Women's reproductive span: a systematic scoping review.

STUDY QUESTION: What is the scope of literature regarding women's reproductive span in terms of definitions, trends and determinants? SUMMARY ANSWER: The scoping review found a wide variation in definitions, trends and determinants of biological, social and effective women's reproductive span. WHAT IS KNOWN ALREADY: A woman's reproductive span refers to her childbearing years. Its span influences a woman's reproductive decisions. STUDY DESIGN SIZE DURATION: A systematic scoping review was conducted. We searched MEDLINE, PubMed, JSTOR, CINAHL, Web of Science and Scopus electronic databases from inception to January 2021 without imposing language or date restrictions. We searched unpublished sources including the Global Burden of Disease, Demographic and Health Surveys, and National Health and Nutrition Examination Surveys. The list of relevant references was searched by hand. Sixty-seven reports on women's reproductive span were included in this review. PARTICIPANTS/MATERIALS SETTING METHODS: This scoping systematic review followed an established framework. The reporting of this scoping review followed the reporting requirements provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, Extension for Scoping Reviews. Identified records were independently screened and data were extracted. We performed conceptual synthesis by grouping the studies by available concepts of reproductive span and then summarized definitions, measures used, temporal trends, determinants, and broad findings of implications on population demographics and assisted reproduction. Structured tabulation and graphical synthesis were used to show patterns in the data and convey detailed information efficiently, along with a narrative commentary. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 67 relevant reports on women's reproductive span were published between 1980 and 2020 from 74 countries. Most reports (42/67) were cross-sectional in design. Literature on reproductive span was conceptually grouped as biological (the interval between age at menarche and age at menopause), effective (when a woman is both fertile and engaging in sexual activity) and social (period of exposure to sexual activity). We summarized the working definitions, trends and determinants of each concept. Few articles addressed implications on demographics and assisted reproduction. LIMITATIONS REASONS FOR CAUTION: A formal assessment of methodological quality of the included studies was not performed because the aim of this review was to provide an overview of the existing evidence base regardless of quality. WIDER IMPLICATIONS OF THE FINDINGS: The review produced a comprehensive set of possible definitions of women's reproductive span, trends, and potential determinants. Further advancement of these findings will involve collaboration with relevant stakeholders to rate the importance of each definition in relation to demography and fertility care, outline a set of core definitions, identify implications for policy, practice or research and define future research opportunities to explore linkages between reproductive spans, their determinants, and the need for assisted reproduction. STUDY FUNDING/COMPETING INTERESTS: This work received funding from the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by the World Health Organization (WHO). The authors had no competing interests. STUDY REGISTRATION NUMBER: N/A.

A sub-population of high proliferative potential-quiescent human mesenchymal stem cells is under the reversible control of interferon alpha/beta.

Type I interferon (IFN) is shown to control the reversible quiescence of a primitive human bone marrow mesenchymal stem cell (MSC) subpopulation. A 24 h pre-treatment of Stro1+/GlycoA- or CD45-/GlycoA- subpopulations with a monoclonal antibody (mAb) against the IFNAR1 chain of the human type I IFN receptor (64G12), or with a polyclonal anti-IFNalpha antibody, resulted in a marked increase in the number of very large colonies (CFU-F >3000 cells) obtained in the presence of low, but necessary, concentrations of bFGF. Over a 2-month culture period, this short activation promoted a faster and greater amplification of mesenchymal progenitors for adipocytes and osteoblasts. Activation correlated with inhibition of STAT1 and STAT2 phosphorylation and of STAT1 nuclear translocation. A non-neutralizing anti-IFNAR1 mAb was ineffective. We demonstrate that control and activated MSCs express ST3GAL3, a sialyltransferase necessary to produce the embryonic antigens SSEA-3 and -4. Interestingly, activated MSC progeny expressed SSEA-3 and -4 at a higher level than control cultures, but this was not correlated with a significant expression of other embryonic markers. As MSCs represent an essential tool in tissue regeneration, the use of 64G12, which rapidly recruits a higher number of primitive cells, might increase amplification safety for cell therapy.

Direct signal transduction via functional interferon-alphabeta receptors in CD34+ hematopoietic stem cells.

