Case Study Adverse Reactions to Transplantation
Four weeks after receiving a bone marrow transplant, Mary Smith developed jaundice and a skin rash on her hands, feet, and face. She also had occasional episodes of vomiting and diarrhea. Clinical chemistry results showed her serum liver enzymes (LDH, ALT) and bilirubin level to be elevated. What is the most likely cause of Mary's symptoms and what is the best therapy?
Answer: Ms. Smith has an acute graft-versus-host (GVH) reaction. Such reactions usually occur when immunologically competent cells are introduced into an immunocompromised host. When they develop, it is usually within 100 days following trans plant. In choosing tissues and organs for transplantation, the HLA antigens of donors and patients are matched as closely as possible to decrease the risk of rejection. However many minor antigenic markers that can cause immunological incompatibility differ between individuals. In this case, T lymphocytes from the donor's bone marrow are attacking her skin, liver, stomach, and intestines. Patients with GVH reactions are already receiving cyclosporine or other immunosuppressive therapy. When a GVH reaction is diagnosed, treatment with corticoste-roids, such as prednisone and prednisolone, is usually added.
Most drugs used today are designed to treat symptoms rather than cure the underlying disease. Notable exceptions include cytotoxic chemotherapeutic agents, as described in Chapter 56, and agents that restore or modulate hormone function, as outlined in Chapter 57. However, increased understanding of the molecular and genetic etiology of diseases may permit permanent modification of organ function by drug-oriented methods. The first disease-associated gene, (3-globin, was cloned over 25 years ago. It is now theoretically possible to isolate, sequence, and analyze genes causally associated with many heritable and acquired human diseases, including cystic fibrosis, Duchenne's muscular dystrophy, and Gaucher's disease. Moreover, with the complete sequencing of the human genome, many of the estimated 100,000 human genes may become candidates for genetic manipulations. Thus, it is now possible to propose molecular pharmacological and genetic approaches to therapy . Many of these approaches fall under the general rubric of gene therapy.
Germ cell gene therapy will require considerable discussion about ethical issues and extensive information before it can be applied to humans, but somatic cell gene therapy in humans is now being extensively explored. During the past 5 years in the United States alone, more than 500 human gene therapy clinical trials aimed at treating conditions ranging from inherited disorders such as cystic fibrosis to cancer and AIDS, have been approved by the Office of Biotechnology Activities (OBA, formerly the Recombinant DNA Advisory Committee) of the National Institutes of Health. Nearly 3500 patients have been enrolled in these studies (Fig. 58.1).
With few exceptions, gene therapy was considered safe if not particularly effective until the death of an 18-year-old man in 1999, the first fatal outcome for a pa tient in a phase I gene therapy protocol. This death has stimulated a substantial review of the oversight mechanisms in human gene transfer research. One of the first successes of gene therapy was reported in 2000, when three infants with a fatal form of severe combined immunodeficiency syndrome (SCID) received ex vivo gene therapy with a recombinant mouse leukemia viral vector encoding the 7C receptor gene. After 10 months, 7C transgene expression in T- and NK cells was detected and T-, B-, and NK-cell counts and function were comparable to those of age-matched controls.
Although numerous obstacles must be overcome before gene therapy will be routinely employed, a rigorous approach to investigating the safety and efficacy of gene transfer will ensure that clinical strategies employing genetic manipulation are rationally incorporated into the therapeutic armamentarium.
GENE THERAPY: DEFINITION AND GOALS
The broadest definition of human gene therapy includes the in vivo (direct administration of the gene therapy formulation) and ex vivo (transfection of cells in tissue culture by gene therapy followed by administration of the transfected material into the patient) transfer of defined genetic material to cells of patients. Principles of gene therapy include transfer of one or more transgenes to prevent a disease, prevent an adverse consequence of a disease, or facilitate recovery from the consequence. Although most of the controversy and excitement have centered on the transfer of functional genes, the therapeutic potential of genes that abrogate aberrant function (e.g. antisense and ribonucleic acid-based strate-
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