Blood and Marrow Transplant Research

The Pediatric Blood and Marrow Transplant Program Laboratory at UCSF Benioff Children's Hospital has several research projects involving various aspects of transplantation, including the development of approaches for T cell depletion and stem cell enrichment.

T Cells

Since 1982, one segment of the laboratory has been involved in processing bone marrow stem cells to remove T cells in order to minimize the risk of developing graft-versus-host disease (GvHD) when using cells from parents and other partially mismatched relatives.

In Utero

Our researchers also have developed animal models, using mice and rhesus monkeys, for evaluating safe and effective ways of transplanting bone marrow stem cells into a fetus. The long-term goal of this research is to develop an optimal approach to treating human fetuses diagnosed with immunodeficiency diseases, hemoglobinopathies (or diseases of the red blood cells) and other genetic diseases.

Advantages to Transplantation in Utero

With standard bone marrow transplantation (BMT), high-dose chemotherapy and radiation therapy is necessary to prevent rejection of the donor bone marrow and to make space in the recipient's bone marrow cavity for the donor stem cells to grow. However, the chemotherapy and radiation also cause significant damage to healthy tissues such as the brain, lungs, liver and kidneys and possible death, which is why researchers are looking to fetal treatment options. Because the immune system in the fetus is immature, it is unable to reject donor cells early in gestation. Therefore, a BMT during this time should result in engraftment without the need for chemotherapy and radiation therapy.

Animal Models

The Pediatric BMT Laboratory has established an animal model in mice and rhesus monkeys of in utero bone marrow stem cell transplantation in which 70 percent of the animals engraft and the histocompatibility, or tissue typing, difference between the donor and recipient does not play a major role. However, the percent of donor cells that engraft is low, suggesting that competition for "space" within the marrow cavity remains a major barrier to successful in utero transplantation.

Over the past several years, we have focused on the role that specialized donor immune cells, dendritic cells (DC) and T lymphocytes and natural killer (NK) cells can play in enhancing engraftment of donor bone marrow stem cells in utero. We found that some recipients of DC plus bone marrow achieved full donor blood cell engraftment although many remained only partially engrafted. These animals also had a significantly higher mortality and this was associated with GvHD, something that was not seen in control groups. More recently, we have found that donor T and NK cells can generate significant donor cell engraftment in utero without fatal GvHD, a finding that we are actively pursuing.

The results of these studies will help us to design approaches either at the time of transplant or following birth to increase the percent of donor cells that durably engraft in utero in order to ultimately cure children with:

  • Severe immunodeficiency disorders
  • Defects in red blood cell production, including thalassemia, or Cooley's anemia and sickle cell disease
  • Certain genetic diseases, such as Hurlers' mucopolysaccharidosis and adrenoleukodystrophy (ADL)

This in utero transplant model has helped scientists and clinicians understand the complexities of engraftment in the fetus and the mechanisms that allow the recipient to accept the donor cells without the need for preparative chemotherapy.

Gene Cloning

The gene cloning research in the BMT laboratory involves one of the most severe types of inherited immunodeficiency diseases, called severe combined immunodeficiency disease (SCID), which occurs in some Native American Indian populations at a very high rate. The large majority of these patients have been successfully treated at UCSF Benioff Children's Hospital with bone marrow transplants.

Scientists in the Pediatric BMT Laboratory identified and cloned the gene on human chromosome 10 that is responsible for SCID in Athabascan-speaking Native Americans (SCIDA) including the Navajo and Apache Indians. They found a unique genetic mutation in this gene, which is called Artemis, which results in this disorder. They are currently working on understanding the function and role of Artemis in the development of T and B lymphocytes. To this end, they have recently engineered a mouse model of SCIDA that they will use to develop more optimal therapeutic approaches for SCIDA and other severe primary immunodeficiencies as well as possibly treating disorders that involve immune dysregulation such as autoimmune diseases and cancer.

