Immunology (Lippincott Illustrated Reviews Series) 2nd Edition

Chapter 18: Immune Pharmacotherapy

I. OVERVIEW

It is sometimes desirable to boost or supplement the normal immune response to maintain good health. However, on other occasions, as in the case of transplantation, the normal response of the immune system creates problems. And in other instances, such as allergy or autoimmunity, undesirable immune responses develop. In many of these situations, immune response can be enhanced, diminished, or altered by pharmacologic agents or other treatments, as described in this chapter.

II. MEASURES THAT ENHANCE THE IMMUNE RESPONSE

Immunotherapy is the application of therapeutic treatments for the purpose of increasing or augmenting immune function. Such treatments may include the use of agents (e.g., adjuvants) that enhance immune responses in a nonspecific way. More specifically targeted therapies include the application of cytokines that stimulate the activity of particular cell types or the administration of human serum immunoglobulin to supplement or replace suboptimal immunoglobulin levels or isotypes in patients with various immune deficiencies.

A. Adjuvant therapy

In addition to the primary treatment, adjuvant therapy is administered to nonspecifically stimulate immune responses, either directly or indirectly. Adjuvants administered with vaccines can indirectly enhance the effect of the vaccine indirectly by attracting antigen-presenting cells and increasing their expression of costimulatory molecules. Bacillus Calmette-Guérin (BCG), prepared from an inactivated form of Mycobacterium and is commonly used around the world as a tuberculosis vaccine, can serve as an effective adjuvant for vaccination or immunization. However, it can also be used directly for postsurgical treatment of superficial bladder cancer. A BCG suspension is periodically instilled into the bladder over a period of 6 weeks; this promotes inflammation and, in doing so, stimulates antitumor immune responses.

B. Cytokine therapy

Innate and adaptive immune responses are regulated by various influences, including cytokines. Cytokines affect the induction and intensity of cellular growth and differentiation, cell activation, tissue inflammation, and tissue repair. Both type I (IFN-α/β) and type II (IFN-γ) interferons have been used as immunotherapeutic agents to heighten immune responsiveness in patients with viral infections such as hepatitis B or hepatitis C virus. Both natural and engineered interferons are rapidly cleared from the circulation, but their availability can be prolonged by conjugation to polyethylene glycol to create a pegylated form. Chronic treatment with pegylated recombinant IFN-α decreases the risk of subsequent hepatocarcinoma in about 20% of individuals with chronic hepatitis C viral infection. Additionally, IFN-α2β combination therapy with ribavirin, an antiviral agent, can result in a sustained clinical response in approximately 50% of the cases. Interferons can also be effective in treating patients with immune deficiency diseases such as chronic granulomatous disease (CGD, a disease caused by defective killing of microbes by phagocytes). The incidence of serious infection is greatly diminished in CGD patients treated with proinflammatory cytokines such as recombinant IFN-γ. The most common side effects of interferon therapies are flu-like symptoms that can become severely debilitating.

Cytokine therapy has also been applied in the treatment of cancer. Immunotherapy against tumors has been traditionally unreliable, and only recently have more reliable treatment regimens been developed. These include the use of IFN-α for treatment of hairy cell leukemia, IL-2 for treatment of some renal carcinomas and melanomas, and IFN-γ and TNF-α for treatment of ovarian tumors. IL-2 can activate NK cells, an important component for the destruction of tumor cells.

Tumors can sometimes outgrow the immune response. An attempt to increase antitumor immune responses has involved the isolation of T cells from excised tumors and their proliferation in vitro by adding IL-2 to the cultures. It is presumed that these T cells (tumor-infiltrating lymphocytes) will include many that are specifically directed against tumor antigens. Proliferation in vitro before reinfusion increases the probability that the cells will encounter their target tumor cells. Exogenous IL-2 may also be given to the patient to encourage continued proliferation of the antitumor T cells in vivo.

Another antitumor approach is the engineering of tumor cells to make them more immunogenic. Transfection with active cytokine genes, as well as genes producing constitutive expression of molecules such as CD80 and CD86, can convert tumor cells into a type of quasi-antigen-presenting cells that express tumor antigens. When returned to the patient, the engineered tumor cells may be able to interact with tumor antigen–specific T cells and facilitate their activation.

Finally, cytokines can even sometimes function to a degree as adjuvants. For example, immune responses to melanoma peptide vaccines appear to be enhanced when IL-12 is injected together with the vaccines.