Affinity purified, freshly isolated CD34+ progenitors were shown to express low levels of type I interferon (IFN) receptors (740 +/- 60 binding sites/cell, K(d) 0.7 +/- 0.04 nM) determined by Scatchard's analysis using a radiolabelled, neutralizing, monoclonal antibody directed against the IFNAR1 chain of the human type I IFN receptor. Treatment of freshly isolated (day 0), highly purified (>95% pure) CD34+ cells with recombinant IFN-alpha resulted in rapid tyrosine phosphorylation and activation of STAT1, Tyk2 and JAK1 as shown by Western immunoblotting. Similarly, IFN treatment was shown by confocal microscopy to result in rapid nuclear localization of the transcription factors IRF1 and STAT2, demonstrating the presence of functional IFN receptors on freshly isolated (day 0) CD34+ cells. The number of specific type I IFN receptor binding sites expressed on hematopoietic progenitor cells increased to some 1440 +/- 40 per cell after 11 days of cultivation of CD34+ cells in vitrosuggesting that receptor expression increases with cell differentiation. IFN-mediated signal transduction and the inhibitory effect of IFN-alpha on 7 or 14 days CFU-GM and BFU-E colony formation was abrogated in the presence of the anti-IFNAR1 mAb, indicating that IFN-alpha acts directly on the proliferation of human hematopoietic progenitor cells via receptor activated signal transduction without excluding the induction of other cytokines or growth factors by residual accessory cells.

A murine B cell lymphoma expressing human HER2 / neu undergoes spontaneous tumor regression and elicits antitumor immunity.

In the present study we describe a novel murine tumor model in which the highly malignant murine B cell lymphoma 38C13 has been transduced with the cDNA encoding human tumor-associated antigen HER2/neu. This new cell line (38C13-HER2/neu) showed stable surfiace expression but not secretion of human HER2/neu. It also maintained expression of the idiotype (Id) of the surface immunoglobulin of 38C13, which serves as another tumor-associated antigen. Surprisingly, spontaneous tumor regression was observed following s.c. but not i.v. injection of 38C13-HER2/neu cells in immunocompetent syngeneic mice. Regression was more frequently observed with larger tumor cell challenges and was mediated through immunological mechanisms because it was not observed in syngeneic immunodeficient mice. Mice that showed complete tumor regression were immune to challenge with the parental cell line 38C13 and V1, a variant of 38C13 that does not express the Id. Immunity could be transferred with sera, suggesting that an antibody response mediated rejection and immunity. Continuously growing s.c. tumors as well as metastatic tumors obtained after the i.v. injection of 38C13-HER2/neu maintained expression of human HER2/neu, which can serve as a target for active immunotherapy. As spontaneous tumor regression has not been observed in other human murine models expressing human HER2/neu, our results illustrate the enormous differences that can exist among different murine tumors expressing the same antigen. The present model provides a useful tool for the study of the mechanisms of protective immunity to B cell lymphoma and for the evaluation of different therapeutic approaches based on the stimulation or suppression of the immune response.

Localization of a receptor nonapeptide with a possible role in the binding of the type I interferons.

Interferons (IFNs) in common with other cytokines activate Janus tyrosine kinases and latent STAT transcription factors upon binding to their cell surface receptor. Type I IFNs bind to a receptor composed of two transmembrane polypeptides, IFNAR1 and IFNAR2, which belong to the class II cytokine receptor family that also includes the cellular receptors for IFN-gamma, interleukin-10 and coagulation protease factor VII (tissue factor). The extracellular domain of the type I IFN receptor chain IFNAR1, has four fibronectin type-III sub-domains. Human IFNAR1 has intrinsic weak affinity for type I IFNs and plays an essential role in transmembrane signaling, formation of a high affinity complex with IFN and the modulation of ligand specificity. In order to characterise the ligand binding site on IFNAR1 we analysed the epitope recognized by the anti-IFNAR1 mAb, 64G12, which inhibits the binding and biological activities of both IFN-alpha and IFN-beta. The target peptide recognized by the 64G12 mAb was determined by screening a set of 48 overlapping peptides covering the first two subdomains (residues 23-229) of the extracellular region of IFNAR1. The results of this study show that the peptide (FSSLKLNVY), localized within the first sub-domain (residues 89-97) of IFNAR1, which is recognized by the 64G12 mAb, most likely overlaps a site to which both IFN-alpha and IFN-beta bind in the ligand-receptor complex. Thus, since the 64G12 mAb can neutralize the biological activities of all the type I IFNs tested, we suggest that the target peptide recognized by the 64G12 mAb, is a possible anchorage point on IFNAR1, common to binding of both IFN-alpha and IFN-beta.

