A 45-year-old man with high-risk acute myelogenous leukemia undergoes high-dose chemotherapy followed by an allogeneic stem cell transplant from an unrelated donor. He receives tacrolimus and low-dose methotrexate as prophylaxis for graft-vs-host disease. One month after blood count recovery, he develops a skin rash despite ongoing tacrolimus therapy. A skin biopsy confirms grade II acute graft-vs-host disease. How should this case be pharmacologically managed at this point?
Agents that suppress the immune system play an important role in preventing the rejection of organ or tissue grafts and in the treatment of certain diseases that arise from dysregulation of the immune response. While precise details of the mechanisms of action of a number of these agents are still obscure, knowledge of the elements of the immune system is useful in understanding their effects. Agents that augment the immune response or selectively alter the balance of various components of the immune system are also becoming important in the management of certain diseases such as cancer, AIDS, and autoimmune or inflammatory diseases. A growing number of other conditions (infections, cardiovascular diseases, organ transplantation) are also areas for immune manipulation.
ELEMENTS OF THE IMMUNE SYSTEM
The immune system has evolved to protect the host from invading pathogens and to eliminate disease. When functioning at its best, the immune system is exquisitely responsive to invading pathogens while retaining the capacity to recognize self tissues and antigens to which it is tolerant. Protection from infection and disease is provided by the collaborative efforts of the innate and adaptive immune systems.
The innate immune system is the first line of defense against invading pathogens (eg, bacteria, viruses, fungi, parasites) and consists of mechanical, biochemical, and cellular components. Mechanical components include skin/epidermis and mucus; biochemical components include antimicrobial peptides and proteins (eg, defensins), complement, enzymes (eg, lysozyme, acid hydrolases), interferons, acidic pH, and free radicals (eg, hydrogen peroxide, superoxide anions); cellular components include neutrophils, monocytes, macrophages, natural killer (NK) cells, and natural killer-T (NKT) cells. Unlike adaptive immunity, the innate immune response exists prior to infection, is not enhanced by repeated infection, and is generally not antigen-specific. An intact skin or mucosa is the first barrier to infection. When this barrier is breached, an immediate innate immune response, referred to as “inflammation,” is provoked and ultimately leads to destruction of the pathogen. The process of pathogen destruction can be accomplished, for example, by biochemical components such as lysozyme (which breaks down bacterial peptidoglycan cell walls) and complement activation. Complement components (Figure 55–1) enhance macrophage and neutrophil phagocytosis by acting as opsonins (C3b) and chemoattractants (C3a, C5a), which recruit immune cells from the bloodstream to the site of infection. The activation of complement eventually leads to pathogen lysis via the generation of a membrane ...