Immune System Decline in the Elderly Probed

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Two elderly men
 
Immune system deterioration in the elderly, commonly believed to be a primary function of thymus gland shriveling with age, has now been linked to aging bone marrow cells as well. This finding of Prof. Amiela Globerson of the Institute's Department of Cell Biology indicates that rather than independently governing immune system decline, the thymus is itself influenced by the aging of the bone marrow cells it is charged with nursing. This knowledge may advance the ongoing search for techniques to bolster immune system function in the elderly.

Since the thymus is a major site for the maturation of T lymphocytes white blood cells concerned with immunity to infection and protection against cancer the shriveling of the gland has been commonly implicated in the weakening of the body's immune response with age. These lymphocytes develop from stem cells that originate in bone marrow and then travel to the thymus; there they mature and receive "training" in the recognition of foreign invaders and in avoiding reactions against the body's self-constituents.
 

Prof. Globerson. Findings in old cells

Prof. Globerson has now found that the influence is mutual: the bone marrow cells not only are nurtured by the thymus, but regulate thymus tissue function as well. She demonstrated that aged bone marrow cells are unable to develop fully in the thymus, or to convey proper signals to the gland. This implies that efforts to retard immune system degeneration should focus not only on the thymus gland but on aging processes in the bone marrow as well.

Globerson exposed fetal thymus tissue culture to radiation, thereby destroying the T cells while leaving the "stroma" the organ-tissue constituents intact. She then inserted stem cells from young animals into some of the thymus stromas, and stem cells from old animas into others. The old cells were found to undergo less clonal expansion and produce far fewer T cells than the younger cells. Therefore, the aging of stem cells is likely to play a major role in declining immune system function.

Prof. Globerson holds the Harold S. And Harriet B. Brady Chair of Cancer Research
 
Life Sciences
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Shedding Light on Infertility

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Dr. Boris Tartakovsky. Preventing miscarriage

A Weizmann Institute scientist has shown that the injection of certain natural growth factors into pregnant mice helps prevent them from miscarrying. Dr. Boris Tartakovsky of the Institute's Department of Chemical Immunology found two growth factors, or cytokines, that dramatically reduce miscarriages among mice that are naturally prone to abort, as well as among normal mice injected with an abortion-inducing substance.

The findings may help shed light on the cause of many unexplained cases of repeated miscarriages and infertility among women. It is also hoped that the research could eventually lead to techniques for improving the success rate of in-vitro or test-tube pregnancies.

These studies are an outgrowth of Dr. Tartakovsky's earlier work which led to the discovery of a particular cytokine, CSF-1, that impairs fertility in mice. Since some cytokines block the action of others, Tartakovsky sought to identify growth factors that might possibly promote pregnancy. He eventually found two: tumor necrosis factor-alpha (TNF-a) a pro-inflammatory substance produced by many tissues, and granulocyte macrophage colony stimulating factor (GM-CSF), a promoter of white blood cell production.

Tartakovsky's experiments showed that the abortion-inducing effects of CSF-1 could be largely overcome by parallel injections with pregnancy-promoter GM-CSF. He also demonstrated that TNF-a dramatically reduced miscarriages in a strain of mice highly prone to spontaneous abortions. Moreover, CSF-1-induced embryo damage was found to occur before embryo implantation, and correcting this effect must be attempted at an early phase if the embryo is to be salvaged.

This latter finding could have implications in human test-tube embryo implantation and may suggest a possible strategy for improving the low success rate (about 20%) associated with this procedure.

Dr. Tartakovsky holds the Pauline Recanati Career Development Chair in Immunology.
 

Embryo at implantation stage

Life Sciences
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The Goal: Early Diagnosis of High-Risk Fetuses

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Keeping the fetus healthy

 

Identification of fetuses likely to suffer from future neurodevelopmental problems due to placental malfunction may become possible as early as four to six weeks after conception, thanks to a new technique developed by Weizmann Institute scientists and physicians from the Tel Aviv Medical Center. Based on a simple urine analysis, the new method should markedly facilitate the prevention or mitigation of postnatal complications such as infant death or mental retardation.


