra. Peyer's patches: An enriched source of precursors for IgA producing immunocytes in the rabbit. Journal of Experimental Medicine 134:188-200, 1971. Czerkinsky C, SJ Prince, SM Michalek, et al. IgA antibody-producing cells in peripheral blood after antigen ingestion: Evidence for a common mucosal system. Proceedings of the National Academy of Sciences, USA 84: 2449-2453, 1987. D'Cruz OJ, HA Pereira, GG Haas. Sperm immobilizing activity of a synthetic bioactive peptide 2044 of 37-kDa cationic antimicrobial protein (CAP37) of human neutrophils. Journal of Andrology 16:432-440, 1995. de Aizpurua HJ, GJ Russell-Jones. Oral vaccination: Identification of classes of proteins that provoke an immune response upon oral feeding. Journal of Experimental Medicine 167:440-451, 1988. DeClercq E. Antiviral agents: Characteristic activity spectrum depending on the molecular target with which they interact. Advances in Virus Research 42:1-55, 1993. deGraaf JH, RYJ Tamminga, WA Kamps, et al. Expression of cellular adhesion molecules in Langerhans cell histiocytosis and normal Langerhans cells. American Journal of Pathology 147:1161-1171, 1995.
OCR for page 466
--> de Vries P, RS van Binnendijk, et al. Measles virus fusion protein presented in an immune-stimulating complex (ISCOM) induces haemolysis-inhibiting and fusion-inhibiting antibodies, virus specific T cells and protection in mice. Journal of General Virology 69:549-559, 1988. de Waal A, AV Goes, A Mensink, et al. Magainins affect respiratory control, membrane potential and motility of hamster spermatozoa. Federation of European Biological Societies Letters 293:219-223, 1991. Devlin MC, BN Barwin. Barrier contraception. Advances in Contraception 5:197-204, 1989. Duits AJ, A van Puijenbroek, H Vermuelen, et al. Immunoadjuvant activity of a liposomal IL-6 formulation. Vaccine 11:777-781, 1993. Dunbar BS, MG O'Rand, eds. A Comparative Overview of Mammalian Fertilization. New York: Plenum Press. 1991. Edelman R. Vaccine adjuvants. Review of Infectious Disease 2:370, 1980. Edelstein MC, JE Gretz, TJ Bauer, et al. Studies on the in vitro spermicidal activity of synthetic magainins. Fertility and Sterility 55:647-649, 1991. Edwards JNT, HB Morris. Langerhans cells and lymphocyte subsets in the female genital tract. British Journal of Obstetrics and Gynaecology 92:974-982, 1985. El-Demiry MIM, TB Hargreave, A Busuttil, et al. Immunocompetent cells in human testis in health and disease. Fertility and Sterility 48:470-479, 1987. El-Demiry MIM, TB Hargreave, A Busuttil, et al. Lymphocyte sub-populations in the male genital tract. British Journal of Urology 57:769-774, 1985. El-Demiry MIM, K James. Lymphocyte subsets and macrophages in the male genital tract in health and disease. European Journal of Urology 14:226-235, 1988. Eldridge JH, JK Staas, JA Meulbroek, et al. Biodegradable microspheres as a vaccine delivery system. Molecular Immunology 3:287-294, 1991. Elias CJ, L Heise. The Development of Microbicides: A New Method of HIV Prevention for Women (Working Papers No. 6). New York: The Population Council . 1993. Elson CO, JA Heck, W Strober. T-cell regulation of murine IgA synthesis. Journal of Experimental Medicine 149:632-643, 1979. Foldesy RG, RE Homm, SL Levinson, et al. Multiple actions of a novel vaginal contraceptive compound, OR 13904. Fertility and Sterility 45:550-555, 1986. Forrest BD, DJA Shearman, JT LaBrooy. Specific immune reponses in humans following rectal delivery of live typhoid vaccines. Vaccine 8:209-212, 1992. Fowler JE, DL Kaiser, M Mariano. Immunologic response of the prostate to bacteriuria and bacterial prostatis: Part 1. Immunoglobulin concentrations in prostatic fluid. Journal of Urology 128:158-164, 1982. Fowler JE, M Mariano. Immunoglobulin in seminal fluid of fertile, infertile, vasectomy and vasectomy reversal patients. Journal of Urology 129:869-872, 1983. Fowler JE, M Mariano. Immunologic response of the prostate to bacteriuria and bacterial prostatitis. II. Antigen specific immunoglobulin in prostatic fluid. Journal of Urology 128:165-170, 1982. Franek J, J Libich, V. Kubin. Mechanisms of antibacterial immunity of mucous membranes. Folia Microbiologia 29:375-384. 1984. Ganz T, RI Lehrer. Defensins. Current Opportunities in Immunology 6:584-589, 1994. Gay FP. Local resistance and local immunity to bacteria. Physiology Reviews 4:191-214, 1924. Goldblum RM, S Ahlstedt, B Carlsson, et al. Antibody forming cells in human colostrum after oral administration. Nature 257:797-799, 1975. Greenwood S, AJ Margolis. ''Outercourse." Advances in Planning and Parenting 15:126-128, 1981. Grun JL, PH Maurer. Different T helper cell subsets elicited in mice utilizing two different adjuvant vehicles: The role of endogenous interleukin 1 in proliferative responses. Cell Immunology 121:134-145, 1989.
