Immunodeficient rodents are indispensable research models for biomedical investigators for studies in oncology, immunology, and infectious diseases. Today, biomedical researchers use a number of naturally occurring and transgenic strains of immunodeficient mice and rats to study the immune system, rejection of tissue transplants, infections, cancer and tumor growth.
With the development of "knockout" immunodeficient mice, in which genes affecting the immune system are inactivated in the research animal, new fields of research are being opened to precisely study the role of selected components of the immune system. The recent flurry of advances in designing research animals including models with multiple immunocompromised functions or genetic deficiencies began some 20 years after the discovery of mice with a single, naturally occurring immunodeficiency.
In the early days of immune function research, observers noted that all animals have the physiological ability to "self-discriminate." That is, the body can discriminate between its own cells and those of another animal even one of the same species and then launch an immune response against foreign cells or substances. Early researchers also noted that blood cells called lymphocytes appeared to play a key role in the immune response.
Like other blood cells, lymphocytes differentiate from pluripotent stem cells in bone marrow (Figure 1). Lymphocytes that continue their maturation in bone marrow develop into B cells, while those that migrate to the thymus and complete maturation there become T cells. Mature B cells and T cells are most concentrated in lymph nodes, the spleen, and other lymphatic organs where the lymphocytes are most likely to encounter antigensforeign substances that evoke the production of antibodies and cytotoxic cellular responses.
Both B and T cells are able to recognize antigens. B cells are responsible for humoral, or serum, immunity by producing immunoglobulins, or Igs. These Igs are divided into five chief classesIgG, IgM, IgA, IgD, and IgEeach with special properties. T cells, making up about 70 percent of all lymphocytes, are responsible for cellular immunity, meaning they attack and kill antigens directly. T cells do not themselves make antibodies but they help regulate the production of antibodies by the B cells. There are four types ofT lymphocyteshelper, cytotoxic, delayed hypersensitivity (associated with allergies) and suppressor.
Differentiation of B and T cells into a vast variety of cloned cell types, each responding to a specific antigen, involves two phases: the primary or antigen-independent phase and the secondary or antigen-dependent phase. During the primary phase, stem cells proceed through stages of differentiation to generate vast amounts of B or T cell clones, each with unique antigen receptors. The antigen-binding proteins of B cells (immunoglobulin or Ig) and T cells (T cell receptor or TCR) consist of similar, but quite distinct polypeptide chains. The immune system generates an incredibly diverse range of gene sequences, or antigen-binding specificities for antibodies.
The secondary (antigen-dependent) phase involves only B cells, which can recognize an infinite number of antigens (but each individual B cell recognizes only one antigen). When a particular antigen binds to the antigen receptors on the appropriate B cell, that B cell is triggered to proliferate into a large clone of cells, all responsive to the specific antigen. In this clonal selection process, some of the cloned B cells become long-lived memory cells and others differentiate into plasma cells secreting antibodies.
Another type of immune cell was discovered in 1975, the natural killer (NK) cell, which looks like a lymphocyte but contains granules resembling granulocytes. NK cells apparently recognize some feature of the target cells, either directly or via receptors that attach to the tails of antibodies on the target cell's surface. As a result, NK cells act by releasing the contents of their granules to kill the target cells or by recruiting the help of other immune cells.
Differences in antigens between individual animals of the same species are called alloantigens; when they are major factors in the rejection of allogeneic tissue grafts, they are called histocompatibility antigens. A group of closely linked genes producing gene products prominently displayed on cell surfaces, comprises the Major Histocompatibility Complex (MHC). MHC antigens play a major role in immunity and in self-recognition in the differentiation of cells and tissues and they are therefore a critical factor in the immune system's rejection of foreign tissues, even tissue from animals of the same species. In humans, the MHC is called HLA, for human leukocyte group A antigens. Research shows that the mouse MHC is very similar in structure to the human HLA.
Three classes of gene products are encoded in the MHC. Class I molecules are expressed on nearly all cell surfaces. Class II molecules are expressed only on B lymphocytes, some monocytes, and activated T lymphocytes. Class III molecules are components of complement proteins, which act in concert with immunoglobulins to direct an appropriate immune response. Self versus non-self discrimination in the immune response is closely controlled by MHC class I and II molecules.
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