Effect of maternal antibodies on influenza virus-specific immune response elicited by inactivated virus and naked DNA.

While vaccines are effective in adults, they are less successful in newborns and infants. Neonatal unresponsiveness to vaccines could be owing to immaturity of lymphocytes and/or to inhibition by maternal antibodies. Unresponsiveness of newborn to vaccines can be overcame by genetic immunization. In the present study we investigated the effect of maternal antibodies on the anti-influenza virus protective response in progeny born to dams immunized with plasmid containing the hemagglutinin gene or UV-inactivated virus. The effect of maternal antibodies was studied in plasmid immunized F1 mice born to BALB/c dams, previously immunized with virus or plasmid and crossed with C57BL/6 males, as well as in offspring born to BALB/c dams immunized with plasmid and then immunized with UV-inactivated WSN virus. We have found that the inhibition period of the anti-HA antibody response in offspring born to dams immunized with DNA is shorter than that of offspring born to dams immunized with virus. Furthermore, there is a persistent inhibitory effect on B cells from offspring born to dams immunized with virus or injected with antiviral monoclonal antibodies (MoAb), after the decline of maternal antibody titers. The analysis of the haemagglutinin-specific clonotype reactivity pattern of offspring born to dams immunized with inactivated influenza virus or with a plasmid showed that clonotypes producing antibodies specific for the immunizing virus strain were predominant in offspring born to dams immunized with DNA compared to those born to dams immunized with virus. Maternal antibodies do not affect cell-mediated immunity. These findings might be used to design efficient vaccination schedules for newborns and infants.

Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin-1, in patients with scleroderma and other connective tissue diseases.

A duplication in the fibrillin-1 gene has been implicated as the cause of the tight skin 1 (tsk1) phenotype, an animal model of scleroderma or systemic sclerosis (SSc). In addition to the production of abnormal fibrillin-1 protein, the tsk1 mouse also produces autoantibodies to fibrillin-1. Among a population of Choctaw Native Americans with the highest prevalence of SSc yet described, a chromosome 15q haplotype containing the fibrillin-1 gene has been strongly associated with SSc. With a recombinant human fibrillin-1 protein, autoantibodies to fibrillin-1 were detected in the sera of Native American SSc patients that correlated significantly with disease. Abs to fibrillin-1 also were detected in sera from Japanese, Caucasian, and African-American SSc patients. Compared with other ethnic groups, Japanese and Native American SSc patients had significantly higher frequencies of anti-fibrillin-1 Abs. Sera from patients with diffuse SSc, calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly, and telangiectasias syndrome and mixed connective tissue disease also had significantly higher frequencies of anti-fibrillin-1 Abs than sera from controls or patients with other non-SSc connective tissue diseases (lupus, rheumatoid arthritis, and Sjögren's syndrome). Ab specificity for fibrillin-1 was demonstrated by the lack of binding to a panel of other purified autoantigens. The results presented demonstrate for the first time the presence of high levels of anti-fibrillin-1 Abs in a significant portion of patients with SSc.

Alpha-fetoprotein derived from a human hepatoma prevents growth of estrogen-dependent human breast cancer xenografts.

Alpha-fetoprotein (AFP) is a transport protein that has growth-regulatory properties in many different tissues. It is known to interfere with responses stimulated by estrogen. The purpose of this study was to determine whether human AFP would inhibit the growth of human breast cancer. AFP was isolated from the culture supernatant of human hepatoma cells (HepG2) grown in serum-free medium and was purified by immunoaffinity chromatography. Human breast cancers were grown as xenografts under the kidney capsule of severe combined immunodeficient mice. The minimum inhibitory dose of AFP against estradiol (E2)-stimulated growth of human MCF-7 breast cancer xenografts was 10 microg/mouse/day, and maximum inhibition (no growth) was achieved with 100 microg/mouse/day. Daily treatment was required to sustain inhibition. This 100-microg dose of AFP also inhibited xenograft growth of E2-dependent T47 human breast carcinoma. Estrogen receptor-negative MDA MB 231 and BT20 human breast carcinoma xenografts were not inhibited by AFP (100 microg/mouse/day). Elevation in serum E2 occurred during AFP treatment. AFP did not compete with agonists for the estrogen receptor. These laboratory results are consistent with the findings of a literature search, which consistently showed an association between elevated pregnancy levels of AFP and subsequent reduced risk for breast cancer later in life. We conclude that AFP can inhibit growth of estrogen-dependent breast cancer and warrants further development as an agent for the treatment and perhaps even the prevention of human breast cancer.