OCR for page 467
--> Guy-Grand D, C Griscelli, P Vassalli. The mouse gut T lymphocyte, a novel type of T cell: Nature, origin and traffic in mice in normal and graft-versus-host conditions. Journal of Experimental Medicine 169:1277-1294, 1978. Hafner L, C Rush, P Timms. Lactobacilli: Vehicles for antigen delivery to the female urogenital tract. IN Abstract book of the 7th International Congress of Mucosal Immunology, Prague, Czechoslovakia, August 1992. Haimovici F, DJ Anderson. Antifertility effects of antisperm cell-mediated immunity in mice. Journal of Reproductive Immunology 22:281-298, 1992. Hallenberger S, V Bosch, HJ Angliker, et al. Inhibition of cleavage activation of HIV- 1 glycoprotein gp160. Nature 360:358-361, 1992. Halpern MS, ME Koshland. Novel subunit in secretory IgA. Nature 228:1276-1278, 1970. Halstensen TS, H Scott, P Brandtzaeg. Intraepithelial T cells of the TCR gamma/delta+ CD8- and V deltal/J delta 1+ phenotypes are increased in coeliac disease. Scandinavian Journal of Gastroenterology 30:665-672, 1989. Haneberg B, D Kendall, HM Amerongen, et al. Induction of specific IgA in small intestine, colonrectum, and vagina measured with a new method for collection of secretions from local mucosal surfaces. Infectious Immunology 62(1):15-23, 1994. Hanson LA. Comparative immunological studies of the immune globulins of human milk and of blood serum. International Archives of Allergy and Applied Immunology 18:241-267, 1961. Haslett S. Barrier methods of contraception. Nursing Standard 4:24-27, 1990. Hatcher RA, DL Warner. New condoms for men and women, diaphragms, cervical caps, and spermicides: Overcoming barriers to barriers and spermicides. Current Opinions in Obstetrics and Gynecology 4:513-521, 1992. Hattori T, A Koito, KJ Takatsuki, et al. Involvement of tryptase-related cellular protease(s) in human immunodeficiency virus type 1 infection. Federation of European Biochemical Societies Letters 248:48-52, 1989. Holmgren J, N Lycke, C Czerkinsky. Cholera toxin and cholera toxin B subunit as oral-mucosal adjuvant and antigen vector systems. Vaccine 11:1179-1184, 1993. Holzmann B, BW McIntyre, IL Weissman. Identification of a murine Peyer's patch-specific lymphocyte homing receptor as an integrin molecule with an a chain homologous to human VLA-4a . Cell 56:37-46, 1989. Homm RE, GE Doscher, EG Hummel, et al. Relative antifertility activity of three vaginal contraceptive products in the rabbit: Relationship to in vitro data. Contraception 13:479-488, 1976. Homm RE, RG Foldesy, DW Hahn. ORF 13904, a new long-acting vaginal contraceptive. Contraception 32:267-274, 1985. Hornick CL, F. Karush. Antibody affinity-III: The role of multivalency. Immunochemistry 9:325-340, 1972. Husband AJ, VL Clifton. Role of intestinal immunization in urinary tract defence. Immunology and Cell Biology 67:371, 1989. Husband AJ, JL Gowans. The origin and antigen-dependent distribution of IgA containing cells in the small intestine. Journal of Experimental Medicine 148:1146, 1978. Husby S, J Mestecky, Z Moldoveanu, et al. Oral tolerance in humans: T cell but not B cell tolerance after antigen feeding. Journal of Immunology 152:4663-4670, 1994. Isaacs CE, S Kashyap, WC Heird, et al. Antiviral and antibacterial lipids in human milk and infant formula feeds. Archives of Diseases in Children 65:861-864, 1990. Itohara S, AG Farr, JJ Lafaille, et al. Homing of a yS thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature 343:754-757, 1990. Jacobsen LO, EK Marks, EL Simmons, et al. Immune response in irradiated mice with Peyer's patch shielding. Proceedings of the National Academy of Sciences, USA 108:487-493, 1961. Jalanti R, H Isliker. Immunoglobulins in human cervicovaginal secretions. International Archives of Allergy and Applied Immunology 53:402-409, 1977.