Regulation of chemokine/cytokine network during in vitro differentiation and HIV-1 infection of human monocytes: possible importance in the pathogenesis of AIDS.

The monocyte/macrophage lineage represents heterogeneous cell populations characterized by major differences in the phenotype and functional activities. These cells are a major source of soluble factors, such as cytokines and chemokines, which can both affect HIV replication and AIDS pathogenesis. Although monocytes/macrophages are unanimously considered important targets of HIV-1 infection, the HIV-induced alterations in their physiological functions at different stages of differentiation are still matter of debate. In this article, we review our data on the regulation of chemokine/cytokine network with regard to macrophage differentiation and HIV-1 infection, in comparison with studies from other groups. The ensemble of the results emphasizes that: 1) macrophages markedly differ with respect to monocytes for a variety of responses potentially important in the pathogenesis of HIV infection; and 2) the experimental conditions can influence the HIVmonocyte/macrophage interactions, reflecting the possible in vivo existence of a spectrum of responses among macrophage populations.

Oromucosal interferon therapy: pharmacokinetics and pharmacodynamics.

Oromucosal administration of [125I]-labeled recombinant human interferon-alpha1-8 (IFN-alpha1-8), which is biologically active in the mouse, resulted in readily detectable levels of radioactivity in the serum of animals within 5 min. Biologically active IFN could not be detected in the serum at any time after oromucosal administration, however, and SDS-PAGE analysis showed that the material present in the serum was of low molecular weight and most probably reflected absorption of degradation products following digestion of IFN in the stomach and small intestine. Furthermore, oromucosal administration of murine IFN-alpha/beta (MuIFN-alpha/beta) had no significant effect on the expression of IFN-responsive genes in either peripheral blood mononuclear cells or splenic lymphocytes even though in the same animals IFN treatment activated gene transcription locally in the lymphoid tissue of the oropharyngeal cavity and caused a marked systemic antiviral activity. Oromucosal administration of MuIFN-alpha/beta had no significant effect on either the number of circulating peripheral blood leukocytes or the number of granulocyte-macrophage colonies recovered from the bone marrow of IFN-treated animals. These results suggest that the mechanism of action of oromucosal IFN therapy is distinct from that of parenterally administered IFN and may involve, in the abundant lymphoid or epithelial tissue of the oropharyngeal cavity, either production of a soluble factor or activation of a specific cell population that enters the circulation to mediate the elimination of virus-infected or neoplastic cells.

Eradication of pre-established lymphoma using herpes simplex virus amplicon vectors.

Herpes simplex virus amplicon vectors expressing RANTES (HSVrantes) and the T-cell costimulatory ligand B7.1 (HSVB7.1) were studied for their ability to elicit a tumor-specific T-cell response in a murine lymphoma model. HSVB7.1- and HSVrantes-transduced EL4 cells expressed high levels of B7.1 and RANTES as analyzed by flow cytometry and enzyme-linked immunosorbent assay, respectively. Inoculation of ex vivo HSVB7.1 transduced cells in syngeneic mice resulted in regression of both transduced cells and nontransduced cells inoculated contralaterally. Direct intratumoral injection of HSVB7.1 and/or HSVrantes alone or in combination into established EL4 tumors led to complete tumor regression in injected tumors as well as in nontransduced contralaterally implanted tumor, whereas control tumors or tumors injected with HSVlac expressing beta-galactosidase did not regress. Maximal protection was achieved with combined injection of HSVB7.1 and HSVrantes; mice showing tumor regression were resistant to rechallenge with parental EL4 cells, and tumor cell-specific cytolytic T-cell activity was observed in mice demonstrating regression. HSV amplicon-mediated delivery of immune effector molecules may represent a useful strategy for immunotherapy in the setting of pre-existing tumor.

High pressure fourier transform infrared spectroscopy of poly(dA)poly(dT), poly(dA) and poly(dT).