C. Antibody replacement therapy

The administration of exogenous immunoglobulin (human immune globulin or HIg) can be effective therapy for individuals with generalized antibody deficiencies (hypogammaglobulinemia or agammaglobulinemia). The immune globulin products are typically administered intravenously (intravenous immune globulin or IVIG). HIg consists mostly of IgG with trace amounts of IgM and IgA. Because it is derived from pooled immune human sera, it can react against a broad range of epitopes. The benefit provided by HIg lasts for approximately 1 month (the serum half-life of IgG is about 23 days); therefore HIg injections must be repeated at monthly intervals to maintain sufficient antibody levels for protection. Since HIg is an immunomodulating agent that can modulate complement activation, alter antibody production, and suppress various inflammatory mediators, HIg can be beneficial in situations in which immune deficiency is not the underlying problem. It has been demonstrated to be beneficial in treatment of autoimmune idiopathic thrombocytopenic purpura, B cell chronic lymphocytic leukemia, and Kawasaki syndrome (a disease, usually affecting children, that involves inflammation of the blood vessels and other tissues such as heart muscles).

Antibody replacement therapy need not always involve broad-range HIg. People with selective antibody deficiencies, groups at high risk for certain infections (the elderly or infants), or those exposed to certain infectious diseases (e.g., health care workers or laboratory personnel) may benefit from intramuscular injections of a broad-spectrum immune globulin or preparations of immune globulins containing specific antibodies. Preparations of immune globulins containing specific antibodies (e.g., against tetanus, hepatitis B, rabies, cytomegalovirus, and varicella zoster virus) are available for those at high risk or high exposure. With the advent of monoclonal antibody technology, large quantities of antibodies against specific epitopes are available for other therapeutic uses as well. For example, monoclonal antibodies against the CD20 marker are particularly useful in treatment of B cell non-Hodgkin lymphoma.

III. MEASURES THAT DIMINISH THE IMMUNE RESPONSE

The immune system can aggressively reject newly transplanted organs or activating immune cells and thus inducing autoimmune diseases. The immune response can be controlled by using drugs or other measures to prevent or to treat these conditions. Measures that diminish the immune response can be either specific or nonspecific.

A. Anti-inflammatory agents

Inflammation is a response to foreign substances, causing direct or indirect activation of the innate immune system. Inflammation is characterized by increased blood flow, increased capillary permeability, and leakage of plasma and blood components into the interstitial spaces and the migration of leukocytes into the inflamed site. Histamine, serotonin, prostaglandins, bradykinin, chemokines, and leukotrienes are chemical mediators of inflammation that are released from granulocytic cells such as mast cells, basophils, and eosinophils. Phagocytic cells such as neutrophils and macrophages can engulf foreign substances, triggering the release of inflammatory molecules. Anti-inflammatory drugs, such as corticosteroid and prednisone, and nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, are used to control inflammation.

1. Corticosteroids: These drugs, specifically glucocorticoids, have broad and potent anti-inflammatory and immunosuppressive effects. Glucocorticoids have been used for the treatment of rheumatoid arthritis since 1949. This drug is currently widely used to nonspecifically treat many inflammatory diseases and conditions, including autoimmune disorders, allergic diseases, and asthma, and to prevent organ rejection.

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Figure 18.1

Glucocorticoid and the cytosolic glucocorticoid receptor.

Glucocorticoids are steroid hormones that bind to the cytosolic glucocorticoid receptor (Fig.18.1). This newly formed complex then enters into the cell nucleus and binds to the glucocorticoid response elements in the promoter region of the specific gene, causing an increase in expression of the target genes or prevents the expression of the target genes. Glucocorticoids are effective anti-inflammatory agents, although the specific mechanism of their anti-inflammatory effect is not completely understood. Known effects of corticosteroids include the following:

• Inhibition of transcription of genes encoding cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-α

• Diminished B-cell clone expansion and decreased antibody synthesis

• Decreased IL-2 production, reducing T-cell proliferation

• Decreased size and lymphoid content of the spleen and lymph nodes

• Functional modification of certain T-cell subsets

• Increased synthesis of lipocortin-1, which inhibits the production of lipid mediators such as prostaglandin, and leukotrienes

• Decreased numbers of T cells, eosinophils, and mast cells in the lamina propria of the airways

• Inhibition of monocyte and neutrophil chemotaxis

• Changes in leukocyte distribution, causing lymphopenia (decreased numbers of lymphocyte) and neutrophilia (increased numbers of neutrophils)

Many conditions and diseases, such as inflammatory bowel disease, systemic lupus erythematosus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and rheumatoid arthritis, respond to corticosteroids. Corticosteroids are currently available in many forms such as oral, intravenous, intramuscular, inhalation, and topical administrations. Inhalation and intranasal corticosteroids are widely used in the treatment of asthma and rhinitis. Topical administration is effective in the treatment of atopic dermatitis and ocular allergy. To minimize immune responses against graft antigens, corticosteroids are useful in organ transplant rejection crises, particularly in cases of imperfectly matched grafts.