OCR for page 468
--> Janossy G, N Tidman, ES Selby, et al. Human T lymphocytes of the inducer and suppressor type occupy different microenvironments. Nature 288:81-84, 1980. Jarry A, N Cerf-Benussan, N Brousse, et al. Subsets of CD3+ (T cell receptor alpha/beta or gamma/ delta) and CD3-lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. European Journal of Immunology 20:1097-1103, 1990. Jefferson WL. Non-ionic surfactant spermicidal agents. British Journal of Family Planning 11:131-135, 1986. Jones PD, JJ Cebra. Restriction of gene expression in B lymphocytes and their progeny: 111. Endogenous IgA and IgM on the membranes of different plasma cell precursors. Journal of Experimental Medicine 140:966-976, 1974. Jones PP, R Tha Hla, B Morein, et al. Cellular immune responses in the murine lung to local immunisation with influenza A virus glycoproteins in micelles and immunostimulatory complexes (ISCOMs). Scandinavian Journal of Immunology 27:645-652, 1988. Kamat BR, PG Isaacson. The immunocytochemical distribution of leukocytic subpopulations in human endometrium. American Journal of Pathology 127:66-73, 1986. Kaminski JM, NA Nuzzo, L Bauer, et al. Vaginal contraceptive activity of aryl 4-guanidinobenzoates (acrosin inhibitors) in rabbits. Contraception 32:183-189, 1985. Katz DH, JF Marceletti, MH Khalil, et al. Antiviral activity of 1-docosanol, an inhibitor of lipidenveloped viruses including herpes simplex. Proceedings of the National Academy of Sciences, USA 88:10825-10829, 1991. Katz DH, JF Marceletti, LE Pope, et al. n-Docosanol: Broad spectrum antiviral activity against lipid-enveloped viruses. Annals of the New York Academy of Sciences 724:472-488, 1994. Kilshaw PJ, SJ Murant. Expression and regulation of ß7(ß) integrins on mouse lymphocytes: Relevance to the mucosal immune system. European Journal of Immunology 21:2591-2597, 1991. Kilshaw PJ, SJ Murant. A new surface antigen on intraepithelial lymphocytes in the intestine. European Journal of Immunology 20:2201-2207, 1990. Klebanoff SJ. Effects of the spermicidal agent nonoxynol-9 on vaginal microbial flora. Journal of Infectious Diseases 165:19-25, 1992. Klebanoff SJ, RW Coombs. Viricidal effects of Lactobacillus acidophilus on human immunodeficiency virus type 1: Possible role in heterosexual transmission. Journal of Experimental Medicine 174: 289-292, 1991. Koito A, T Hattori, T Murakami, et al. A neutralizing epitope of human immunodeficiency virus type 1 has homologous amino acid sequences with the active site of inter-a-trypsin inhibitor . International Immunology 1:613-618, 1989. Kojima H, S-P Wang, C-C Kuo, et al. Local antibody in semen for rapid diagnosis of Chlamydia trachomatis epididymitis. Journal of Immunology 140:528-531, 1988. Kreiss J, E Ngugi, K Holmes, et al. Efficacy of nonoxynol-9 contraceptive sponge use in preventing heterosexual acquisition of HIV in Nairobi prostitutes. Journal of the American Medical Association 268:477-482, 1992. Krieger JN, MF Rein. Canine prostatic secretions kill Trichomonas vaginalis. Infectious Immunology 37:77-81, 1982. Kroese FGM, EC Butcher, AM Stall, et al. Many of the IgA producing plasma cells in the murine gut are derived from self-replenishing precursors in the peritoneal cavity. International Immunology 1:75-84, 1988. Kutteh WH, RP Edwards, AC Menge, et al. IgA immunity in female reproductive tract secretions. IN Local Immunity in Reproductive Tract Tissues. PD Griffin, PM Johnson, eds. Oxford, UK: Oxford University Press, 1993. Kutteh WH, C Kutteh, RE Blackwell, et al. Secretory immune system of the female reproductive tract. II. Local immune system in normal and infected fallopian tube. Fertility and Sterility 54:51-55, 1990.