The effect of hydrostatic pressure upon the DNA duplex, poly(dA)poly(dT), and its component single strands, poly(dA) and poly(dT) has been studied by fourier-transform infrared spectroscopy (FT-IR). The spectral data indicate that at 28 degrees C and pressures up to 12 kbar (1200 MPa) all three polymers retain the B conformation. Pressure causes the band at 967 cm(-1), arising from water-deoxyribose interactions, to shift to higher frequencies, a result consistent with increased hydration at elevated pressures. A larger pressure-induced frequency shift in this band is observed in the single stranded polymers than in the double stranded molecule, suggesting that the effect of pressure on the hydration of single strands may be greater than upon a double stranded complex. A pressure-dependent hypochromicity in the bands attributed to base stacking indicates that pressure facilitates the base stacking in the three polymers, in agreement with previous assessments of the importance of stacking in the stabilization of DNA secondary structure at ambient and high pressures.

Inhibition of HIV type 1 infection with a RANTES-IgG3 fusion protein.

The natural ligands for the chemokine receptors CCR5 (RANTES, MIP-1alpha, and MIP-1beta) and CXCR4 (SDF-1) can act as potent inhibitors of infection by the human immunodeficiency virus type 1 (HIV-1) at the level of viral entry. Unlike antibody-mediated inhibition, chemokine-mediated inhibition is broadly effective. Different HIV-1 strains can utilize the same coreceptor(s) for viral entry and, therefore, can be blocked by the same chemokine(s). HIV-1 strains that are highly resistant to neutralization by V3-specific antibodies are sensitive to inhibition by chemokines. Therefore, the use of chemokine-derived molecules constitutes a potential therapeutic approach to prevent infection by HIV-1. We have generated a fusion protein between RANTES and human IgG3 (RANTES-IgG3). The effectiveness of RANTES-IgG3 inhibition of infection by HIV-1 was similar to that of rRANTES. Inhibition of HIV-1 by RANTES-IgG3 was specific for CCR5-dependent but not CXCR4-dependent HIV-1 isolates. Fusion of a chemokine to an IgG moiety offers two desirable properties with respect to the recombinant chemokine alone. First, IgG fusion proteins have extended half-lives in vivo. Second, molecules with IgG heavy chain moieties may be able to cross the placenta and potentially induce fetal protection.

A RANTES-antibody fusion protein retains antigen specificity and chemokine function.

The successful eradication of cancer cells in the setting of minimal residual disease may require targeting of metastatic tumor deposits that evade the immune system. We combined the targeting flexibility and specificity of mAbs with the immune effector function of the chemokine RANTES to target established tumor deposits. We describe the construction of an Ab fusion molecule with variable domains directed against the tumor-associated Ag HER2/neu, linked to sequences encoding the chemokine RANTES (RANTES.her2.IgG3). RANTES is a potent chemoattractant of T cells, NK cells, monocytes, and dendritic cells, and expression of RANTES has been shown to enhance immune responses against tumors in murine models. RANTES.her2.IgG3 fusion protein bound specifically to HER2/neu Ag expressed on EL4 cells and on SKBR3 breast cancer cells as assayed by flow cytometry. RANTES.her2.IgG3 could elicit actin polymerization of THP-1 cells and transendothelial migration of primary T lymphocytes. RANTES.her2.IgG3 prebound to SKBR3 cells also facilitated migration of T cells. RANTES.her2.IgG3 bound specifically to the CCR5 chemokine receptor, as demonstrated by flow cytometry, and inhibited HIV-1 infection via the CCR5 coreceptor. RANTES.her2.IgG3, alone or in combination with other chemokine or cytokine fusion Abs, may be a suitable reagent for recruitment and activation of an expanded repertoire of effector cells to tumor deposits.

Prolonged allograft survival in cynomolgus monkeys treated with a monoclonal antibody to the human type I interferon receptor and low doses of cyclosporine.

A monoclonal antibody (mAb) directed against the extracellular domain of the IFNAR1 chain of the human interferon-alpha (IFN-alpha) receptor (IFN-alphaR), which inhibits activation of the Jak-Stat signal transduction pathway, administered together with a subeffective dose of cyclosporine induced prolonged survival of skin allografts in major histocompatibility complex (MHC) divergent cynomolgus monkeys. Skin biopsies from animals treated with anti-IFN-alphaR mAb and cyclosporine revealed very low levels of MHC class I and class II antigen expression and the absence of histologic signs of rejection. Monkey antibodies (IgG) to the mouse antihuman IFN-alphaR mAb were not detected in the serum of any of the animals treated with the anti-IFN-alphaR mAb either alone or together with cyclosporine. The anti-IFN-alphaR mAb abrogated activation of the Jak-Stat signal transduction pathway in IFN-treated cells. These results, which show that selective and long-lasting immunosuppression can be obtained by short-term administration of an IFN-alpha antagonist together with a subeffective dose of cyclosporine, may have important implications for the therapy of human allograft rejection.