There are risks associated with corticosteroid usage. Clinically significant adverse effects because of corticosteroid usage are related to the dose, duration, and route of administration. Chronic high-dose systemic therapy can cause significant adverse effects. In children, for example, chronic administration of glucocorticoids can slow linear bone growth. Other clinically significant adverse effects include hypothalamic pituitary axis suppression, infection, hypertension, cataracts, hyperglycemia, and osteoporosis. Individuals using corticosteroids should be closely monitored for any adverse reactions.

2. Nonsteroidal anti-inflammatory drugs (NSAIDs): These drugs include aspirin and ibuprofen. NSAIDs have anti-inflammatory, antipyretic, and analgesic effects (Fig. 18.2). In addition to providing clinical benefit in the treatment of anti-inflammatory diseases, aspirin is also used to treat conditions requiring inhibition of platelet aggregation. NSAIDs irreversibly block the prostaglandin synthase enzyme, which has two isoforms: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 and COX-2 are responsible for thromboxane and prostaglandin synthesis. But COX-2 is induced only in inflammatory lesions. The inhibitory effects of prostaglandins include decreases in edema, leukocyte infiltration, pain, and fever. The inhibition of thromboxane production reduces platelet aggregation. The anti-inflammatory effect of NSAIDs is usually observed at high doses, whereas the analgesic (pain-relieving) effect is dose-responsive (Fig. 18.2).

Prostaglandin synthesis associated with COX-1 involves protection of the gastrointestinal tract and regulation of normal cellular processes, such as vascular homeostasis, platelet aggregation, and kidney function. Prostaglandin synthesis associated with COX-2 is induced in inflammatory lesions. Therefore, the desirable effects of NSAIDs are thought to be caused by the inhibition of COX-2, and the side effects are thought to be caused by inhibition of COX-1. For this reason, COX-2-selective agents were developed. However, long-term treatments with COX-2-selective inhibitors have been shown to increase the risk of myocardial infarctions and strokes. As a result, some of these COX-2-selective inhibitors have been withdrawn from the market.

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Figure 18.2

NSAIDs: aspirin and ibuprofen. Inhibition of prostaglandin synthesis diminishes inflammation by blocking cyclooxygenase.

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Figure 18.3

Rheumatoid arthritis. Rheumatoid arthritis–induced damage to joint cartilage is caused by the CD4+ T cell recognition of the initiating antigen within the joint, triggering the release of inflammatory cytokines. Production of IgG antibodies against the initiating antigen also contributes to the inflammation through the formation of immune complexes. X-ray of hand of patient with severe rheumatoid arthritis.

In general, NSAIDs are used clinically to treat mild-to-moderate pain and inflammatory conditions, such as rheumatoid arthritis. Aspirin’s inhibition of platelet aggregation makes it clinically useful in the prevention of coronary artery thrombosis and transient ischemic attack. The main adverse effects of chronic NSAID use are gastric irritation, erosion, and hemorrhage. Other clinically significant effects include renal tubular necrosis and acute renal failure.

B. Immunosuppressive measures

Autoimmune diseases occur when adverse immune response develops against self-epitopes. Autoimmune diseases can result from damage inflicted on cells and tissues by humoral or cell-mediated immune responses and sometimes by both. Suppressor cells of various types serve to maintain immune tolerance. When the numbers of these suppressor cells decline with age, the risk of autoimmune diseases is enhanced in aged individuals by allowing previously suppressed autoreactive lymphocytes to become active. Immune responses in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus can be diminished in some cases by pharmacologic agents. Immune suppressive measures are also used to diminish overt and often catastrophic effects of graft rejection or in the treatment of bronchial asthma.

1. Rheumatoid arthritis therapy: Rheumatoid arthritis (RA) is a chronic multisystem, inflammatory, autoimmune disease that affects the synovia and cartilages of small and large joints as well as other organ systems. It is a destructive disease that involves both cell-mediated and humoral immune responses (Fig. 18.3). The initial underlying cause of RA is still unknown. Cartilage damage is because of the CD4+ T-cell recognition of antigen(s) within the joint that triggers the release of inflammatory cytokines that lead to the accumulation of neutrophils and macrophages. Within the inflamed synovia are B cells, plasma cells, CD4+ T cells, and various types of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), IL-1, IL-8, and IFN-γ. Rheumatoid factors (IgM or IgG autoantibodies directed against the Fc region of circulating IgG) are formed that facilitate the formation of immune complexes. In most patients with RA, antibodies to cyclic citrullinated peptide (anti-CCP) are detected before RA symptoms develop. In advanced stages of RA, deposition and complement fixation of these immune complexes may contribute not only to joint destruction but also to vasculitis, carditis, and pleuritis.