OCR for page 469
--> Kutteh WH, J Mestecky. Secretory immunity in the female reproductive tract. American Journal of Reproductive Immunology 31:40-46, 1994. Lehner T, LA Bergmeier, C Panagiotidi, et al. Induction of mucosal and systemic immunity to a recombinant simian immunodeficiency viral protein. Science 258:1365-1369, 1992. Lehner T, R Brookes, C Panagiotidi, et al. T- and B-cell functions and epitope expression in nonhuman primates immunized with simian immunodeficiency virus antigen by the rectal route. Proceedings of the National Academy of Sciences, USA 90:8638-8642, 1993. Lehrer RI. Defensins: Antimicrobial and cytotoxic peptides of mammalian cells. Annual Review of Immunology 11:105-128, 1993. Lenaerts V, R Gurny. Bioadhesive Drug Delivery Systems. Boca Raton, FL: CRC Press. 1990. London SD, JJ Cebra, DH Rubin. Intraepithelial lymphocytes contain virus-specific MHC-restricted precursors after gut mucosal immunization with reovirus serotype 1/Lang. Regional Immunology 2:99-105, 1989. Ma JK-C, A Hiatt, M Hein, et al. Generation and assembly of secretory antibodies in plants. Science 268:716-719, 1995. Mann J, DJM Tarantola, TW Netter, eds. A Global Report: AIDS in the World. Cambridge, MA: Harvard University Press. 1992. Mardh P-A, S Colleen, J Sylwan. Inhibitory effect on the formation of chlamydial inclusions in McCoy cells by seminal fluid and some of its components. Investigations in Urology 17:510-513, 1980. Masters WH, VE Johnson. Human Sexual Response. New York: Bantam Books. 1980. Mauck CK, M Cordeo, HL Gabelnick, et al., eds. Barrier Contraceptives: Current Status and Future Prospects. New York: Wiley-Liss. 1994. Mayer KH, DJ Anderson. Issue of the day: Heterosexual HIV transmission. Infectious Agents and Disease 4:273-284, 1995. Mazanec MB, JG Nedrug, et al. A three-tiered view of the role of IgA in mucosal defense. Immunology Today 14:430-435, 1993. McAnulty PA, DB Morton. The immune response of the genital tract of the female rabbit following local and systemic immunization. Clinical Laboratory Immunology 1:255-260, 1978. McCune JM, LB Rabin, MB Feinberg, et al. Endoproteolytic cleavage of gp160 is required for the activation of human immunodeficiency virus. Cell 53:5-57, 1988. McDermott MR, J Bienenstock. Evidence for a common mucosal system. 1. Migration of B immunoblasts into intestinal, respiratory and genital tissues. Journal of Immunology 122:1892-1898, 1979. McDermott MR, CH Goldsmith, KL Rosenthal, L Brais. T lymphocytes in genital lymph nodes protect mice from intravaginal infection with Herpes Simplex type 2. Journal of Infectious Diseases 159:460-466, 1989. McGhee JR, KW Beagley, K Fujihashi, et al. Regulatory mechanisms in mucosal immunity: Roles for T helper cell subsets and derived cytokines in the induction of IgA responses. IN Local Immunity in Reproductive Tract Tissues. PD Griffin, PM Johnson, eds. Oxford, UK: Oxford University Press. 1993. McGhee JR, J Mestecky, MT Dertzbaugh, et al. The mucosal immune system: From fundamental concepts to vaccine development. Vaccine 10:75-88, 1992. McMillan A, G McNeillage, H Young. Antibodies to Neisseria gonorrhoeae: A study of the urethral exudates of 232 men. Journal of Infectious Diseases 140:89-95, 1979. McShane PM, I Schiff, DE Trentham. Cellular immunity to sperm in infertile women. Journal of the American Medical Association 253:3555-3558, 1985. Mestecky J. The common mucosal immune system and current strategies for induction of immune responses in external secretions. Journal of Clinical Immunology 7:265-276, 1987. Mestecky J, JR McGhee. The secretory IgA system. IN Local Immunity in Reproductive Tract Tissues. PF Griffin, PM Johnson, eds. Oxford, UK: Oxford University Press. 1993.
