Severe Combined Immunodeficiency Disease Treatment

Severe combined immunodeficiency disease (SCID) represents a group of diseases with many different causes but, in general, results in children who have severe defects in the function of their lymphocytes. These deficiencies result in a significant reduction or absence of function of T and B cells (called lymphocytes) that is essential for fighting bacterial, viral and certain fungal infections.

Children with SCID usually become sick from infections, skin rashes and failure to gain weight within the first three to six months of life and without critical care and a transplant often die prior to 1 year of age.

The UCSF Benioff Children's Hospital Bone Marrow Transplant Program is studying the use of bone marrow stem cell transplants for children with SCID. Currently, bone marrow stem cell transplantation is the only known treatment for children with SCID. Since the majority of children with SCID who might benefit from a BMT do not have the most optimal tissue-matched brother or sister, half-matched parents have been used as donors. However, to successfully use this approach, the parental bone marrow stem cells must be treated in a special way to remove donor T cells (called T cell depletion) that can cause fatal reactions called graft-versus-host disease (GvHD).

The goals of this protocol are to determine:

The most optimal approach for transplantation in order to increase engraftment of T cell depleted transplants and the incidence of B cell engraftment with minimal toxicity in SCID patients
The efficacy and safety of stem cell enriched T cell depleted parental peripheral blood hematopoietic stem cells (PBSC). See below for more information about PBSC.

White Blood Cells

White bloods cells fight off infection in the body. There are various types of white blood cells:

Lymphocytes — Lymphocytes are white blood cells in the body that are crucial for fighting infections. They consist of two general types of cells, T cells and B cells. T cells are responsible for fighting all types of germs, but they also may cause rejection of donor bone marrow and reactions called graft-versus-host disease (GvHD). GVHD occurs when T cells from the donor attack certain tissues, such as the skin, liver and intestines, of the recipient.

B Cells — B cells are essential for making certain chemicals or proteins called antibodies that help protect against bacterial and viral infections. Antibodies develop when an individual is exposed to germs or has been given an immunization. They then will protect the individual when there is a subsequent exposure to the same germ. Antibodies can be purified from healthy, normal blood donors and administered to children with SCID in the form of gammaglobulin infusions.

Natural Killer (NK) Cells — The exact function of NK cells is unknown, although it is thought that they may be important in rejecting donor bone marrow following the bone marrow transplant. Some patients with SCID have low to absent function of their NK cells.

Neutrophil — Neutrophils are very important white cells for fighting many bacterial and fungal infections. Unfortunately, neutrophils alone are not sufficient to protect people from all of the germs to which the body is exposed. In general, the majority of patients with SCID have normal numbers and functions of their neutrophils.

Bone Marrow Stem Cell Transplant

Bone marrow contains young cells called stem cells, which manufacture the essential components found in the blood, including:

Platelets, which help prevent bleeding
White cells, which protect against infection
Red cells, which carry oxygen to tissues in the body

Bone marrow from a donor can be transplanted into a recipient in order to restore these functions, which is called engraftment. For children with SCID, in particular, the function of their T cells and B cells also can be restored with a bone marrow transplant (BMT).

For the majority of children undergoing a BMT for diseases other than SCID, preparation before transplant, called conditioning, that includes chemotherapy and sometimes radiation therapy is essential in order to obtain engraftment.

For many children with SCID, donor marrow may engraft without any conditioning, although up to 50 percent will require additional conditioning prior to transplant to eliminate any residual immune function and allow engraftment of donor marrow. However, in approximately 75 percent to 80 percent of children with SCID who have a successful BMT, donor B cells do not engraft, so that most who are cured of their T cell deficiency will still require gammaglobulin for the rest of their lives. One of the goals of the work that the UCSF Benioff Children's Hospital BMT Program over the years has been to do a BMT that would achieve T and B cell engraftment without requiring any pre-transplant conditioning therapy.

Peripheral Blood Stem Cells

A second source of bone marrow stem cells is the blood that circulates throughout the body in arteries and veins. When normal people are treated with a type of chemical normally made in small amounts in the body called granulocyte colony stimulating factor (G-CSF), increased numbers of stem cells leave the marrow and enter the blood stream. These cells, referred to as peripheral blood stem cells (PBSC) can be collected along with other white cells through a process called leukapheresis, a standard procedure commonly used in blood banks. In the past 10 years, leukapheresis has been used routinely for collecting stem cells from patients with cancer for subsequent transplantation back into the patient. It also now is used for collecting bone marrow stem cells from healthy parents or siblings for transplantation into matched or mismatched children or adult patients.

The UCSF Benioff Children's Hospital BMT Program is researching answers to the following questions regarding PBSC transplants:

How often will the transplants engraft?
How safe is the procedure?
Will there be a sufficient number of healthy donor stem cells to restore marrow function?
Will secondary or "booster" transplants be necessary after the initial transplant to accelerate the recovery of the immune system?
Are there any complications associated with this particular source of bone marrow stem cell?

Minimizing the Risk of Graft-versus-Host Disease

A major problem for patients who might benefit from a transplant is finding a compatible donor, which reduces the risk of graft-versus-host disease (GvHD). Generally, 80 percent of children with SCID will have no closely matched donor available. Parents and many siblings are only partially compatible with their children and only can donate marrow or blood stem cells if it is treated to remove the T cells that are responsible for GvHD. Techniques are now available for purifying stem cells and removing T cells from mismatched marrow or peripheral blood from a mother, father or sibling, which can be used safely when a closely matched relative is not available.

One technique used to select stem cells and remove T cells involves targeting the bone marrow stem cells with a special antibody that is attached to an iron chemical and attaches only to the stem cells. When placed in a powerful magnetic field, the antibody-bound stem cells are collected. Over 1000 transplants have been done using this approach. Based on these results it appears that sufficient T cells can be removed to significantly reduce the risk of GvHD.

The UCSF Benioff Children's Hospital BMT Program is trying to determine:

The most optimal regimen for treating a child with SCID that will result in both T and B cell engraftment
The safety and benefit of using stem-cell enriched and T-cell depleted PBSC from parents, siblings or other close relatives.