Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 55. Immunopharmacology

Immunopharmacology: Introduction

Although the immune system is essential for protection against pathogens, in certain instances its powerful destructive mechanisms do more harm than good. Examples include hypersensitivity reactions, autoimmune disorders, and rejection reactions to transplanted tissues. Drugs that suppress immune mechanisms play an important role in treating these conditions. Increasingly, monoclonal antibodies targeting proteins with key roles in immune responses are being developed as immunosuppressive agents. In some situations, drugs that potentiate the immune response provide benefit.

High-Yield Terms to Learn

Antigen-presenting cells (APCs) Dendritic and Langerhans cells, macrophages, and B lymphocytes involved in the processing of proteins into cell surface forms recognizable by lymphoid cells B cellsLymphoid cells derived from the bone marrow that mediate humoral immunity through the formation of antibodies Clusters of differentiation (CDs) Specific cell surface constituents identified by number (eg, CD4, CD8) Cytokines Polypeptide modulators of cellular functions, including interferons, interleukins, and growth-stimulating factors Immunophilins A family of cytoplasmic proteins that bind to the immunosuppressants cyclosporine, tacrolimus, and sirolimus and assist these drugs in inhibiting T- and B-cell function Major histocompatibility complex (MHC) Cell surface molecules that bind antigen fragments and, when bound to antigen fragments, are recognized by helper T cells. MHC class I molecules are expressed by all cells, whereas MHC class II molecules are expressed by antigen-presenting cells Monoclonal antibody (MAb) An antibody produced by a hybridoma clone that selectively binds to an antigen of biological or medical interest. T cells Lymphoid cells derived from the thymus that mediate cellular immunity and can modify humoral immunity. The main subclasses of T cells are CD4 (helper) cells and CD8 (cytotoxic) cells

Immune Mechanisms

Overview

Using the concerted actions of complement components, phagocytic cells, and natural killer (NK) cells, the innate immune system initiates the defense against pathogens and antigenic insult. If the innate response is inadequate, the adaptive immune response is mobilized. This culminates in the activation of T lymphocytes, the effectors of cell-mediated immunity, and the production of antibodies, by activated B lymphocytes, the effectors of humoral immunity. The subsets of lymphocytes that mediate different parts of the immune response can be identified by specific cell surface components or clusters of differentiation (CDs). For example, helper T (TH) cells bear the CD4 protein complex, whereas cytotoxic T lymphocytes express the CD8 protein complex.

Antigen Recognition and Processing

This critical inaugural step in the adaptive immune response involves antigen-presenting cells (APCs), which process antigens into small peptides that can be recognized by T-cell receptors (TCRs) on the surface of CD4 TH cells (Figure 55-1). The most important antigen-presenting cell surface molecules are the major histocompatibility complex (MHC) class I and II proteins. The activation of TH cells by the class II MHC-peptide complex requires the participation of costimulatory and adhesion molecules in addition to activation of T-cell receptors.

FIGURE 55-1

Scheme of cell-mediated and humoral immune responses. An immune response is initiated by internalization and processing of antigen by an antigen-presenting cell such as a macrophage. The class II MHC-peptide complex is recognized by the T-cell receptor (TCR) on T-helper (TH) lymphocytes, resulting in T-cell activation. Activated (TH) cells secrete cytokines such as IL-2, which cause proliferation and activation of TH1 and TH2 cells. TH1 cells produce IFN- and TNF-, which activate macrophages and NK cells. A humoral response is triggered when B lymphocytes bind antigen via their surface immunoglobulins. They are then induced by TH2-derived cytokines (eg, IL-4, IL-5) to proliferate and differentiate into memory cells and antibody-secreting plasma cells.

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 55-3.)

Cell-Mediated Immunity

Activated TH cells secrete interleukin-2 (IL-2), a cytokine that initiates proliferation and activation of 2 subsets of helper T cells, TH1 and TH2 (Figure 55-1). TH1 cells orchestrate cell-mediated immunity and delayed hypersensitivity reactions. They produce interferon (IFN)-, IL-2, and tumor necrosis factor (TNF)- (also known as lymphotoxin). These cytokines activate macrophages, CD8 cytotoxic T lymphocytes (CTLs), and NK cells. Activated CTLs recognize processed peptides that are bound to class I MHC molecules on the surface of virus-infected or tumor cells. The CTLs induce target cell death via lytic enzyme and nitric oxide production and by stimulation of apoptosis pathways in the target cells. CTLs also play a role in autoimmune diseases by reacting against normal tissues, such as the synovium in rheumatoid arthritis and myelin in multiple sclerosis. NK cells kill both virus-infected and neoplastic cells.