OCR for page 470
--> Mestecky J, JR McGhee. Oral immunization: Past and present. IN Current Topics in Microbiology and Immunology: New Strategies of Oral Immunization. J Mestecky, JR McGhee, eds. Berlin: Springer Verlag. 1989. Mestecky J, JR McGhee, RR Arnold et al. Selective induction of immune responses in external secretions. Journal of Clinical Investigation 61:731-737, 1978. Mestecky J, J Zikan, W Butler. Immunoglobulin M and secretory immunoglobulin A: Evidence for a common polypeptide chain different from light chains. Science 171:1163-1165, 1971. Metter L, D Schirwani. Macrophage migration inhibitory factor in female sterility. American Journal of Obstetrics and Gynecology 121:117-120, 1975. Michaels EB, EC Hahn, AJ Kenyon. Effect of C31G, an antimicrobial surfactant, on healing of incised guinea pig wounds. American Journal of Veterinary Research 44:1378-1381. 1983. Michalek SM, I Morisaki, IL Gregory, et al. Oral adjuvants enhance salivary IgA responses to purified Streptococcus mutans antigens. Protides Biology of Fluids 32:47-52, 1985. Miller CJ, JR McGhee, MB Gardner. Biology of disease: Mucosal immunity, HIV transmission and AIDS. Laboratory Investigation 68:129-145, 1992. Miller CJ, P Vogel, NJ Alexander, et al. Pathology and localization of SIV in the reproductive tract of chronically infected male rhesus macaques. Laboratory Investigation 70:255-262, 1994. Mims CA. The Pathogenesis of Infectious Disease. London: Academic Press. 1988. Montgomery PC, J Cohn, ET Lally. The induction and characterization of secretory IgA molecules. Advances in Experimental Medicine and Biology 45:453-462, 1976. Moore KS, S Wehrli, H Roder, et al. Squalamine: An aminosterol antibiotic from the shark. Proceedings of the National Academy of Sciences, USA 90:1354-1358, 1993. Mosmann TR, RL Coffman. Thl and Th2 cells: Different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology 145-173, 1989. Mowat AM. The regulation of immune responses to dietary protein antigens. Immunology Today 8:93-98, 1987. Mowat AM, AM Donachie, G Reid, et al. Immune-stimulating complexes containing Quil A and protein antigen prime class 1 MHC-restricted T lymphocytes in vivo are immunogenic by the oral route. Immunology 72:317-322, 1991. Murray PD, DT McKenzie, SL Swain, et al. Interleukin 5 and interleukin 4 produced by Peyer's patch T cells selectively enhance immunoglobulin A expression. Journal of Immunology 139:2669-2674, 1987. National Research Council. Neem: A Tree for Solving Global Problems. Washington, DC: National Academy Press. 1992. Naz RK, K Metha. Cell-mediated immune responses to sperm antigens: Effect on mouse sperm and embryos. Biology of Reproduction 41:533-542, 1989. Neurath AR, S Jiang, N Strick, et al. Bovine beta-lactoglobulin modified by 3-hydroxyphatalic anhydride blocks the CD4 cell receptor for HIV. Nature Medicine 2:230-234, 1996. Niruthisard S, RE Roddy, S Chutivongse. Use of nonoxynol-9 and reduction in rate of gonococcal and chlamydial cervical infections. Lancet 339:1371-1375, 1992. Niruthisard S, RE Roddy, S Chutivongse. The effects of frequent nonoxynol-9 use on the vaginal and cervical mucosa. Sexually Transmitted Diseases 18:176-179, 1991. Norman LR, J Cornett. Discussing nonpenetrative sexual activities as safer sex alternatives for HIV prevention with HIV-infected clients. Presentation at workshop sponsored by the Centers for Disease Control, Washington, DC, 1995. Norsigian J. Feminist perspective on barrier use. IN Barrier Contraceptives: Current Status and Future Prospects. CK Mauck, M Cordero, HL Gabelnick, et al., eds. New York: Wiley-Liss. 1994. O'Hagan DT, JP McGhee, J Holmgren, et al. Biodegradable microparticles for oral immunization. Vaccine 11:149-154, 1992. O'Hagan DT, D Rafferty, S Wharton. Intravaginal immunization in sheep using a bioadhesive microsphere antigen delivery system. Vaccine 11:660-664, 1993.