A B7.1-antibody fusion protein retains antibody specificity and ability to activate via the T cell costimulatory pathway.

We describe the construction and characterization of an Ab fusion protein specific for the tumor-associated Ag HER2/neu linked to sequences encoding the extracellular domain of the B7.1 T cell costimulatory ligand. The Ab domain of the fusion molecule will specifically target HER2/neu-expressing tumor cells, while the B7.1 domain is designed to activate a specific immune response. We show that the B7.1 fusion Ab retained ability to selectively bind to the HER2/neu Ag and to the CTLA4/CD28 counter-receptors for B7.1. Specific T cell activation was observed when the B7.1 Ab fusion protein was bound to HER2/neu-expressing cells. The use of the B7.1 Ab fusion protein may overcome limitations of gene transfer and/or standard Ab therapy and represents a novel approach to the eradication of minimal residual disease.

Comparison of Fourier-transform infrared spectroscopic screening of exfoliated cervical cells with standard Papanicolaou screening.

To compare Fourier-transform infrared (FTIR) spectroscopy in screening cervical cytology and standard Papanicolaou (Pap) screening with colposcopic directed biopsy as a "gold standard," we prospectively gathered FTIR samples and Pap smears of all patients attending our program's colposcopy clinics, from February to October 1995. We recorded demographic data for each patient including colposcopy, cytology, treatment follow-up, and histology. Using the colposcopically directed biopsy as the gold standard, exfoliated cervical cells from 301 patients were collected to compare cytology and FTIR spectroscopy. Based on previously established criteria, we provided distinctive definitions of both negative/positive FTIR, cytology, and histology. Results of 301 cases showed 196 positive and 105 negative cytologies. The sensitivity, specificity, false-negative rate, and false-positive rate for the Pap test were 86.6, 90.5, 13.4, and 9.5%, respectively. However, FTIR results versus histology showed 215 positive and 86 negative with a sensitivity of 98.6% and specificity of 98.8%. False-negative and false-positive rates were 1.4 and 1.2%, respectively. In the 12 cervical cancers there were no false-negative FTIR results but 3 false-negative Pap smears. The positive and negative predictive values for FTIR were 99.5 and 96.5% while the Pap values were 95.9 and 72.3%. Compared to standard Pap smears, FTIR has a better false-negative rate and negative predictive value in this preliminary study. Further work, to establish the range of each of the spectral criteria for different grades of dysplasia and that among various infectious effects, needs to be conducted before applying this research tool to a population-based study.

Inhibition of HIV-1 replication using a mutated tRNALys-3 primer.

Cellular tRNALys-3 serves as the primer for reverse transcription of human immunodeficiency virus, type 1 (HIV-1). tRNALys-3 interacts directly with HIV-1 reverse transcriptase, is packaged into viral particles and anneals to the primer-binding site (PBS) of the HIV-1 genome to initiate reverse transcription. Therefore, the priming step of reverse transcription is a potential target for antiviral strategies. We have developed a mutant tRNALys-3 derivative with mutations in the PBS-binding region such that priming specificity was re-directed to the highly conserved TAR stem-loop region. This mutant tRNA retains high-affinity binding to HIV-1 reverse transcriptase, viral encapsidation, and is able to prime at both the targeted TAR sequence and at the viral PBS. Constitutive expression of mutant tRNA in T-cells results in marked inhibition of HIV-1 replication, as determined by measurements of viral infectivity, syncytium formation, and p24 production. Inhibition of retroviral replication through interference with the normal process of priming constitutes a new anti-retroviral approach and also provides a novel tool for dissecting molecular aspects of priming.

Post-translational up-regulation of the cell surface-associated alpha component of the human type I interferon receptor during differentiation of peripheral blood monocytes: role in the biological response to type I interferon.

