Pediatric Annals

FROM THE NIH 

Severe Combined Immune-Deficiency Disease

Abstract

Ten years ago severe combined immune-deficiency disease (SCID) was invariably fatal within the infant's first year of life. Today, thanks to research by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, (among other organizations) a number of therapeutic procedures have been developed that are helping some infants born with SCID to live relatively normal lives.

The therapeutic procedures are all designed to restore the immune function of the child who has been born with impaired immune responses. The protective capability of the immune system rests largely on the normal maturation and development of two classes of lymphoctyes - the T (thymusderived) cells and the B (bone-marrow-derived) cells.* A number of T-cell subpopulations are generated that serve specialized functions in the body, while B cells also undergo specialization so that they can produce major classes of immunoglobulins (antibodies).

In the infant born with SCID, there are profound deficits in both the number and capabilities of T cells and B cells. Some babies lack the essential blood enzyme adenoside deaminase (ADA); they have inherited their immunodeficiency as an autosomal recessive trait.

How can the pediatrician tell when an infant has SCID? The most common sign is susceptibility to all varieties of infections - including pneumonias due to unusual organisms. There is likely to be persistent oral and cutaneous candidiasis. Intractable diarrhea is also a typical and early finding. Either the child has no thymus glands or they are very small. Tonsils, adenoids, lymph nodes, and Peyer's patches are also either absent or extremely underdeveloped.

Most SCID infants have severe lymphopenia, so simple white blood cell count and differential smear may alert the pediatrician to possibilities of the disease. T-cell and B-cell function must be assessed in order to make a definitive diagnosis. An indication of B-cell activity begins with the detection of immunoglobulins. However, it is not unusual for normal infants to have extremely low levels of immunoglobulins, so comparisons should be made with age-matched babies. Usually newborns and young infants have normal levels of IgG, received from their mothers; a low serum IgM level, however, could suggest immune deficiency.

T-cells can be enumerated because of the ability of these lymphocytes to bind untreated sheep erythrocytes in a rosette patteriVand by their ability to synthesize deoxyribonucleic acid and to divide in response to stimulation with mitogens such as phytohemagglutinin. Skin tests with common antigens such as Candida can provide additional information, in older children, but very young children may have inadequate sensitizing exposure to make these tests useful.

The treatment of choice for the child with severe combined immune deficiency is transplantation of bone marrow from a related HLA-identical donor.

Sixty-three percent of 69 SCID patients given HLA-identical, mixed-leukocyte-culture, unreactive marrow from a related donor lived at least six months, the Advisory Committee of the International Bone Marrow Transplant Registry reported after a recent review.

For most children, however, no histocompatible donors are available. Injections of unrelated fetal liver cells have been used to restore immune competence in infants, with varying amounts of success. When taken before 12 weeks' gestation, fetal liver is a source of healthy stem cells that can produce lymphocytes. Cultured thymic epithelium cells have also been used to restore competency. At the University of Wisconsin, researchers working with National Institutes of Health grants have found that seven of 15 adenoside deaminase-positive SCID patients have shown both T-cell and B-cell responses following thymic cell transplants. B-cell reconstitution, for some unknown reason, far exceeds T-cell restoration following thymic-cell transplantation.

The researchers at the University of Wisconsin are now evaluating this procedure in ADA-negative patients. They…

Ten years ago severe combined immune-deficiency disease (SCID) was invariably fatal within the infant's first year of life. Today, thanks to research by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, (among other organizations) a number of therapeutic procedures have been developed that are helping some infants born with SCID to live relatively normal lives.

The therapeutic procedures are all designed to restore the immune function of the child who has been born with impaired immune responses. The protective capability of the immune system rests largely on the normal maturation and development of two classes of lymphoctyes - the T (thymusderived) cells and the B (bone-marrow-derived) cells.* A number of T-cell subpopulations are generated that serve specialized functions in the body, while B cells also undergo specialization so that they can produce major classes of immunoglobulins (antibodies).

In the infant born with SCID, there are profound deficits in both the number and capabilities of T cells and B cells. Some babies lack the essential blood enzyme adenoside deaminase (ADA); they have inherited their immunodeficiency as an autosomal recessive trait.

How can the pediatrician tell when an infant has SCID? The most common sign is susceptibility to all varieties of infections - including pneumonias due to unusual organisms. There is likely to be persistent oral and cutaneous candidiasis. Intractable diarrhea is also a typical and early finding. Either the child has no thymus glands or they are very small. Tonsils, adenoids, lymph nodes, and Peyer's patches are also either absent or extremely underdeveloped.

Most SCID infants have severe lymphopenia, so simple white blood cell count and differential smear may alert the pediatrician to possibilities of the disease. T-cell and B-cell function must be assessed in order to make a definitive diagnosis. An indication of B-cell activity begins with the detection of immunoglobulins. However, it is not unusual for normal infants to have extremely low levels of immunoglobulins, so comparisons should be made with age-matched babies. Usually newborns and young infants have normal levels of IgG, received from their mothers; a low serum IgM level, however, could suggest immune deficiency.

T-cells can be enumerated because of the ability of these lymphocytes to bind untreated sheep erythrocytes in a rosette patteriVand by their ability to synthesize deoxyribonucleic acid and to divide in response to stimulation with mitogens such as phytohemagglutinin. Skin tests with common antigens such as Candida can provide additional information, in older children, but very young children may have inadequate sensitizing exposure to make these tests useful.

The treatment of choice for the child with severe combined immune deficiency is transplantation of bone marrow from a related HLA-identical donor.

Sixty-three percent of 69 SCID patients given HLA-identical, mixed-leukocyte-culture, unreactive marrow from a related donor lived at least six months, the Advisory Committee of the International Bone Marrow Transplant Registry reported after a recent review.

For most children, however, no histocompatible donors are available. Injections of unrelated fetal liver cells have been used to restore immune competence in infants, with varying amounts of success. When taken before 12 weeks' gestation, fetal liver is a source of healthy stem cells that can produce lymphocytes. Cultured thymic epithelium cells have also been used to restore competency. At the University of Wisconsin, researchers working with National Institutes of Health grants have found that seven of 15 adenoside deaminase-positive SCID patients have shown both T-cell and B-cell responses following thymic cell transplants. B-cell reconstitution, for some unknown reason, far exceeds T-cell restoration following thymic-cell transplantation.

The researchers at the University of Wisconsin are now evaluating this procedure in ADA-negative patients. They suspect that a thymic transplant won't be able to synthesize enough ADA to provide for the needs of these patients, although in the first child treated there seemed to be some benefit in the form of increased T-cell responses and longer intervals between blood transfusions.

Other NIH-supported research is taking place on the problem at Case Western Reserve University and New York University Schools of Medicine. Frozen, irradiated red blood cells are being given to ADA-negative SCID children in an effort to restore some T-cell response. There are serious concerns about the long-term effect of this line of therapy - the risk of hepatitis, for example, and the possibility that the child will develop antibodies against minor blood-group determinants. Nevertheless, enzyme replacement may offer a way to treat ADA-negative SCID children until a histocompatible bone-marrow donor can be found.

10.3928/0090-4481-19801101-11

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