OCR for page 471
--> O'Reilly RJ, L Lee, BG Welch. Secretory IgA antibody responses to Neisseria gonorrhoeae in the genital tract secretions of infected females. Journal of Infectious Diseases 133:113-125, 1976. Ogra PL, DT Karzon. Distribution of poliovirus antibody in serum, nasopharynx and alimentary tract following segmental immunization of lower alimentary tract with poliovirus. Journal of Immunology 102:1423-1427, 1969. Ogra PL, SS Ogra. Local antibody response to polio vaccine in the human genital tract. Journal of Immunology 110:1307-1311, 1973. Owen RL, AL Jones. Epithelial cell specialization within Peyer's patches: An ultrastructural study of intestinal lymphoid follicles. Gastroenterology 66:189-203, 1974. Parker CM, KL Cepek, GJ Russell, et al. A family of ß7 integrins on human mucosal lymphocytes. Proceedings of the National Academy of Sciences, USA 89:1924-1928, 1992. Parr MB, EL Parr. A comparison of antibody titres in mouse uterine fluid after immunization by several routes, and the effect of the uterus on antibody titres in vaginal fluid. Journal of Reproduction and Fertility 89:619-625, 1989a. Parr MB, EL Parr. Immunohistochemical localization of secretory component and immunoglobulin A in the urogenital tract of the male rodent. Journal of Reproduction and Fertility 85:115-124, 1989b. Parr MB, HP Ren, LD Russell, et al. Urethral glands of the male mouse contain secretory component and immunoglobulin A plasma cells and are targets of testosterone. Biology of Reproduction 47:1031-1039, 1992. Patton DL, SK Wang, CC Kuo. In vitro activity of nonoxynol-9 on HeLa 229 cells and primary monkey cervical epithelial cells infected with Chlamydia trachomatis. Antimicrobial Agents and Chemotherapy 36:1478-1482, 1992. Pierce NF, JL Gowans. Cellular kinetics of the intestinal immune response to cholera toxoid in rats. Journal of Experimental Medicine 142:1550, 1975. Potts M. The urgent need for a vaginal microbicide in the prevention of HIV transmission. American Journal of Public Health 84:890-891, 1994. Pudney J, DJ Anderson. Immunology of the human male urethra. American Journal of Pathology 147:155-165, 1995. Quayle AJ, J Pudney, D Muñoz, et al. Characterization of T lymphocytes and antigen presenting cells in the murine male urethra. Biology of Reproduction 51:809-820, 1994. Quigg JM. Development and evaluation of pH sensitive bioerodible polymers for the controlled release of vaginal contraceptive agents. PhD dissertation, University of Illinois at Chicago, 1991. Quigg JM, IF Miller, SR Mack, et al. Development of polyurethane sponge as a delivery system for aryl 4-guanidinobenzoates. Contraception 38:487-497, 1988. Raff HV, C Bradley, W Donaldson, et al. Comparison of functional activities between IgG and IgM class-switched human monoclonal antibodies reactive with group b streptococci or Escherichia coli K1. Journal of Infectious Diseases 163:346-354, 1991. Romagnani S. Induction of Th and Th2 responses: A key role for the "natural" immune response? Immunology Today 13:379-381, 1992. Rosenberg MJ, AJ Davison, JH Chen et al. Barrier contraceptives and sexually transmitted diseases in women: A comparison of female-dependent methods and condoms. American Journal of Public Health 82:669-674, 1992. Rosenberg MJ, W Rojanapithayakorn, PJ Feldblum, et al. Effect of the contraceptive sponge on chlamydial infection, gonorrhea, and candidiasis: A comparative clinical trial. Journal of the American Medical Association 257:2308-2312, 1987. Rush CM, LM Hafner, P Timms. Lactobacilli: Vehicles for antigen delivery to the female urogenital tract. Advances in Experimental Medicine and Biology 371B:1547-1552, 1995. Sadownik A, G Deng, V Janout, et al. Rapid construction of a squalamine mimic. Journal of the American Chemical Society 117:6138-6139, 1995.
