Immunodeficiency Disorders Are Treated by Replacement of the Defective Element

Although there are no cures for immunodeficiency disorders, there are several treatment possibilities. In addition to the drastic option of total isolation from exposure to any mi-crobial agent, treatment options for the immunodeficiencies include:

■ replacement of a missing protein

■ replacement of a missing cell type or lineage

■ replacement of a missing or defective gene

For disorders that impair antibody production, the classic course of treatment is administration of the missing protein immunoglobulin. Pooled human gamma globulin given either intravenously or subcutaneously protects against recurrent infection in many types of immunodeficiency. Maintenance of reasonably high levels of serum immunoglobulin (5 mg/ml serum) will prevent most common infections in the agammaglobulinemic patient. This is generally accomplished by the administration of immunoglobulin that has been selected for antibodies directed against a particular organism. Recent advances in the preparation of human monoclonal antibodies and in the ability to genetically engineer chimeric antibodies with mouse V regions and human-derived C regions make it possible to prepare antibodies specific for important pathogens (see Chapter 5).

Advances in molecular biology make it possible to clone the genes that encode other immunologically important proteins, such as cytokines, and to express these genes in vitro, using bacterial or eukaryotic expression systems. The availability of such proteins allows new modes of therapy in which immunologically important proteins may be replaced or their concentrations increased in the patient. For example, the administration of recombinant IFN-y has proven effective for patients with CGD, and the use of recombinant IL-2 may help to restore immune function in AIDS patients. Recombinant adenosine deaminase has been successfully administered to ADA deficient SCID patients.

Cell replacement as therapy for immunodeficiencies has been made possible by recent progress in bone-marrow transplantation (see Chapter 21). Replacement of stem cells with those from an immunocompetent donor allows development of a functional immune system (see Clinical Focus Chapter 2). High rates of success have been reported for those who are fortunate enough to have an HLA-identical donor. Careful matching of patients with donors and the ability to manipulate stem-cell populations to select CD34+ precursor cells continues to minimize the risk in this procedure, even when no ideal donor exists. These procedures have been highly successful with SCID infants when haploidentical (complete match of one HLA gene set or haplotype) donor marrow is used. T cells are depleted and CD34+ stem cells are enriched before introducing the donor bone marrow into the SCID infant. Because this therapy has been used only in recent years, it is not known whether transplantation cures the immunodeficiency permanently. A variation of bone-marrow transplantation is the injection of paternal CD34+ cells in utero when the birth of an infant with SCID is expected. Two infants born after this procedure had normal T-cell function and did not develop the infections that characterize SCID.

If a single gene defect has been identified, as in adenosine deaminase deficiency or chronic granulomatous disease, replacement of the defective gene may be a treatment option. Clinical tests of such therapy are underway for SCID caused by ADA deficiency and for chronic granulomatous disease with defective p67phox, with promising initial results. Disease remission for up to 18 months was seen in the SCID patients and up to 6 months in the CGD patients. A similar procedure was used in both trials. It begins with obtaining cells (CD34 + stem cells are usually selected for these procedures) from the patient and transfecting them with a normal copy of the defective gene. The transfected cells are then returned to the patient. As this treatment improves, it will become applicable to a number of immunodeficiencies for which a genetic defect is well defined. As mentioned above, these include defects in genes that encode the 7 chain of the IL-2 receptor, JAK-3, and ZAP-70, all of which give rise to SCID.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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