Prof. Ephraim Yavin of the Institute's Neurobiology Department and Prof. Shaul Harel of the Tel Aviv Medical Center and Tel Aviv University have studied the link between "ischemic," or blood-deprived fetuses and intrauterine growth retardation (IUGR), which occurs in 3% to 10% of all pregnancies and is responsible for 33% of all low birthweight infants. IUGR -- often recognized at birth by large head circumference relative to body weight --is common among low-income populations, smokers and certain ethnic groups and families. Although up to 30% of IUGR infants "catch up" to normal children within a few years, the disorder is linked to infant and early childhood mortality, cerebral palsy, speech and learning disabilities and small body size.


IUGR often arises from circulatory problems in the expectant mother, which cause a temporary disturbance in the flow of oxygen and glucose to the developing fetal brain. If oxygen supply returns quickly enough, damage can be kept within a recoverable range; however Yavin and Harel found that partial restoration of oxygen-rich blood causes the cerebral blood elements and the placenta to produce lipid-derived hormones called protaglandins. One of them, thromboxane, acts to constrict the blood vessels -- decreasing blood supply to the brain and exacerbating the ischemic damage -- while the other, prostacyclin, serves to dilate the vessels, thereby reducing the damage. By measuring the ratio of these two compounds in blood and urine samples of a pregnant woman, it should be possible to determine the danger of her baby suffering from developmental retardation.

Currently, ischemic fetuses are identified through Doppler ultrasound measurements of blood flow from mother to fetus and from the fetal heart to the fetal brain. These measurements become reliable only after 18-20 weeks of pregnancy. It is believed that Yavin's and Harel's new method could be used as early as 4-6 weeks into pregnancy.

This research is supported by the Gulton Foundation, NY, Fidia s.p.a., Italy, and the Revson Foundation of the Israel Academy of Science and Humanities.
 
Life Sciences
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Two Proteins with Therapeutic Potential Discovered

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Urinary proteins stop excess hormone production
 

A natural immune-system hormone implicated in vascular failure occurring in septic shock and cerebral malaria can be neutralized by two urine proteins recently discovered at the Institute. Furthermore, since the hormone may contribute to tissue damage accompanying autoimmune disorders, graft rejection and graft-versus-host disease, the proteins may be effective against these disabilities as well.


The hormone in question, known as "tumor necrosis factor" (TNF), is formed by white blood cells in response to injury or infection. However, TNF production can become excessive, leading to the destruction not only of substances foreign to the body but also of healthy tissues, thus inducing the onset of various diseases. Prof. David Wallach of the Institute's Department of Membrane Research and Biophysics, along with Ph.D. student Harmut Engelmann (M.D.) and Dr. Dan Aderka of Ichilov Hospital, discovered two urinary proteins called TBPI and TBPII (TNF-binding proteins I and Ii) that inhibit TNF activity.

The purification and amino acid sequencing of the TBPs was carried out by the group of Prof. Wallach in collaboration with Institute researchers Prof. Menachem Rubinstein, Dr. Dalia Rotman and Dr. Daniella Novick. Based on the sequencing, Prof. Wallach and doctoral students Yaron Nophar, Oliver Kemper and Cord Brakebosch cloned the genes for these proteins. Analysis of the gene structure revealed a close evolutionary relationship between the TBPs and segments of known hormone receptors.

Patents for the TBPs and their genes have been registered by Yeda Research & Development Co. Ltd., and recombinant TBP is already being synthesized by an Israeli company, InterPharm. Preclinical trials have shown that natural and recombinant forms of the protein, in microgram amounts, effectively protect against septic shock in mice. Clinical trials in humans are expected soon.

Prof. Rubinstein holds the Edna and Maurice Weiss Chair of Interferon Research.
 
Life Sciences
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