OCR for page 472
--> Schonwetter BS, ED Stolzenberg, MA Zasloff. Epithelial antibiotics induced at sites of inflammation. Science 267:1645-1648, 1995. Sharman D, E Chantler, M Dukes, et al. Comparison of the action of nonoxynol-9 and chlorhexidine on sperm. Fertility and Sterility 45:259-264, 1986. Shedlovsky L, D Belcher, I Levenstein. Titrations of human seminal fluid with acids and alkalis and their effects on the survival of sperm motility. American Journal of Physiology 136:535-541, 1942. Shelton JA, E Goldberg. Local reproductive tract immunity to sperm-specific lactate dehydrogenase-C4. Biology of Reproduction 35:873-876, 1986. Sherwood JK, L Zeitlin, KJ Whaley, et al. Controlled release of antibodies for long-term topical passive immuno-protection of female mice against genital herpes. Nature Biotechnology 14:468-471, 1996. Sobrero AG. Use and effectiveness of condoms, diaphragms, cervical cap, vaginal sponge, and spermicides. IN Gynecology and Obstetrics, Vol. 6. GI Zatuchni, JJ Laferla, JJ Sciarra, eds. Philadelphia: J.B. Lippincott. 1989. Stein Z. HIV prevention: An update on the status of methods women can use. American Journal of Public Health 83(10):1379-1382, 1993. Stein Z. HIV prevention: The need for methods women can use. American Journal of Public Health 80:460-462, 1990. Stone KM. HIV, other STDs, and barriers. IN Barrier Contraceptives: Current Status and Future Prospects. CK Mauck, M Cordero, HL Gabelnick, et al., eds. New York: Wiley-Liss. 1994. Stratton P, NJ Alexander. Prevention of sexually transmitted infections. Infectious Disease Clinics of North America 7(4):841-859, 1993. Sullivan DA, CR Wira. Hormonal regulation of immunoglobulins in the uterus: Uterine response to multiple estradiol treatments. Endocrinology 114:650-658, 1984. Svennerholm A-M, LA Hanson, J Holmgren, et al. Different secretory immunoglobulin A antibody responses to cholera vaccination in Swedish and Pakistani women. Infectious Immunology 30:427-430, 1980. Takahashi H, T Takeshita, B Morein, et al. Induction of CD8+ cytotoxic T cells by immunization with purified HIV- envelope protein in ISCOMS. Nature 344:873-875, 1990. Talwar GP, S Garg, R Singh, et al. Praneem polyherbal cream and suppositories. IN Barrier Contraceptives: Current Status and Future Prospects. CK Mauck, M Cordero, HL Gabelnick, et al. New York: Wiley-Liss. 1994. Thapar MA, EL Parr, JJ Bozzola, et al. Secretory immune responses in the mouse vagina after parenteral or intravaginal immunization with an immunostimulating complex (ISCOM) . Vaccine 9:129-133, 1991. Thapar MA, EL Parr EL, MB Parr. Secretory immune response in mouse vaginal fluid after pelvic, parenteral or vaginal immunization. Immunology 70:121-125, 1990. Thormar H, CE Isaacs, HR Brown, et al. Inactivation of enveloped viruses and killing of cells by fatty acids and monoglycerides. Antimicrobial Agents in Chemotherapy 31:27-31, 1987. Titus RG, JM Chiller. Orally induced tolerance. International Archives of Allergy and Applied Immunology 65:323-338, 1981. Tjokronegoro A, S Sirisinha. Quantitative analysis of immunoglobulins and albumin in secretion of female reproductive tract. Fertility and Sterility 26:413-417, 1975. Tomasi TB, EM Tan, A Soloman, et al. Characteristics of an immune system common to external secretions. Journal of Experimental Medicine 121:101, 1965. Tomasi TB, S Ziegelbaum. The selective occurence of gamma 1A globulins in certain body fluids. Journal of Clinical Investigation 42:1552-1560, 1963.