Humoral Immunity

The B lymphoid cells, which are capable of differentiating into antibody-forming cells, mediate humoral immunity. The humoral response is triggered when B lymphocytes bind antigen via their surface immunoglobulins. The antigens are internalized, processed into peptides, bound to MHC class II molecules, and presented on the B-cell surface. When T-cell receptors on TH2 cells are activated by the MHC II-peptide complex, they release interleukins (IL-4, IL-5, IL-6, IL-10, IL-13). These cytokines induce B-lymphocyte proliferation and differentiation into memory B cells and antibody-secreting plasma cells (Figure 55-1). Antibodies produced by plasma cells bind to antigens on the surface of pathogens and trigger the precipitation of viruses and the destruction of bacteria by phagocytic cells or lysis by the complement system.

The proliferation and differentiation of both B and T lymphocytes are under the control of a complex interplay between the cytokines (Table 55-1) and other endogenous molecules, including leukotrienes, and prostaglandins. For example, IL-10 and IFN- downregulate TH1 and TH2 responses, respectively (Figure 55-1).

TABLE 55-1 Cytokines that modulate immune responses.

Cytokine Characteristic Properties Interferon- (IFN-) Activates NK cells, antiviral, oncostatic Interferon- (IFN-) Activates NK cells, antiviral, oncostatic Interferon- (IFN-) Activates TH1, NK, cytotoxic T cells, and macrophages; antiviral, oncostatic Interleukin-2 (IL-2) T-cell proliferation, activation of TH1, NK, and LAK cells

Interleukin-11 (IL-11) B-cell differentiation, megakaryocyte proliferation (see Chapter 33) Tumor necrosis factor- (TNF-) Proinflammatory, macrophage activation, oncostatic Tumor necrosis factor-(TNF-) Proinflammatory, chemotactic, oncostatic Granulocyte colony-stimulating factor (G-CSF) Granulocyte production (see Chapter 33) Granulocyte-macrophage colony-stimulating factor (GM-CSF) Granulocyte, monocyte, eosinophil production (see Chapter 33)

Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.

Abnormal Immune Responses

Abnormal immune responses include hypersensitivity, autoimmunity, and immunodeficiency states. Immediate hypersensitivity is usually antibody-mediated and includes anaphylaxis and hemolytic disease of the newborn. Delayed hypersensitivity, associated with extensive tissue damage, is cell-mediated. Autoimmunity arises from self-reactive lymphocytes that react to one's own molecules, or self antigens. Examples of autoimmune diseases that are amenable to drug treatment include rheumatoid arthritis and systemic lupus erythematosus. Immunodeficiency states can be genetically acquired (eg, DiGeorge syndrome) or can result from extrinsic factors (eg, HIV infection).

Immunosuppressive Agents

The primary immunosuppressive agents are a diverse group of drugs that range from the corticosteroid hormonal drugs (discussed also in Chapter 39) to antimetabolite anticancer drugs (discussed also in Chapter 54) to drugs that more selectively target cells of the immune system.

Corticosteroids

Mechanism of Action

Glucocorticoids act at multiple cellular sites to cause broad effects on inflammatory and immune processes (see Chapter 39). At the biochemical level, their actions on gene expression decrease the synthesis of prostaglandins, leukotrienes, cytokines, and other signaling molecules that participate in immune responses (eg, platelet activating factor). At the cellular level, the glucocorticoids inhibit the proliferation of T lymphocytes and are cytotoxic to certain subsets of T cells. Although glucocorticoids impair cell-mediated immunity to the greatest extent, humoral immunity is also dampened and continuous therapy lowers IgG levels by increasing the catabolic rate of this class of immunoglobulins.