In addition to glucocorticoids such as prednisone, therapies for RA include disease-modifying antirheumatic drugs (DMARDs), TNF-α inhibitors, IL-1 receptor inhibitors, and immunomodulators. NSAIDs that inhibit cyclooxygenase and blocking prostaglandin formation help to reduce the pain and inflammation associated with RA. DMARDs such as methotrexate, antimalarial drugs, gold salt therapy, and sulfasalazine can mitigate the disease process but usually do not lead to complete remission.

How DMARDs actually work is not fully understood, but it appears that they modify the immune system. DMARD treatment may take up to 6 to 8 months to become fully effective. Although effective in treating RA, the side effects of DMARD treatment are often significant, and people taking the drug require frequent monitoring.

The most widely used DMARD as an immunosuppressive agent in the treatment of rheumatic disease is methotrexate. This drug inhibits DNA synthesis by inhibiting dihydrofolate reductase, an enzyme required for the conversion of folic acid into its active form, tetrahydrofolate (an enzyme that is involved in the synthesis of thymidine). Toxicity of methotrexate treatment is mainly associated with rapidly dividing cells. Therefore, it can have significant adverse effects within the gastrointestinal mucosa and bone marrow, mainly suppression. Other clinically significant adverse effects include hepatic fibrosis and hypersensitivity pneumonitis. Because of the severe side effects, only low doses of methotrexate are used to treat RA.

Other DMARDs agents that are used in the treatment of RA are alkylating agents such as cyclophosphamide and purine analogs such as azathioprine. These agents inhibit cell proliferation. These immunosuppressive agents also have significant adverse effects, including hepatic toxicity, and are associated with an increased risk of cancer and infection.

Systemic inflammatory processes and local joint destruction in RA involves cytokines. The development of drugs that inhibit cytokines and cytokine function proved to be useful in treating patients with RA. TNF-α-neutralizing monoclonal antibodies, soluble recombinant TNF-α receptors, and IL-1 receptor–blocking proteins are several treatment options currently available for patients.

Using monoclonal antibodies to effectively bind TNF-α, a cytokine that is crucial to the disease process, is one way of treating RA. Another is to use a so-called immunoadhesin molecule, a fusion protein produced by recombinant DNA technology that combines the constant domain of an antibody molecule with the ligand-recognition domain of a cytokine receptor. A third way is by using a recombinant protein that mimics a naturally occurring IL-1 receptor antagonist, which would effectively block the IL-1 binding site.

TNF-α receptor inhibitors, such as adalimumab, etanercept, and infliximab, can effectively inactivate TNF-α. TNF-α inhibitors can decrease the signs and symptoms of RA and can reduce the progression of joint damage. In addition, their onset of action is faster than that of DMARDs. Adverse effects associated with cytokine inhibitors include infections such as the reactivation of latent tuberculosis infections.

Anti-IL-1 receptor antagonist is yet another agent that is used in the treatment of RA. IL-1 is a protein found in increased amounts in joints of individuals with RA. Use of the antagonist reduces the binding of IL-1 to the IL-1 receptor (IL-1R). Serious side effects of this drug are an increase in infection and a decrease in the number of white blood cells and platelets.

In patients who have had inadequate responses to anti-TNF antagonist therapies, other treatment options include selective T-cell costimulation modulator (abatacept), CD-20 directed cytolytic antibody (rituximab), or IL-6 receptor inhibitor (toclizumab). Serious side effects of these drugs also include infections.

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Figure 18.4

Bronchial asthma. A. A normal bronchus and the bronchus of a patient with asthma; bronchial inflammation associated with edema, mucus production, and obstruction. B. Histologic section of asthmatic bronchiole.

2. Asthma therapy: Asthma is a common, chronic inflammatory respiratory disorder. The pathogenesis of asthma involves inflammatory cells such as mast cells, neutrophils, eosinophils, and CD4+ Th2 cells. Inflammation of the bronchi causes bronchial constriction and airway hyperresponsiveness, leading to recurrent dyspnea and episodes of wheezing and coughing in susceptible individuals (Fig.18.4). Chronic asthma can develop into refractory inflammation of the airways, accompanied by increased bronchial edema, mucus production, and bronchial obstruction. Airflow obstruction is often reversible, either spontaneously or following treatment. A predisposing factor in the development of bronchial asthma is atopy, the genetic predisposition to develop IgE-mediated responses to common allergens such as mold. Other causes or common triggers of asthma include respiratory infections and animal dander (e.g., from cats).