SCID is a group of heterogeneous inherited diseases of the immune system resulting in severe and usually fatal infections. Those affected are sometimes referred to as "bubble babies." The incidence of SCID in the Navajo and Apache Nations -- collectively known as Athabascan-speaking Native Americans -- is among the highest of any inherited disease. The UCSF Benioff Children's Hospital BMT Program has cared for more than 20 Athabascan-speaking children with SCID.

Benefits to Isolating Artemis, the Gene That Causes SCIDA

The cloning of Artemis and identification of a unique mutation resulting in SCIDA allowed us to develop a rapid test for those children affected with the disease as well as the identification of unaffected carriers. The early diagnosis of SCID is crucial for the successful use of bone marrow transplantation in these children.

Now that we have identified the disease gene and developed a rapid method to detect the mutation, we are able to identify healthy individuals who are carriers of the mutation in addition to children with the disease prior to birth through prenatal diagnosis. We are beginning the process of studying the gene and developing ways in which the defective gene can be replaced with a normal gene. Thus avoiding the need for a bone marrow transplant form another individual. Finally, since this genetic mutation results in an extremely specific defect that is selective for the immune system, identification of the gene could lead to a better understanding of how the body's defense mechanisms grow and are regulated and could result in novel approaches to treating other diseases of the immune system that result in rheumatoid arthritis, scleroderma, hemolytic anemia and certain cancers.

Mouse Model of SCIDA

After cloning the mouse equivalent of Artemis in humans we engineered a mutation in the gene that mimicked that found in the Navajos and Apaches. We are now studying these healthy-appearing animals to determine to what extent they will be like children with the disease. This unique animal model will be critical in helping us to not only understand the role that this gene plays in the normal development and functioning of the immune system but also how it helps the body repair damage that occurs to our DNA during the normal process of day-to-day living. This animal model also can help us to develop better ways to treat children with a variety of immunodeficiency diseases using bone marrow transplantation both before and immediately after birth and to develop an approach using gene therapy to cure this disease.

Athabascan-Speaking Native Americans

The Navajo and Apache Indians are part of the Athabascan linguistic group of Native Americans who migrated to the Southwestern United States from Alaska and Canada between 700 and l500 A.D. In l864, the Navajo Nation was reduced to an estimated 4,000 individuals living in relatively isolated family units. Since then, they have become the fastest-growing population in North America and currently number approximately 200,000 people. The Navajo are an endogamous people divided into 50 to 60 clans, with 2 to 4000 people per clan. The Navajo society is matriarchal and matrilineal with clan identification following maternal, or the mother's, lines. It is believed that all Athabascan-speaking peoples originated in Asia and crossed into North America via the Bering land mass.

We have identified two Athabascan-speaking families from the Dogrib Indians, living in the Canadian Northwest Territories, who have had three children with SCID. Both the immunologic and clinical phenotypes in these children are identical to those in the Navajo and Apache. The genetic closeness of Athabascans in the Southwestern United States with those in the Northwest Territories, such as the Dogrib, has been suggested by studies of a variety of genetic markers.

Athabascan SCID

While the incidence of some inherited diseases, such as cystic fibrosis, is very low in the Navajo and Apache, there is a uniquely high incidence of SCID. Athabascan SCID is inherited as an autosomal recessive disease with an estimated incidence of one in 2,000 live births and an estimated gene frequency of 2.1 percent. This is compared to the estimated incidence of one in 500,000 for autosomal recessive SCID among outbred populations and one in l0,000 for first cousin marriages.

Gene Therapy

Gene therapy is a new and exciting approach to curing a variety of genetic diseases, certain infectious diseases and even many cancers by potentially correcting defective cells in the bone marrow. Researchers in the Pediatric Bone Marrow Transplant Lab have begun a project to correct the mouse equivalent of SCIDA using novel approaches to gene transfer into bone marrow stem cells. Using novel mechanisms for inserting a normal Artemis gene into cells from an animal with SCIDA, they hope to be able to develop the basis for a gene therapy trial in humans with SCIDA over the next several years.

Related Information

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Blood and Marrow Transplant

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