Immunologic Aspects of Organ Transplantation

Susan Smith MN, PhD

Disclosures

June 17, 2002

The Innate Immune System

Unlike other physiologic systems, the immune system cannot be associated with a single organ or tissue. The innate immune system consists of natural or nonspecific mechanisms for the protection of an individual against foreign antigens. These natural defenses are present from birth and do not necessarily require exposure to antigens for their development. Natural defenses, the body's first line of defense, consist of both anatomic and chemical barriers to microbial invasion. Anatomic barriers include the skin, mucous membranes, and ciliated epithelia. Chemical barriers include gastric acid, lysozymes, natural immunoglobulins, and the interferons (IFNs). Soluble mediators of innate immune defenses are listed in Table 1 .

Organization of the Immune System

The effectiveness of the immune system depends upon the ability of its components to get to where antigen is. Because it cannot be reliably anticipated where antigen will enter the body (except through the digestive and respiratory systems), the cells of the immune system must be mobile. Being mobile, these cells rely on established "roadways" to transport them to antigen: the circulatory (vascular) system and the lymphatic system. The vascular system is a main thoroughfare for all blood-borne elements. The lymphatics are blind-ended vessels that invade the tissues and run parallel to the capillaries and other circulatory vessels. A clear, protein-rich fluid called lymph (similar to plasma) and leukocytes are carried in the lymphatics. The function of lymphatics is to maintain fluid balance in the tissues by preventing edema (swelling caused by leakage of fluids into the tissues).

The lymphatic system. By surveying body fluid balance in the tissues, the lymphatics (Figure 1) are uniquely qualified to take up antigen if it enters the tissues by a breach of the skin. The lymphatics then deliver antigen to lymphocytes in the lymph nodes (Figure 2). Lymph nodes are located at the junctions of lymphatic vessels and form a complete network for the draining and filtering of extravasated lymph from interstitial fluid spaces. Afferent lymphatics carry lymph to the lymph nodes; efferent lymphatics serve as exit routes for lymphocytes from lymph nodes. Lymphatics dump antigen-cleared fluid into the blood system at 2 main sites: the right lymphatic duct and the thoracic duct. The right lymphatic duct drains most of the right side of the body into the right subclavian vein and the thoracic duct drains the rest of the body into the left subclavian vein and the left internal jugular vein.

Figure 2.

The lymph node.

What then, is the fate of antigen that has been processed by macrophages and dendritic cells in the medulla of the lymph node? Antigen is presented to T helper (Th) cells, which respond by clonal proliferation in the lymph node paracortical areas, resulting in the production of cytokines that drive the remainder of the response (Figure 3). Cytotoxic T lymphocytes (CTLs) present in the paracortical areas of the lymph node also require antigen processing and presentation. Once antigen of the appropriate specificity has been presented to the CTL (by any nucleated cell, not just macrophages or dendritic cells), the CTL undergoes clonal proliferation. These close cousins of Th cells complete their response by differentiating into killers that make bullet-like molecules, including serine esterases, perforin (related to the complement component C9, part of the membrane attack complex [MAC]), and granzymes. These molecules directly lyse the CTL target that originally presented antigen to it.

Figure 3.

Fate of antigen in the lymph node.

The spleen. The physiologic function of the spleen is not completely understood, but it is known that it has reticuloendothelial, immunologic, and storage functions. The spleen produces monocytes, lymphocytes, and IgM antibody-producing plasma cells. If antigen enters the system directly through the bloodstream, it is filtered by the spleen, where it encounters circulating lymphocytes.

Anatomic and Chemical Defenses

The skin is a remarkable organ. It has the distinction of being the largest and most important organ of the human body. Cells in the skin provide a barrier against penetration of excess water, evaporation of the body fluid into the environment, and protection against the ultraviolet rays of the sun. The skin also provides the initial physical barrier to external environmental antigens. The outermost skin layer, the stratum corneum, is the main barrier to microbial invasion. Certain conditions such as pH, humidity, and temperature influence the growth of potentially pathogenic organisms on the skin. Alterations in normal conditions related to these factors favor the development of infection. The normally acid pH of the skin inhibits growth of microorganisms. When the acid-base balance of the skin is altered in favor of a higher pH, this protective mechanism is lost. When water loss from epidermal cells exceeds intake, the stratum corneum can dry and crack, predisposing the host to microbial invasion. On the other hand, excessive moisture decreases barrier efficiency.

Skin cells are constantly exfoliating, and in this process organisms are sloughed along with dead skins cells. In addition, the skin is colonized with "normal flora" that, through various mechanisms, protects the host from colonization of potentially pathogenic organisms. Resident flora maintain the skin's pH in the acidic range and compete effectively for nutrients and binding sites on epidermal cells, making it difficult for nonresident flora to survive. Normal flora consists mainly of aerobic cocci and diphtheroids. When normal flora are altered, such as occurs with long-term or broad-spectrum antibiotic therapy and with the use of disinfectants or occlusive dressings, potentially pathogenic organisms become "opportunistic." Opportunistic organisms take advantage of the lack of competition for nutrients and epidermal binding sites and multiply, leading to potentially lethal infections.

The skin is not a passive organ. Normal human epidermis contains specialized dendritic antigen-presenting cells (APCs) called Langerhans cells, and keratinocytes that secrete immunoregulatory cytokines. Langerhans cells express macrophage-type surface markers and immune-response-associated antigens. These cells perform antigen presentation functions similar to those performed by the macrophages that are necessary for Th cell activation. They trap antigen, travel to the lymph nodes, and present antigen to lymphocytes capable of mounting a stronger and more complete immune response.

Cytokines are chemical messenger molecules that give orders to target cells. The binding of a cytokine to its specific receptor on the surface of a target cell initiates a chain of chemical reactions that lead to cell maturation, growth, proliferation, molecule production, and death. Cytokines can be differentiated according to their source (eg, cytokines produced by lymphocytes are called lymphokines), target cells, and effects on target cells. Many cytokines work in concert on the same target cells.

The sebaceous glands, mammary glands, respiratory epithelium, gastrointestinal (GI) mucosa, genitourinary mucosa, and conjunctivae all secrete a protective immunoglobulin (Ig) called secretory IgA. Ciliated respiratory epithelial cells (cilia or small hairs that beat in concert to sweep antigen back out of the body cavities) facilitate the removal of bacteria and other foreign antigens from the respiratory tract, and the low pH of the gastric mucosa prevents bacterial growth in the stomach. Mucus acts as biological quicksand, trapping antigen before it can enter the organs.

Hemopoiesis

All of the cells of the immune system begin to develop in fetal life. After birth, the marrow of the long bones assumes the function of hemopoiesis (or hematopoiesis), the production of blood cells (Figure 4). There is evidence that all blood cells are derived from a single progenitor cell, a pluripotent stem cell, distinguished by 2 characteristics. The first is the ability to generate more of its own kind. Thus, the pluripotent stem cell is self-renewing. Second, some of the pluripotent stem cells that are the progeny of the initial cell become committed to different hemopoietic lineages that eventually give rise to all the formed elements of the blood: red blood cells (RBCs) or erythrocytes, white blood cells (WBCs) or leukocytes, and platelets. If you were to take a small drop of your blood, place it on the end of a glass slide, smear it up the length of the slide, and fix and stain it, the formed elements of the blood would be visible under a microscope (Figure 5). The vast majority of what you would see would be erythrocytes, with a fair number of platelets in each microscopic field. The focus of this discussion will be leukocytes.

Figure 4.

Hemopoeisis in the bone marrow.

Figure 5.

Normal blood smear.

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