Navigation

Immunology Basics

The human immune system is a vast and complex collection of structures, cells, chemicals, and other elements; many individuals spend their entire working lives trying to better understand its intricate actions and reactions. It is outside the scope of this document to give more than a brief summary of information about immunity; however, some knowledge of the immune system and the way that it functions is crucial to understanding organ transplantation and the suppression of organ rejection. (For sources of more thorough discussions of immune function, see Links.)

Self and Non-self

The immune system can distinguish between material that the body considers "self," and material that it considers "non-self," for example bacteria, viruses, or foreign organs. Further, in regard to the self/non-self properties, the immune system can learn to recognize new "non-self" elements, and to remember those that it encountered in the past. When presented with a "non-self" molecule or structure, the immune system can produce specific cells to chemically "fit" receptors on the invading element, like a key in a lock. By attaching an immune cell to an invader—and only to an invader—the system can martial other cells to attack and destroy the non-self matter. Another example of the complexity of the immune system is the fact that it can sense when the foreign elements have been eradicated, and turn off the production of the attacking cells; it is self-limiting.

A section of a specific chromosome known as the Major Histocompatibility Complex (MHC) mediates much of the immune response. Because the genes of the MHC vary tremendously from person to person, transplanted tissue is recognized as "non-self" (an exception would be tissues from identical twins, whose entire genetic code is derived from a single, split zygote). The MHC also allows the different types of immune cells (B-cells, T-cells, macrophages, and others) to chemically communicate with each other. These cells can alert each other to an invader, specify its location, identify its nature (if it has been seen before) or specify its characteristics (if it is a new type), and signal when the danger has passed and production of the attackers is no longer needed.

There are two classes of MHC antigens, Class I and Class II. Class I antigens alert killer T-cells (T-8 or CD-8 protein) to the presence of body cells that have been invaded by bacteria or viruses, or changed by cancer or disease. Class II antigens, located on B-cells and other immune cells, can capture and break down antigens, making them more visible to the helper T-cells (T-4 or CD-4 protein). These two classes of antigens become more important to us in our consideration of transplants when we discuss tissue typing and donor/recipient matching.

Structures and Cells of the Immune System

The lymphatic system is populated by lymphocytes, the class of cells that are the principal operating units of the immune system. Produced in the bone marrow, the lymphocytes develop into several types: the B-cells, the T-cells—so named because they mature in either the Bone marrow, or in the Thymus gland—and the phagocytes (the root phage- meaning "eat") and the phagocyte subcategories: macrophages, microphages, erythrophages, and others. The macrophages are the large white blood cells that can engulf and destroy a foreign cell or a particle of debris in the body. The lymphocytes circulate constantly throughout the body, by way of both the circulatory system and the lymphatic system.

Lymphoid organs are the operating organs of the immune system, located throughout the body, and connected by the lymphatic system, which very roughly parallels the circulatory system. (Your physician probably begins a search for signs of infection by checking for swelling in the lymph "glands", small nodes concentrated in the neck, armpits, abdomen, and groin. Such swelling indicates that the lymphocytes are replicating and attacking a foreign organism; an immune response to an infection is underway.)

Over the course of a lifetime, hundreds of thousands, millions, of invading organisms, confront the immune system. In order to have enough physical space for all the cells that "remember" the previous infections, the immune system conserves a minimal number of each cell type. When the body is again threatened by the same organism, these few cells rapidly replicate, to create a large number of cellular copies capable of fighting the infection. As mentioned, once the danger has passed, the number of the attacking cells declines to await another invader.

B-cells, T-cells, and their action

T4 cell, with virus particles attached to receptors.

B-cells produce antibodies, chemical substances that can destroy a virus or bacterium. Each B-cell codes for a specific foreign organism, a specific antigen—the rhinovirus of the common cold, for example. If presented with its matching antigen, the B-cell then "clones" itself into more B-cells and produces large plasma cells, which manufacture quantities of the antibody that the particular B-cell codes for. Antibodies belong to a family of chemicals known as immunoglobulins. There are different classes of immunoglobulins—IgA, IgD, IgE, IgG, and IgM. Two principal types are IgG and IgA. IgG circulates in the blood and through the tissues, coating infectious organisms and making them easier targets for the immune cells. IgA is concentrated more in the tears, saliva, and secretions of the respiratory and GI tract. IgA is plentiful in the tissues that surround the portals to the body, in other words, points where organisms can enter without a cut or a break in the skin.

