Contraceptive Research and Development Looking to the Future (1996) / Chapter Skim
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Appendix D: Barrier Methods and Mucosal Immunologic Approaches
Appendix D: Barrier Methods and Mucosal Immunologic Approaches
Pages 430-473
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From page 430... ...
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.
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. 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)
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From page 432... ...
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.
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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)
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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.
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From page 435... ...
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.
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From page 436... ...
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, H2O2, lactoferrin, and B-defensins (Cohen et al.
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From page 437... ...
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.
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From page 438... ...
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.
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. Milk Fatty Acids Lipids found in human milk and epidermis display antibacterial and antiviral activity (Isaacs et al.
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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 Anti-HIV inhibition 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
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1986) , to inactivate HIV, and to cause changes in cervical mucus that prevent penetration by spermatozoa (Chantler et al.
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for penetration through the zona pellucida and that certain acrosin inhibitors are potent contraceptives when placed vaginally in animal models. Aryl 4-guanidinobenzoates such as 4′-acetamidophenyl 4-guanidinobenzoate (AGB)
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From page 443... ...
This unfortunately can facilitate the sexual exchange of STD pathogens that otherwise would be killed by the acid and gives those pathogens additional time to reach target cells in the new host. Exposing cell-free HIV to the acid pH ranges normally found in healthy vaginal secretions reduces both its infectivity and the survival of HIV-infected lymphocytes (Voeller and Anderson 1992a, 199b)
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Monoclonal antibodies of human origin, expected to be potent, flexible, specific, sturdy, and inexpensive, can now be developed to serve as natural protective agents for mucosal surfaces (Cone and Whaley 1994; Ma et al.
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Preventing sexual transmission of disease and pregnancy with topically applied antibodies. American Journal of Reproductive Immunology 32:114–131, 1994.
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It also depends on the ability to deliver immunogens to achieve the desired effect at the appropriate site within the male or female reproductive tract. Since both the lower female and the male genital tract mucosa are considered part of the common mucosal system, there is an implication that mucosa-targeted immunization would induce effective genital tract immune responses.
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From page 447... ...
. Given the importance of the mucosal system and the fact that the human body actually synthesizes and secretes more antibodies into mucus than it does into blood, it is surprising that so little is known about how the secreted antibodies function in mucus to protect the human mucosal surfaces.
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. Although immune cells are found throughout the mucosae, antigen uptake and induction of immune responses occur predominantly in specialized inductive sites.
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An elegant study by Czerkinsky and colleagues provides support for the notion of a common mucosal system in man: Streptococcus mutans-specific, IgA-producing cells were isolated from blood seven days after oral immunization and seven days prior to the appearance of antigen-specific IgA in saliva and tears (Czerkinsky et al.
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are also produced by T lymphocytes at mucosal surfaces, especially at sites of infection. The T cells in the lamina propria are also predominantly CD4-positive memory (CD45RO+)
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. MUCOSAL IMMUNOLOGY OF THE HUMAN GENITAL TRACT IN FEMALES Plasma cells are present in the greatest concentration in the subepithelial layers of the human endocervix, but substantial numbers are also seen in the ectocervix, vagina, and fallopian tubes (Kutteh et al.
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From page 452... ...
. Animal studies have also clearly shown that the mucosal immune system in the female urogenital tract is regulated by sex hormones; in an extensive series of experiments by Wira and associates, local immunoglobulin levels in the reproductive tract were shown to be under the control of estradiol and progesterone (Sullivan and Wira 1984; Wira and Sullivan 1985)
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. After activation, Langerhans cells migrate from the epithelium to draining lymph nodes, where they present antigens to T lymphocytes, thereby initiating a specific immune response.
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. However, recent studies suggest that the penile urethra may be the primary source of sIgA in semen from normal men: In penile urethral tissue taken at autopsy from a series of 15 immunologically normal men, epithelial cells were observed to stain strongly for secretory component and numerous IgA positive plasma cells were seen in the submucosa, indicating that the urethra contains all the elements for production of sIgA (Pudney and Anderson 1995)
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. However, many studies have also indicated that optimal mucosal immune responses appear to be obtained by immunization at that mucosal site or an adjacent mucosal locale.
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First, the mucosal immune system has evolved primarily to avoid sensitization of the individual to antigens in food that escape degradation. As a consequence, the majority of antigenic material is not absorbed so that oral immunization requires substantial amounts of antigen to achieve an immune response.
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Development of new technology may soon offer a number of possible delivery systems for immunogens, and research into vaccines for enteric, respiratory and, particularly, sexually transmitted diseases will inevitably offer insights into options for mucosal immunization for different purposes. Mucosally active adjuvants (adjuvare = to help)
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However, in the case of immunocontraception, reversibility may be highly desirable and a long-term effect might well be disadvantageous; that would not be the case for protection from sexually transmitted infection. A second, potentially catastrophic disadvantage in connection with an immunocontraceptive would be induction of herd immunity owing to transmission of the organism in secretions; in this instance, inactivated organisms, while less efficient as inducers of mucosal immunity, would be the clear preference.
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Mucosal immunization with biodegradable microspheres has achieved specific systemic and secretory immune responses, as well as the generation of cytotoxic T lymphocytes (CTLs) (Eldridge et al.
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that are chemically coupled to cholera toxin B subunit. The vaccine has been used successfully for oral/vaginal and oral/rectal immunization regimes in macaques, inducing serum and local antibody and T cell proliferative responses in draining lymph nodes after oral and rectal immunization regimes (Lehner et al.
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From page 461... ...
Rectal immunization alone can also induce good sIgA titres in vaginal secretions, for two possible reasons: First, the rectal mucosa is endowed with numerous lymphoid follicles that allow very effective induction of the immune response; second, as discussed earlier, the genital tract and rectum are adjacent mucosae and share draining lymph nodes. Optimal Immunization of the Male Reproductive Tract A limited number of studies have demonstrated that infection or inflammation in the male reproductive tract leads to the appearance of specific IgA.
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Cellular immune responses to sperm have been detected in male and female infertility patients (Anderson and Hill 1995; McShane et al. 1985; Metter and Schirwani 1975)
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From page 463... ...
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)
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Brandtzaeg P, E Christiansen, F Muller, et al. Humoral immune response patterns of human muco sae, including the reproductive tracts: The induction of immunity at mucosal surfaces.
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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.
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Langerhans cells and lymphocyte subsets in the female genital tract. British Journal of Obstetrics and Gynaecology 92:974–982, 1985.
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in human immunodeficiency virus type 1 infection. Federation of European Biochemical Societ ies Letters 248:48–52, 1989.
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IgA immunity in female reproductive tract secretions. IN Local Immunity in Reproductive Tract Tissues.
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Mestecky J The common mucosal immune system and current strategies for induction of immune responses in external secretions.
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Selective induction of immune responses in external secretions. Journal of Clinical Investigation 61:731–737, 1978.
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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.
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Secretory immune responses in the mouse vagina after parenteral or intravaginal immunization with an immunostimulating complex (ISCOM)
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Wasserheit JN. Epidemiological synergy: Interrelationships between human immunodeficiency vi rus infection and other sexually transmitted diseases.
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