OCR for page 473
--> Trussell J. Contraceptive efficacy of barrier contraceptives. IN Barrier Contraceptives: Current Status and Future Prospects. CK Mauck, M Cordero, HL Gabelnick, et al., eds. New York: Wiley-Liss. 1994. Tsai C-C, KE Follis, A Sabo et al. Prevention of SIV infection in macaques by (R)-9-(2 phosphonylmethoxypropyl) adenine. Science 270:1197-1199, 1995. Tung KSK, EH Goldberg, E Goldberg. Immunobiological consequence of immunization of female mice with homologous spermatozoa: Induction of infertility. Journal of Reproductive Immunology 1:145-158, 1979. Voeller B, DJ Anderson. Heterosexual transmission of HIV. Journal of the American Medical Association 31:27-31, 1992a. Voeller B, DJ Anderson. pH and related factors in the urogenital tract and rectum that affect HIV- I transmission. Mariposa Occasional Paper No. 16, Topanga, CA, 1992b. Wachsmann D, JP Klein, M Scholler, et al. Local and systemic immune response to orally administered liposome-associated soluble S. mutans cell wall antigens . Immunology 54:189-193, 1983. Walter BA, GA Digenis et al. High-performance liquid chromatographic (HPLC) analysis of oligomeric components of the spermicide nonoxynol-9. Pharmacology Research 8:409-411, 1991a. Walter BA, AA Hawi et al. Solubilization and in vitro spermicidal assessment of nonoxynol-9 and selected fraction using rabbit spermatozoa. Pharmacology Research 8:403-408, 1991b. Wang YE, A-F Holstein. Intraepithelial lymphocytes in the human epididymis. Cell and Tissue Research 233:517- 521, 1983. Wasserheit JN. Epidemiological synergy: Interrelationships between human immunodeficiency virus infection and other sexually transmitted diseases. Sexually Transmitted Diseases 19:61-77, 1992. Wiley JA, SJ Herschkorn, N Padian. Heterogeneity in the probability of HIV transmission per sexual contact: The case of male-to-female transmission in penile-vaginal intercourse. Statistics in Medicine 8:93-102, 1988. Wira CR, CP Sandoe. Effect of uterine immunization and estradiol on specific IgA and IgG antibodies in uterine, vaginal and salivary secretions. Immunology 68:24-36, 1989. Wira CR, DA Sullivan. Estradiol and progesterone regulation of IgA, IgG and secretory component in cervicovaginal secretions of the rat. Biology of Reproduction 32:90-95, 1985. Wolff H, DJ Anderson. Immunologic characterization and quantization of leukocyte subpopulations in human semen. Fertility and Sterility 49:497-504, 1988a. Wolff H, DJ Anderson. Male genital tract inflammation associated with increased numbers of potential human immunodeficiency virus host cells in semen. Andrologia 20:404-410, 1988b. Yang SL, GFB Schumacher. Immune response after vaginal application of antigens in the rhesus monkey. Fertility and Sterility 32:588-598, 1979. Zaneveld LJD. Vaginal contraception since 1984: Chemical agents and barrier devices. IN Contraceptive Research and Development, 1984 to 1994: The Road from Mexico City to Cairo and Beyond. PFA Van Look, G Pérez-Palacios, eds. Delhi: Oxford University Press. 1994a. Zaneveld LJD. Vaginal contraceptive efficacy: Animal models. IN Barrier Contraceptives: Current Status and Future Prospects. CK Mauck, M Cordero, HL Gabelnick, et al., eds. New York: Wiley-Liss. 1994b. Zaneveld LJD, AK Bhattacharyya, DS Kim, et al. Primate model for the evaluation of vaginal contraceptives. American Journal of Obstetrics and Gynecology 129:368-372, 1977. Zaneveld LJD, RT Robertson, WL Williams. Synthetic enzyme inhibitors as antifertility agents. Federation of European Biochemical Societies Letters 11:345-347, 1970. Zheng H-Y, TM Alcorn, MS Cohen. Effects of H202-producing lactobacilli on Neisseria gonorrhoeae growth and catalase activity. Journal of Infectious Diseases 170:1209-1215, 1994.
Representative terms from entire chapter: