Origin of IgA and IgG Antibodies in the Female Reproductive Tract: Regulation of the Genital Response by Estradiol

Engineering sperm-binding IgG antibodies for the development of an effective nonhormonal female contraception

Science Translational Medicine ◽

10.1126/scitranslmed.abd5219 ◽

2021 ◽

Vol 13 (606) ◽

pp. eabd5219

Author(s):

Bhawana Shrestha ◽

Alison Schaefer ◽

Yong Zhu ◽

Jamal Saada ◽

Timothy M. Jacobs ◽

...

Keyword(s):

Biomedical Applications ◽

Reproductive Tract ◽

Human Sperm ◽

Female Reproductive Tract ◽

Infertile Woman ◽

Igg Antibodies ◽

Contraceptive Methods ◽

Sperm Binding ◽

Polyvalent Immunoglobulins ◽

Unique Surface

Many women risk unintended pregnancy because of medical contraindications or dissatisfaction with contraceptive methods, including real and perceived side effects associated with the use of exogenous hormones. We pursued direct vaginal delivery of sperm-binding monoclonal antibodies (mAbs) that can limit progressive sperm motility in the female reproductive tract as a strategy for effective nonhormonal contraception. Here, motivated by the greater agglutination potencies of polyvalent immunoglobulins but the bioprocessing ease and stability of immunoglobulin G (IgG), we engineered a panel of sperm-binding IgGs with 6 to 10 antigen-binding fragments (Fabs), isolated from a healthy immune-infertile woman against a unique surface antigen universally present on human sperm. These highly multivalent IgGs (HM-IgGs) were at least 10- to 16-fold more potent and faster at agglutinating sperm than the parent IgG while preserving the crystallizable fragment (Fc) of IgG that mediates trapping of individual spermatozoa in mucus. The increased potencies translated into effective (>99.9%) reduction of progressively motile sperm in the sheep vagina using as little as 33 μg of the 10-Fab HM-IgG. HM-IgGs were produced at comparable yields and had identical thermal stability to the parent IgG, with greater homogeneity. HM-IgGs represent not only promising biologics for nonhormonal contraception but also a promising platform for engineering potent multivalent mAbs for other biomedical applications.

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Regulation of reproductive tract immunoglobulins by oestradiol-17β in the European Red Fox (Vulpes vulpes)

Reproduction Fertility and Development ◽

10.1071/r97035 ◽

1997 ◽

Vol 9 (5) ◽

pp. 531 ◽

Cited By ~ 3

Author(s):

James de Jersey ◽

Lyn A. Hinds ◽

Mark P. Bradley

Keyword(s):

Reproductive Tract ◽

Red Fox ◽

Oral Immunization ◽

Reproductive Hormones ◽

Female Reproductive Tract ◽

Antibody Responses ◽

Ovarian Hormone ◽

Igg Antibodies ◽

Exogenous Treatment ◽

Antibody Secretion

The effect of the ovarian hormone, oestradiol-17β, on reproductive tract immunity in the female fox was investigated. Reproductive tract antibody responses were induced by either Peyer’s patch immunization with a recombinant fox sperm protein, or by oral immunization with live, attenuated Salmonella typhimurium. The effect of exogenous oestradiol-17β or the stage of the oestrous cycle on reproductive tract immunity was assessed. The secretion of specific vaginal IgA, but not vaginal IgG, antibodies was reduced by exogenous treatment with oestradiol-17β, while both specific vaginal IgA and vaginal IgG levels declined during the period of natural oestrus. It is concluded that oestradiol-17β, and probably other reproductive hormones, are involved in the regulation of antibody-secretion in the fox reproductive tract, and that reproductive status is an important factor to consider in the design and application of vaccines which aim to induce immunity within the female reproductive tract.