Clinical Use

Glucocorticoids are used alone or in combination with other agents in a wide variety of medical conditions that have an underlying undesirable immunologic reaction (see Chapter 39). They are also used to suppress immunologic reactions in patients who undergo organ transplantation and to treat hematologic cancers (see Chapter 54).

Toxicity

Predictable adverse effects include adrenal suppression, growth inhibition, muscle wasting, osteoporosis, salt retention, glucose intolerance, and behavioral changes (see Chapter 39).

Immunophilin Inhibitors

Mechanism of Action

These immunosuppressants interfere with T-cell function by binding to immunophilins, small cytoplasmic proteins that play critical roles in T-cell responses to T-cell receptor activation and to cytokines. Cyclosporine binds to cyclophilin and tacrolimus binds to FK-binding protein (FKBP). Both complexes inhibit calcineurin, a cytoplasmic phosphatase. Calcineurin regulates the ability of the nuclear factor of activated T cells (NFAT) to translocate to the nucleus and increase the production of key cytokines such as IL-2, IL-3, and IFN-. Cyclophilin and tacrolimus both prevent the increased production of cytokines that normally occurs in response to T-cell receptor activation. Sirolimus also binds to FKBP. However, this proliferation signal inhibitor interferes with the response of T cells to cytokines without affecting cytokine production. Sirolimus appears to also inhibit B-cell proliferation and antibody production.

Clinical Uses and Pharmacokinetics

Use of these immunosuppressants is a major factor in the success of solid organ transplantation. They are used in solid organ transplantation and to prevent and treat graft-versus-host (GVH) disease in recipients of allogeneic stem cell transplantation. These agents, particularly cyclosporine and tacrolimus, are also used in some autoimmune diseases, including rheumatoid arthritis, uveitis, psoriasis, asthma, and type 1 diabetes. Sirolimus-eluting stents are used to prevent restenosis after coronary angioplasty.

Cyclosporine and tacrolimus are available as oral or intravenous agents, whereas sirolimus is available only as an oral drug. Because cyclosporine exhibits erratic bioavailability, serum levels are routinely monitored. The drug undergoes slow hepatic metabolism by the cytochrome P450 system and has a long half-life. Its metabolism is affected by a host of other drugs.

Toxicity

Cyclosporine and tacrolimus have similar toxicity profiles. The most common adverse effects are renal dysfunction, hypertension, and neurotoxicity. These drugs can also cause hyperglycemia, hyperlipidemia, and cholelithiasis. Sirolimus is more likely than the other agents to cause hypertriglyceridemia, hepatotoxicity, diarrhea, and myelosuppression.

Mycophenolate Mofetil

Mechanism of Action

This drug is rapidly converted into mycophenolic acid, which inhibits inosine monophosphate dehydrogenase, an enzyme in the de novo pathway of guanosine triphosphate (GTP) synthesis. This action suppresses both B- and T-lymphocyte activation. Lymphocytes are particularly susceptible to inhibitors of the de novo pathway because they lack the enzymes necessary for the alternative salvage pathway for GTP synthesis.

Clinical Use

Mycophenolate mofetil has been used successfully as a sole agent in kidney, liver, and heart transplantations. In renal transplantations, its use with low-dose cyclosporine has reduced cyclosporine-induced nephrotoxicity.

Toxicity

This drug can cause gastrointestinal disturbances and myelosuppression, especially neutropenia.

Thalidomide

This sedative drug, notorious for its teratogenic effects, has complex immune effects that include suppression of TNF- production, increased IL-10, reduced neutrophil phagocytosis, altered adhesion molecule expression, and enhanced cell-mediated immunity. Thalidomide is used for some forms of leprosy reactions, for immunologic diseases (eg, systemic lupus), and as an anticancer drug. It is also effective in treating aphthous ulcers and the wasting syndrome in AIDS patients.

Alefacept

This engineered protein blocks the CD2 receptor found on the surface of T cells (Figure 55-2). The natural ligand for the CD2 receptor is lymphocyte-associated antigen 3 (LFA-3), a 55- to 70-kd protein expressed on the surface of many cells. Alefacept contains the CD2-binding region of LFA-3 fused to a human IgG Fc region. It inhibits T-cell activation and is approved for treatment of psoriasis. Treatment also causes a dose-dependent reduction in circulating T cells, so T-cell counts must be monitored in patients treated with the drug.