Treatments for asthma include bronchodilatory agents such as β2- adrenergic receptor agonists (albuterol), methylxanthines (theophylline), and anticholinergic agents (ipratropium bromide); anti-inflammatory agents, such as corticosteroids, inhaled corticosteroids in combination with long-acting β2 agonist, inhibitors of mast cell degranulation (e.g., cromolyn), and leukotriene antagonists (zileuton, montelukast, and zafirlukast); and an immunomodulatory agent, such as omalizumab, a monoclonal anti-IgE antibody.

3. Transplantation: Most transplants involve some degree of genetic mismatch between host and donor. Transplanted cells, tissues, and organs are susceptible to destruction by the host immune system (host versus graft), and in the case of bone marrow transplantation, it is the host tissues that are susceptible to attack from the immunocompetent cells of the graft (graft versus host). In either case, the successful coexistence of host and graft may depend on the applications of therapy to diminish the destructive responses of the immune system, whether derived from host or donor.

One approach has been the use of immune suppression (or immunosuppression), which is treatment that imposes a broad and general inhibition of immune responsiveness, without regard to specificity. Over the past few decades, however, drugs such as cyclosporine, tacrolimus, and rapamycin have been developed that have more restricted effects on the immune system. Their effects are targeted more closely to those cells reacting to graft antigens while leaving the remainder of the immune system relatively uninhibited in its ability to deal with infectious agents. They are not without risk, however. Patients must often receive the drugs for an extended period. If a significant infection occurs during this period, the immune cells responding to the infectious agent could be inhibited in the same way as those responding to graft alloantigens. In addition, extended use of these drugs is sometimes associated with damage to organs such as the liver.

Cyclosporine is an essential immunosuppressive agent that was discovered in 1976. It has demonstrated significant efficacy in the treatment of graft-versus-host syndrome after transplantation of bone marrow and other organs and in treatment of some autoimmune diseases. Cyclosporine is a specific inhibitor of T cell–mediated immunity. In vitro studies have shown that it selectively alters the immune regulation activities of helper T cells. Specifically, cyclosporine inhibits calcineurin, which is necessary for the activation of T cells. Therefore, it suppresses the production of IL-2. Clinically significant adverse effects include nephrotoxicity, neurotoxicity, and hepatotoxicity.

Tacrolimus is a macrolide antibiotic derived from the bacterium Streptomyces tsukubaensis and is about 50 to 100 times more potent than cyclosporine. Its mechanism of action is similar to that of cyclosporine in that it also selectively alters the activities of helper T cells by inhibiting calcineurin and thus IL-2 synthesis and secretion. Clinically significant adverse effects of tacrolimus are similar to those for cyclosporine, including nephrotoxicity.

Sirolimus (rapamycin) is also a macrolide antibiotic, isolated from the fungus S. hygroscopicus, that is structurally similar to tacrolimus. However, rapamycin interferes with the immune response by blocking IL-2 receptor signaling and inhibiting protein synthesis. Clinically significant adverse effects of rapamycin include hyperlipidemia, leukopenia, and thrombocytopenia.

4. Other autoimmune and inflammatory diseases: Preferred treatments for several autoimmune diseases, some of which are discussed in Chapter 16, are given in Table 18.1. Some of these diseases are systemic (e.g., SLE), whereas others have more limited effects on specific organs and tissues. Autoimmune diseases can result from pathology initiated by humoral responses, cell-mediated immune responses, or both.

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Figure 18.5

Crohn disease. A segmental involvement of the intestine is seen, with discontinuous areas of inflammation. The inflammation involves all layers of the intestine.

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Figure 18.6

Systemic lupus erythematosus. This disorder is associated with autoantibodies against fragments of nucleic acids and chromosomal proteins, producing a systemic inflammation (type III hypersensitivity) that affects many organs and tissues of the body.

CLINICAL APPLICATION

Ankylosing spondylitis

Jeff, a 35-year-old male, presents with low back pain that has persisted for more than 3 months. He describes pain mainly in the sacrum and in the buttocks area and occasionally radiating down the legs. The pain sometimes wakes the patient up at night, and in the morning, he feels that his back is stiff. Physical examination is remarkable for mild loss of lateral flexion of the lumbar spine. Laboratory examination reveals an increased in erythrocyte sedimentation rate and leukocytosis. The rheumatoid factor test is negative. This patient’s human leukocyte antigen typing is positive for HLA-B27. Radiograph of the spine shows mild subchondral bony erosions on the iliac side of the bone calcification and ossification in the sacrum area.

