Frontiers in Immunology: Hybridoma Technology

Through a stratagem known as hybridoma technology, scientists are now able to obtain, in quantity, substances secreted by cells of the immune system-both antibodies and lymphokines. The ready supply of these materials has not only revolutionized immunology but has also created a resounding impact throughout medicine and industry.

A hybridoma is created by fusing two cells, a secreting cell from the immune system and a long-lived cancerous immune cell, within a single membrane. The resulting hybrid cell can be cloned, producing many identical offspring. Each of these daughter clones will secrete, over a long period of time, the immune cell product. A B-cell hybridoma secretes a single specific antibody.

Such monoclonal antibodies, as they are known, have opened remarkable new approaches to preventing, diagnosing, and treating disease. Monoclonal antibodies are used, for instance, to distinguish subsets of B cells and T cells. This knowledge is helpful not only for basic research but also for identifying different types of leukemias and lymphomas and allowing physicians to tailor treatment accordingly. Quantitating the number of B cells and helper T cells is all-important in immune disorders such as AIDS. Monoclonal antibodies are being used to track cancer antigens and, alone or linked to anticancer agents, to attack cancer metastases. The monoclonal antibody known as OKT3 is saving organ transplants threatened with rejection, and preventing bone marrow transplants from setting off graft-versus-host disease.

Monoclonal antibodies are essential to the manufacture of genetically engineered proteins (Genetic Engineering); they single out the desired protein product so it can be separated from the jumble of molecules surrounding it. monoclonal antibodies are also the key to developing new types of vaccines (Vaccines Through Biotechnology).

With growing experience, scientists have devised several sophisticated variants on the monoclonal antibody. For instance, they have created some monoclonal antibodies of human rather than mouse origin; human monoclonal antibodies can be used for therapy without risking an immune reaction to mouse proteins. They have also succeeded in "humanizing" mouse antibodies by splicing the mouse genes for the highly specific antigen-recognizing portion of the antibody into the human genes that encode the rest of the antibody molecule.

Other monoclonal antibodies have been designed to behave like enzymes; these so-called catalytic antibodies or abzymes speed up, or catalyze, selected chemical reactions by binding to a chemical reactant and holding it in a highly unstable "transition state." By, in fact, cutting the proteins to which they bind, such antibodies may be useful for such things as dissolving blood clots or destroying tumor cells. Yet other researchers, by fusing two hybridoma cells that produce two different antibodies, have created hybrid hybridomas that secrete artificial antibodies made up of two nonidentical halves. While one arm of the bispecific antibody binds to one antigen, the second arm binds to another. One may bind to a marker molecule, for instance, and the second to a target cell, creating an entirely new way to stain cells. Or, one arm of a chimeric antibody may bind to a killer cell while the other locks to a tumor cell, creating a lethal bridge between the two.

The SCID Mouse

Research in immunology took a giant step forward with the development and manipulation of the SCID mouse. Lacing an enzyme necessary to fashion a functional immune system of their own, SCID mice-like their human counterparts with Severe Combined Immunodeficiency Disease (Immunodeficiency Diseases)-are helpless not only to fight infection but also to reject transplanted tissue.

In the late 1980s, scientists transformed the SCID mouse into an in vivo model of the human immune system. One group of researchers painstakingly transplanted a human fetal thymus gland and lymph nodes into the adult SCID mouse, then injected them with embryonic human immune cells. Some of these cells traveled to the human thymus, where they matured into T cells; others developed into working B cells and macrophages, circulating through the lymph nodes. A second group of researchers implanted mature human T cells in the SCID mouse. Such systems amount to a living test tube, making it possible to study the effects of drugs and of viruses, including HIV, in an intact mammalian immune system.

Genetic Engineering

Genetic engineering, more formally known as recombinant DNA technology, allows scientists to pluck genes (segments of DNA) from one type of organism and combine them with genes of a second organism. In this way, relatively simple organisms such as bacteria or yeast, or even mammalian cells in culture and mammals such as goats and sheep, can be induced to make quantities of human proteins, including hormones such as insulin as well as lymphokines and monokines. Microorganisms can also be made to manufacture proteins from infectious agents such as the hepatitis virus or the AIDS virus, for use in vaccines.

Another facet of recombinant DNA technology involves gene therapy: replacing defective or missing genes with normal genes. The first approved gene therapy trials involved children with severe combined immunodeficiency disease, or SCID (Immunodeficiency Diseases), which is caused by lack of an enzyme due to a single abnormal gene. The missing gene is introduced into a harmless virus, then mixed with progenitor cells from the patient's bone marrow. When the virus splices its genes into those of the bone marrow cells, it simultaneously inserts the gene for the missing enzyme. Injected back into the patient, the treated marrow cells produce the missing enzyme and revitalize the immune defenses. Researchers are also investigating the use of gene therapy for such diverse conditions as hemophilia, Parkinson's disease, diabetes, a hereditary form of dangerously high cholesterol, and AIDS.

An increasingly important target for gene therapy is cancer. In pioneering experiments, scientists are removing the immune cell known as the tumor-infiltrating lymphocyte or TIL (Immunity and Cancer), or tumor cells themselves, inserting a gene that boosts the cells' ability to make quantities of a natural anticancer product such as tumor necrosis factor (TNF) or interleukin-2, and then growing the restructured cells in quantity in the laboratory. When the altered cells are returned to the patient, they seek out the tumor and deliver large doses of the anticancer chemical. They also appear to mobilize, in some unknown way, additional antitumor defenses.

On the horizon are anticancer vaccines made by manipulating genes. Intended to protect cancer patients against a recurrence, these vaccines can incorporate genes for immunogenic tumor antigens or genes for histocompatibility antigens able to galvanize killer T cells, as well as genes for substances such as TNF or interleukin-2. Other anticancer strategies call for introducing genes that can shut down cancer-promoting oncogenes or replace faulty cancer-restraining suppressor genes.

Genes can be packaged, for delivery, in a variety of ways: inserted into the genetic material of such carriers as the familiar vaccinia virus (Vaccines Through Biotechnology) or inactivated retroviruses, grafted onto a protein carrier that magnifies the immune response (an adjuvant), or tucked into fat globules known as liposomes.

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