Immunologic Aspects of Organ Transplantation

Susan Smith MN, PhD

Disclosures

June 17, 2002

Inflammation

Inflammation is the body's attempt to restore homeostasis; it is the initial reaction to injury and the first step in the healing process. Wound healing cannot occur if the inflammatory response is fully inhibited. A series of cellular and systemic reactions are triggered during the inflammatory response that localize and destroy the offending antigen, maintain vascular integrity, and limit tissue damage. The inflammatory response can be altered or suppressed in many situations: the administration of corticosteroids and other immunosuppressive agents, malnutrition, advanced age, chronic illness, and prolonged stress. Conversely, the inflammatory response can become exaggerated in conditions such as anaphylaxis and septic shock.

Tissue injury provides the initial stimulus for activation of inflammatory mechanisms and results in the cellular release of vasoactive substances such as histamine, bradykinin, and serotonin. The circulatory effects are vasodilation and increased blood flow to the affected site; increased vascular permeability, which facilitates diapedesis of immune cells from the circulation to the tissues; and tenderness or pain. The clotting system is activated in an attempt to "plug up" the injury. Increased blood flow and capillary permeability lead to local interstitial edema and swelling. Leukocyte migration occurs as phagocytes are attracted (by a process called chemotaxis) to the affected site, and dying leukocytes release pyrogens that stimulate the hypothalamus to induce a state of fever. Pyrogens also stimulate the bone marrow to release more leukocytes, thus perpetuating the process. Consider the following example:

It is early evening, and you are walking on the beach, looking out to sea, oblivious to any obstacles in your path. Ouch, stepped on the head of a rusty nail sticking out of a piece of driftwood. Several processes occur simultaneously at the site of the wound: inflammation, the entry of leukocytes into the tissue space, and complement activation (Figure 8). Capillaries, lymphatics, and cells comprising the tissue in your foot have been injured by the nail. Immediately, blood containing immune cells, plasma, and lymph enter the tissue space. The clean-up has begun.

Figure 8.

Innate immunity and inflammation.

Neutrophils in the blood begin crawling through the spaces between endothelial cells to enter the tissue, where they encounter bits of antigen, including bacteria, introduced by the nail. Close contact between the neutrophil membrane and the bacterial membrane activates phagocytosis. The membrane of the neutrophil engulfs the bacterium and eventually pinches off into the cell cytoplasm to form an intracellular vacuole called a phagosome. Preformed enzymes contained within neutrophil lysozomes fuse membranes with the phagosome, forming a phagolysosome, in which the bacterium is digested.

Endothelial cells lining the capillaries are activated. Together with neutrophils, skin fibroblasts, and Langerhans cells, the endothelial cells begin to produce cytokines that are chemotactic for other leukocytes (chemokines). Chemokines such as IL-8 and RANTES (regulated upon activation, normal T-cells expressed and secreted) ( Table 1 ) act as homing signals for WBCs being dumped into the tissue space by damaged capillaries and lymphatics. Diapedesis by chemotaxis is the process of cells crawling out of the vessels between endothelial cells into the tissue space, in response to chemokines. Monocytes are very sensitive to chemotactic stimuli. They begin crawling into the tissue space, where they become macrophages and begin cleaning up debris and bacteria, becoming activated in the process. Activation results in further production of cytokines, which exacerbates inflammation, and attracts more WBCs into the tissue space.

As tissue fluid and blood continue to seep into the tissue space, the clotting cascade is activated to restrain the flow of blood. A series of plasma proteins, collectively referred to as complement, leak out of the plasma into the tissue space (Figure 9). Other proteins released from damaged cells cause the redness and pain associated with inflammation (Figure 8).

Figure 9.

The complement cascade.

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