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Effect of Contraceptive Steroids on the Endometrium of Guinea Pig: SEM study

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100080766 ◽

1977 ◽

Vol 35 ◽

pp. 668-669

Author(s):

Mai M. Said ◽

Ramesh K. Nayak ◽

Randall E. McCoy

Keyword(s):

Guinea Pig ◽

Reproductive Tract ◽

Three Dimensional ◽

Female Reproductive Tract ◽

Human Female ◽

Surface Ultrastructure ◽

Transmission Electron ◽

Sem Study ◽

Uterine Mucosa ◽

Group 1

Burgos and Wislocki described changes in the mucosa of the guinea pig uterus, cervix and vagina during the estrous cycle investigated by transmission electron microscopy. More recently, Moghissi and Reame reported the effects of progestational agents on the human female reproductive tract. They found drooping and shortening of cilia in norgestrel and norethindrone- treated endometria. To the best of our knowledge, no studies concerning the effects of mestranol and norethindrone given concurrently on the three-dimensional surface features on the uterine mucosa of the guinea pig have been reported. The purpose of this study was to determine the effect of mestranol and norethindrone on surface ultrastructure of guinea pig uterus by SEM.Seventy eight animals were used in this study. They were allocated into two groups. Group 1 (20 animals) was injected intramuscularly 0.1 ml vegetable oil and served as controls.

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Surface ultrastructure of danazol treated rat endometrium: A SEM study

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010007641x ◽

1983 ◽

Vol 41 ◽

pp. 556-557

Author(s):

R.P. Apkarian ◽

J.S. Sanfilippo

Keyword(s):

Cross Sections ◽

Reproductive Tract ◽

Preliminary Investigation ◽

Breast Disease ◽

Distal Segment ◽

Uterine Horn ◽

Female Reproductive Tract ◽

Ultrastructural Changes ◽

Cycle Phase ◽

Sprague Dawley

The synthetic androgen danazol, is an isoxazol derivative of ethisterone. It is utilized in the treatment of endometriosis, fibrocystic breast disease, and has a potential use as a contraceptive. A study was designed to evaluate the ultrastructural changes associated with danazol therapy in a rat model. The preliminary investigation of the distal segment of the rat uterine horn was undertaken as part of a larger study intended to elucidate the effects of danazol on the female reproductive tract.Cross-sections (2-3 mm in length) of the distal segment of the uterine horn from sixteen Sprague-Dawley rats were prepared for SEM. Ten rats in estrus served as controls and six danazol treated rats were noted to have alterations of the estrus cycle i.e. a lag in cycle phase or noncycling patterns. Specimens were fixed in 3% glutaraldehyde in 0.05M phosphate buffer containing CaCl2 at pH 7.0-7.4 and chilled to 4°C. After a brief wash in distilled water, specimens were passed through a graded series of ethanol, critical point dryed in CO2 from absolute ethanol, and coated with 6nm Au. Observations were made with an IS1-40 SEM operated at 15kV.

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The application of electron microscopy to diagnosis in gynecologic neoplasms and tumor-like conditions

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100110787 ◽

1984 ◽

Vol 42 ◽

pp. 102-105

Author(s):

Lawrence M. Roth

Keyword(s):

Electron Microscopy ◽

Reproductive Tract ◽

Malignant Tumors ◽

Frozen Section ◽

Cost Effective ◽

Female Reproductive Tract ◽

Ultrastructural Examination ◽

Specific Diagnosis ◽

Potential Value ◽

Gynecologic Neoplasms

The female reproductive tract may be the site of a wide variety of benign and malignant tumors, as well as non-neoplastic tumor-like conditions, most of which can be diagnosed by light microscopic examination including special stains and more recently immunoperoxidase techniques. Nevertheless there are situations where ultrastructural examination can contribute substantially to an accurate and specific diagnosis. It is my opinion that electron microscopy can be of greatest benefit and is most cost effective when applied in conjunction with other methodologies. Thus, I have developed an approach which has proved useful for me and may have benefit for others. In cases where it is deemed of potential value, glutaraldehyde-fixed material is obtained at the time of frozen section or otherwise at operation. Coordination with the gynecologic oncologist is required in the latter situation. This material is processed and blocked and is available if a future need arises.

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