This patient presents with symptoms and signs consistent with ankylosing spondylitis. The pathophysiology of ankylosing spondylitis is caused by inflammation associated with cellular infiltration of lymphocytes, plasma cells, and leukocytes in the affected joints, particularly sacroiliac, spinal facet joints, and paravertebral soft tissues. The etiology is unknown, but approximately 90% to 95% of patients are positive for human leukocyte antigen HLA-B27, and these patients commonly have a family history of the disease.

Initial treatments for this patient include a lifelong exercise program and analgesics such as NSAIDs. Other alternative anti-inflammatory agents (Table 18.1) may provide clinical benefit. As the disease progresses, spinal and hip surgery may be indicated.

CLINICAL APPLICATION

Ulcerative colitis

Rob, a 30-year-old male, presents with frequent episodes of bloody diarrhea, abdominal pain, fecal urgency, and low-grade fever for 1 week. Physical examination reveals a temperature of 38°C, tachycardia, abdominal pain, and bloody stool. Laboratory examination reveals mild anemia and leukocytosis. Colonoscopy examination reveals crypt abscesses and superficial inflammation from the rectum to the colon.

This patient presents with signs and symptoms suggesting ulcerative colitis. The findings on the colonoscopy confirm the diagnosis. The etiology of ulcerative colitis is unknown. Interestingly, the risk of developing ulcerative colitis is associated with nonsmokers and former smokers. Medical treatment options for ulcerative colitis are similar to those listed for Crohn disease in Table 18.1. For patients with severe disease that is refractory to medical therapies, surgery may be indicated.

CLINICAL APPLICATION

Systemic lupus erythematosus

Joy, a 25-year-old female presents, with a butterfly-shaped rash on her cheeks and mild joint pain. Physical examination reveals a temperature of 38°C and a fixed erythema on her cheeks. She also has mild tenderness and swelling in the joints of both of her hands. Laboratory tests revealed mild anemia, leukopenia, and positive tests for antinuclear antibody and anti-double-stranded DNA.

This patient has signs and symptoms consistent with systemic lupus erythematosus (SLE), a disorder associated with autoantibodies against fragments of nucleic acids and chromosomal proteins, producing inflammation that affects many organs and tissues of the body.

For definitive diagnosis, a patient must have four of the following findings at any time: malar rash (butterfly rash, appearing on the face), discoid skin lesion, photosensitivity, oral ulcers, nonserosive arthritis, serositis, renal disorders, neurologic disorder, hematologic disorder, immunologic disorder, and antinuclear antibody. Medical treatment options for SLE are listed in Table 18.1.

IV. THERAPIES USED TO ALTER THE IMMUNE RESPONSE

Therapies are sometimes used to alter the immune response by prevention, stopping the immune response before it starts, or by redirecting it to less harmful immune responses. The management of allergic symptoms or severe and potentially fatal response such as anaphylaxis, on the other hand, provides an example in which redirecting the immune response to less harmful effects provides benefit.

A. Preemptive measures

Once an immune response begins, it is difficult to fully suppress the effect. A more successful approach is to use therapeutic measures before an immune response develops, but this requires that a possible adverse immune response is imminent. Antibiotic therapy is an example of preemptive measure.

1. Antibiotic therapy: Antibiotics are sometimes given to prevent a bacterial infection and limit the development of adaptive immune responses that may be potentially injurious. For example, in addition to causing structural heart disease, rheumatic heart fever was the leading cause of death in many children before 1960. With the development of preventive antibiotic treatment, the incidence of rheumatic fever has declined significantly. Rheumatic fever is associated with a prior group A streptococcal infection such as acute pharyngitis. Rheumatic fever is generally a self-limiting illness; symptoms spontaneously subside over a period of days in the large majority of patients. In some patients, complications develop that lead to the production of self-reactive antibodies that causes autoimmune acute rheumatic fever (ARF), a condition that can result in rheumatic heart disease. Inflammation of the heart, specifically valvular vegetations and mitral valve regurgitation are causes of long-term morbidity. Joints, central nervous system, skin, and subcutaneous tissues may also be affected. Rheumatic fever occurs because of cross-reactivity between streptococcal cell wall and heart tissues, and the use of penicillin or other antibiotics decreases the probability that sufficient antibody will be produced to cause heart disease.

B. Modification of ongoing disease

Therapeutic measures provide benefit by minimizing the course of the disease. Systemic administration of cytokines has been used clinically to alter the course of several diseases. Allergen immunotherapy administered to patients with allergic diseases is a way of redirecting the immune response to less harmful effects.