Human peripheral blood monocytes cultured in vitro exhibit a greater sensitivity to the antiviral effect of type I interferon (IFN) compared to freshly isolated monocytes. We evaluated the effect of macrophage differentiation on the expression of type I IFN receptors (IFN-R). Binding studies with iodinated IFN-alpha 2 and Scatchard plot analysis revealed that a single class of high-affinity receptors was present in freshly isolated monocytes. Monocyte differentiation to macrophages resulted in a three- to fourfold increase in the number of cell surface receptors with no change in their affinity. Polymerase chain reaction analysis of RNA revealed that comparable levels of mRNA for the IFN-R alpha (IFNAR1) and IFNAR2 components were expressed in freshly isolated monocytes and 7-day cultured macrophages. Likewise, the levels of IFNAR1 protein remained constant over time in culture. Immunofluorescence studies revealed that IFNAR1 was localized in intracellular compartments of freshly isolated monocytes, whereas it was predominantly detected on the cell surface in 7-day cultured macrophages. The increased expression of IFN-R on the plasma membrane of cultured macrophages may, at least in part, account for the increased antiviral effect of type I IFN in these cells. These modifications represent one of the events occurring during monocyte differentiation that may play a role in the regulation of macrophage functions.

Comparative study of the expression of cellular proteins in uninfected and HIV infected U937 cells using two dimensional SDS polyacrylamide gel electrophoresis.

The cellular response to HIV infection was determined by analysing the expression of cellular proteins in uninfected and HIV-1 infected U937 cells using two-dimensional protein electrophoresis. HIV infected U937 cells constitute a useful model for the study of the chronic productive infection of cells of the monocyte/macrophage lineage by the human immunodeficiency virus. Our data suggest that the expression of 70 proteins is modified following HIV infection: the expression of approximately half of these proteins was found to be increased, while that of the other half was repressed. We estimate that the expression of around fifteen of these proteins was markedly changed following HIV infection. These results suggest that HIV infection results in the modified expression of approximately 0.5% of total cellular proteins. To our knowledge, this study represents the first global quantitative analysis of the cellular response to HIV infection in a model of chronic infection of cells of the monocyte-macrophage lineage.

Use of enzyme-labelled protein G assay for the detection of anti Borrelia burgdorferi antibodies in wild animal sera.

A modified ELISA was developed for the detection of anti-Borrelia burgdorferi (Bb) IgG antibodies in wild animal sera based on an Enzyme-Labelled-protein G Assay (ELGA). Microplates were coated with an extract of Bb sensu stricto strain (SVI) as antigen. Specific antibodies of the serum samples were detected by a peroxidase-labelled-protein G. Using comparative immunodiagnosis by means of a passive hemagglutination test (HA), ELGA was tested on 82 roe-deer blood samples. A correlation was found between the two methods (r = 0.66). Good reproducibility of titers was observed by ELGA technique. A minimal cross-reactivity was discovered with Leptospira. ELGA could facilitate the recognition of specific antibodies in collections of wild animal sera.

Role of the type I interferons in allograft rejection.

Type I interferons are potent immuno-modulatory cytokines that enhance expression of the major histocompatibility complex (MHC) class I antigens, T-cell cytotoxicity, and natural killer (NK) cell activity, all of which are implicated in graft rejection. A monoclonal antibody (mAb) directed against the extracellular domain of the human interferon gamma (IFN-gamma) receptor (IFN-alpha R), which inhibits both the binding and biological activity of all the type I IFNs tested, exerted a dose-dependent inhibition of the mixed lymphocyte reaction and induced permanent survival of skin allografts in MHC-divergent Cynomologus monkeys treated with a subeffective dose of cyclosporin A. Marked differences were observed in the composition of T lymphocyte subpopulations in anti-IFN-alpha R mAb-treated animals relative to the various control groups. Skin biopsies from animals treated with anti-IFN-R Mab + cyclosporin A revealed very low levels of MHC class I and class II antigen expression and the absence of histological signs of rejection, whereas skin biopsies from control animals exhibited high levels of MHC antigen expression and the histological signs of acute rejection, including a pronounced lymphocytic infiltrate, edema, and necrosis. No monkey antibodies (IgG) to the mouse anti-human IFN-alpha R mAb were detected in the serum of any of the animals treated with the anti-IFN-alpha R mAb either alone or together with cyclosporin A. Treatment of lethally irradiated Cynomologus monkeys with the anti-IFN-alpha R mAb together with a subeffective dose of cyclosporin A was also found to markedly enhance the survival of animals grafted with allogeneic bone marrow cells from donors differing in both MHC class I and class II antigens. These results show that selective and lasting immunosuppression can be obtained by the short-term administration of an IFN-alpha antagonist together with a subeffective dose of cyclosporin A, and may have important implications for the therapy of human allograft rejection.