T-cells fall into two basic types: helper T-cells, and killer T-cells. Helper T-cells assist B-cells in the manufacture of antibodies. They alert other immune cells to the presence of an invading organism. The helper T-cells usually carry the T-3 or T-4 marker (more about these markers later). Killer T-cells (cytotoxic T-cells) can directly attack and destroy infected or damaged cells. The killer T-cells usually carry the T-8 marker. Unlike the B-cell, however, the helper T-cell cannot recognize antigens in their native state; the antigen must be broken down by B-cells or macrophages and presented to the helper T-cell receptors that fit the chemical fragments of the antigen. The T-4 cells respond to antigen that is bound to a Class II MHC molecule, while T-8 cells search for antigen that is bound to Class I MHC molecules.

When a T-cell is activated by contact with its specific antigen—a fragment of a virus, a protein from a bacterium, or a protein present in a transplanted organ—it secretes chemicals known as cytokines or lymphokines. These chemicals attach to locations on the antigen, then call other elements into play. Lymphokines can activate T- and B-cells, macrophages, cause the release of antibodies, and direct all this activity toward areas where the antigen is located.

The T- and B-cell activation and intercommunication are two of the more important actions of the immune system which must be suppressed—or at least confused—in order to prevent rejection of transplanted organs.

Some of the more important cytokines involved in organ rejection are called interleukins because they are messengers between the leukocytes (white blood cells). There are numerous interleukins, but the two of greatest interest to transplantation are Il-1 and Il-2. Il-1, principally derived from B-cells, activates T-cells and other attacking cells. Il-2, produced when an antigen activates a T-cell, encourages the T-cell to replicate and then encourages the new T-cells rapidly to develop. Again, it is often the interruption of this cycle of action that allows transplanted tissue to avoid detection, or at least avoid destruction.

Mentioned earlier, phagocytes and macrophages are in place throughout the body. Some macrophages develop special characteristics depending upon where in the body they reside: lungs, liver, kidneys, brain and other organs host these specialized defense cells. Macrophages also can scavenge dead or worn out cells and remove them from the tissues. Macrophages can be targeted for activation by a lymphokine, which acts upon a receptor on the macrophage, and directs it to seek out a single type of microbe or tumor cell.

The immune response involves numerous other cell types, among them basophils, neutrophils, eosinophils, mast cells, and platelets.

Inflammatory response

An indication that an immune response is underway is the warmth, redness, and swelling that can easily be seen when the infection is near the surface of the skin (although the same reaction goes on anywhere infection is present, even deep in the body.) This inflammatory response is a part of the "complement cascade", a complex chain of events that occur in a precise sequence during an immune response. Chemicals released by the immune cells can dilate blood vessels to increase blood flow, and thus the number of immune cells that can reach the infected location. Swelling arises from the increased flow of lymph and associated immune substances to the area where they are most needed. In addition to the extra fluid present in the area, swelling is aggravated by products of the basophils, mast cells, and other "cell destroyers" that can chemically irritate the surrounding tissue.

Corticosteroids reduce this inflammatory response, which in turn reduces the number of immune cells reaching the source of the antigen, and can slow or stop the complement cascade from triggering other immune responses.

Transplants and immunity

The discussion above indicates the versatility and adaptability of the immune system. These otherwise valuable properties make the immune system the enemy of organ transplants. For a transplanted organ to "take up residence" in a recipient's body, the immune response must be eliminated, or at least minimized. A great deal of this immune suppression is accomplished by a combination of drugs (see Immunosuppressant Drugs later in this discussion). The other major factor influencing donor organ/recipient matching is the histocompatibility of the two different tissues' genetic makeup. Recalling our discussion of self/non-self identification, tissue typing is where you want as many "self" markers as possible to match, and as few "non-self" markers as possible to show up. Next, we will examine HLA, PRA, and tissue typing.

For a much more thorough discussion of immunnology, see Dr. Douglas Fix's General Immunology.