1. Cytokines: These protein molecules act as messengers between cells and affect their functions. Systemic administration of cytokines has been used clinically to alter the course of many diseases, including cancer. Clinical research studies support the use of IFNs as treatments for several malignancies as well as other diseases. IFN-α has been used to treat malignant, chronic myelogenous leukemia, Kaposi sarcoma, hairy cell leukemia, and hepatitis B and C. IFN-β has been used to treat the relapsing type of multiple sclerosis and IFN-γ to treat chronic granulomatous disease. In addition, IFN-γ has also been used to treat patients with severe atopic (IgE-mediated) dermatitis. IFN-γ downregulates IL-4 production and decreases the development of IgE responses. Although the interferons have therapeutic benefits, there are systemic side effects associated with this agent. The most commonly reported side effect is flu-like symptoms.

HIV, the virus that causes AIDS, kills CD4+ T cells and reduces the numbers of monocytes/macrophages. CD8+ T cell numbers can also become reduced. Recently, deaths because of HIV infection in developed countries have declined dramatically owing to highly active antiretroviral therapy (HAART). Although the viral load is decreased with HAART, however, the virus is not eliminated. Several cytokine therapies are currently being tested in clinical or preclinical trials with the objective of restoring the functional immune cells and preventing opportunistic infections, including the following:

• IL-7 to enhance the immune response allowing the host to clear chronic viral infection such as HIV

• IL-12 to enhance HIV specific cell-mediated immunity

• IL-15 to enhance CD8+ T cell function

• IFN-α/IFN-γ to enhance CTL responses

• GM-CSF to enhance monocyte/macrophage function

• G-CSF to increase myeloid cell precursors.

As with most other types of treatments, systemic cytokine therapy is accompanied by adverse side effects. For example, IL-2 supports the growth of T lymphocytes and NK cells but also increases apoptosis in T-cell populations. IL-15 also simulates proliferation of both CD8+ and CD4+ T cell populations and appears to be antiapoptotic.

2. Allergen immunotherapy: Allergen immunotherapy involves subcutaneous administration of an aqueous extract of the allergen repeatedly over a period of weeks to months in gradually increasing doses. The objective of allergen immunotherapy is to reduce responses to allergic triggers, decrease inflammatory responses, and prevent development of persistent disease.

With repeated immunization, antibody production is redirected from being predominantly IgE to being predominantly IgG. IgG antibodies bind and remove the allergen before it can interact with IgE antibodies bound to the surfaces of mast cells. This treatment is indicated for patients with allergic rhinitis, allergic asthma, or stinging insect hypersensitivity. These patients have symptoms that are not easily controlled by avoiding exposure to an allergen, or pharmacologic therapy for them has not proven to be effective. Allergen immunotherapy is normally safe. However, a serious adverse reaction—anaphylaxis—may develop. All patients receiving immunotherapy should be observed for at least 20 minutes following injection, and emergency treatments, including antihistamine and epinephrine, should be available if necessary.

Chapter Summary

• Adjuvants administered with vaccines can indirectly heighten the effect of the vaccine indirectly by attracting antigen-presenting cells and increasing their expression of costimulatory molecules.

• Cytokines affect the induction and intensity of cellular growth and differentiation, cell activation, tissue inflammation, and tissue repair. Both type I (IFN-α/β) and type II (IFN-γ) interferons have been used as immunotherapeutic agents to heighten immune responsiveness in patients with viral infections such as hepatitis B or hepatitis C.

• The administration of exogenous immunoglobulin (human immune globulin or HIg) can be effective therapy for individuals with generalized antibody deficiencies.

• Glucocorticoids are anti-inflammatory steroid hormones that bind to cytosolic glucocorticoid receptors, forming complexes that can enter the nucleus and alter transcription of particular sets of genes. They are used to treat inflammatory bowel disease, systemic lupus erythematosus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and rheumatoid arthritis.

• NSAIDs reduce inflammation by inhibiting prostaglandins and thromboxane synthesis through the inactivation of cyclooxygenase (prostaglandin synthase).

• Rheumatoid arthritis is a chronic multisystem, inflammatory, autoimmune disease that affects the synovia and cartilages of small joints, large joints, and other organ systems. Therapies include glucocorticoids disease-modifying antirheumatic drugs (DMARDs), TNF-α inhibitors, interleukin-1 receptor inhibitors, and immunomodulators.

• Bronchial asthma is a common, chronic inflammatory respiratory disorder. The pathogenesis of asthma involves inflammatory cells such as mast cells, neutrophils, eosinophils, and CD4+ Th2 cells.

• Cyclosporine inhibits calcineurin, suppressing the production of IL-2. Tacrolimus has a mechanism of action similar to that of cyclosporine in selectively inhibiting calcineurin and inhibiting IL-2 synthesis and secretion. Rapamycin blocks the response by blocking IL-2 receptor signaling and inhibiting protein synthesis.

Study Questions

18.1. Which of the following describes a common use of an adjuvant?

A. To diminish B-cell clone expansion and antibody synthesis

B. To enhance the effect of a vaccine

C. To improve antibody deficiencies

D. To inhibit translation of genes encoding numerous cytokines

E. To treat inflammatory diseases including autoimmune disorders

The correct answer is B. Adjuvants are commonly used to enhance the effect of a vaccine. Adjuvant therapy is given in addition to a primary treatment to nonspecifically stimulate immune responses, either directly or indirectly. Antibody deficiencies are sometimes treated with human immune globulin (HIg). Anti-inflammatory agents such as glucocorticoids can diminish B-cell clone expansion and antibody synthesis and can also inhibit translation of cytokine genes. Glucocorticoids are also used to treat inflammatory diseases.

18.2. An individual is given therapy with human immune globulin (HIg). Which of the following conditions would be appropriate for this type of therapy?

A. Agammaglobulinemia

B. Allergy

C. Rheumatoid arthritis

D. Superficial bladder cancer

E. Systemic lupus erythematosus

The correct answer is A. Glucocorticoids bind to intracellular receptors located in the cytosol and then influence (inducing or inhibiting) the transcription of responsive genes. NSAIDs inhibit cyclooxygenase and therefore inhibit the production of prostaglandins, resulting in reduction in edema, leukocyte infiltration, pain, and fever. The NSAID aspirin impairs platelet aggregation by irreversibly inhibiting the cyclooxygenase enzyme and reducing production of thromboxane A2 in platelets. Glucocorticoids are immunosuppressive in nature and inhibit IL-2 production and T-cell proliferation rather than stimulating them. Glucocorticoids are immunosuppressive and do not facilitate response to cytokines by upregulating cytokine receptors.

18.3. Glucocorticoids exert immunosuppressive effects by

A. binding to intracellular receptors and influencing gene transcription.

B. impairing the ability of platelets to aggregate.

C. inhibiting cyclooxygenase and thromboxane production.

D. stimulating IL-2 production and T-cell proliferation.

E. upregulating cell-surface receptors for cytokines.

The correct answer is A. HIg is used to treat agammaglobulinemia, a generalized antibody deficiency that may be improved by administering HIg. Consisting primarily of IgG, HIg is obtained from pooled immune human sera and can provide reactivity against a broad range of epitopes. Anti-inflammatory agents, such as glucocorticoids, are often used to treat allergic disease and rheumatoid arthritis. Superficial bladder cancer is sometimes treated with the direct administration of the Bacillus Calmette-Guérin (BCG) adjuvant. HIg does not have antiviral properties; type I interferons have been used to heighten immune responsiveness in patients with hepatitis B or hepatitis C viruses.

18.4. A 12-year-old female with a history of IgE-mediated responses to various common allergens presents with acute bronchial asthma. Which of the following treatment approaches will most likely be used first in her treatment?

A. Inhaled β2-adrenergic receptor agonist

B. Injected adjuvants

C. Orally administered aspirin

D. Subcutaneously injected cytokines

E. Systemically administered antihistamines

The correct answer is A. Inhaled β2-adrenergic receptor agonists (such as albuterol) are used first to treat acute asthma. Adjuvants are used to heighten immune responses, which is not a goal in treating acute asthma, which may result from allergy. NSAIDs such as aspirin have anti-inflammatory properties but are not quick-acting as an inhaled β2-adrenergic receptor agonist is. Cytokines would not reduce an immune-mediated inflammatory process such as acute asthma. Systemically administered corticosteroids are useful in treating chronic inflammation.

18.5. Following a bone marrow transplant, which of the following therapies will be most appropriate to inhibit T cell–mediated immunity and the development of graft-versus-host responses?

A. Adjuvants

B. Aspirin

C. Corticosteroids

D. Cyclosporine

E. Cytokines

The correct answer is D. Cyclosporine is a specific inhibitor of T cell–mediated immunity and is an immunosuppressive agent with proven efficacy in the treatment of graft-versus-host disease after bone marrow transplantation. Adjuvants heighten immune responses. Aspirin and corticosteroids have broad anti-inflammatory actions. Cytokines are immune mediators that are sometimes used to enhance immunity against tumors, for example.