FIGURE 55-2

The activation of a T cell by an antigen-presenting cell (APC) involves engagement of the T-cell receptor (TCR) by the MHC-peptide complex plus secondary costimulatory signals based on interactions between APC and T-cell surface proteins. Alefacept inhibits the interaction between T-cell CD2 and APC LF-3. Abatacept prevents T-cell CD28 from binding APC CD80/86, and efalizumab interferes with the binding of T-cell FLA-1 to APC ICAM-1.

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 55-2.)

Other Immunosuppressive Agents

A variety of other anticancer drugs (Chapter 54) and antirheumatic drugs (Chapter 36) have clinically useful immunosuppressive actions. Several of the most important of these are listed in Table 55-2.

Table 55-2 Other drugs used as immunosuppressive agents.

Drug Characteristics Azathioprine Prodrug of the anticancer drug mercaptopurine, which interferes with purine nucleic acid metabolism used for rheumatic diseases and organ transplantation (see Chapter 36) Cyclophosphamide Anticancer alkylating agent used in organ transplantation and rheumatic diseases (see Chapters 36 and 54) Leflunomide Inhibitor of dihydroorotate dehydrogenase, an enzyme involved in de novo pyrimidine synthesis. Used in rheumatoid arthritis (see Chapter 36) Hydroxychloroquine Antimalarial drug with immunosuppressive activity used for rheumatoid arthritis and systemic lupus erythematosus (see Chapters 36 and 52) Methotrexate Anticancer drug that inhibits dihydrofolate reductase used for rheumatoid arthritis and hematopoietic stem cell transplantation (see Chapters 36 and 54) Sulfasalazine Prodrug metabolized to sulfapyridine and 5-aminosalisylic acid (5-ASA). Used for rheumatoid arthritis and inflammatory bowel disease (see Chapters 36 and 59)

Antibody-Based Immunosuppressive Agents

Antilymphocyte Globulin and Antithymocyte Globulin

Mechanism of Action

Two types of antisera directed against lymphocytes are available. Antilymphocyte globulin (ALG) and antithymocyte globulin (ATG) are produced in horses or sheep by immunization against human thymus cells. Antibodies in these preparations bind to T cells involved in antigen recognition and initiate their destruction by serum complement. These antibodies selectively block cellular immunity rather than antibody formation, which accounts for their ability to suppress organ graft rejection, a cell-mediated process.

Clinical Use

ALG and ATG are used before allogeneic stem cell transplantation to prevent graft-versus-host reaction. They are also used in combination with other immunosuppressants for solid organs transplantation.

Toxicity

Because humoral immunity may remain intact, injection of ALG or ATG can cause hypersensitivity reactions, including serum sickness and anaphylaxis. Pain and erythema occur at injection sites, and lymphoma has been noted as a late complication.

RhO(D) Immune Globulin

Mechanism of Action

RhoGAM is a human IgG preparation that contains antibodies against red cell Rho(D) antigens. Administration of this antibody to Rho(D)-negative mothers at time of antigen exposure (ie, birth of an Rho(D)-positive child) blocks the primary immune response to the foreign cells.

Clinical Use

Rho(D) immune globulin is used for prevention of Rh hemolytic disease of the newborn. In women treated with Rho(D) immune globulin, maternal antibodies to Rh-positive cells are not produced in subsequent pregnancies, and hemolytic disease of the neonate is averted.

Monoclonal Antibodies

Monoclonal antibodies (MAbs) have the advantage of high specificity because they can be developed for interaction with a single molecule. "Humanization" of murine monoclonal antibodies and wholly human monoclonal antibodies (based on genetic engineering of transgenic mice that make human antibodies, Figure 55-3) have reduced the likelihood of formation of neutralizing antibodies and of immune reactions. Three types of MAbs used as immunosuppressive agents are described in the text that follows, and characteristics of some other therapeutic MAbs, including some used for nonimmunologic purposes, are listed in Table 55-3.

FIGURE 55-3

Structures of immunoglobulin-based TNF- antagonists. CH, constant heavy chain; CL, constant light chain; Fc, complex immunoglobulin region; VH, variable heavy chain; VL, variable light chain. Red regions, human derived; blue regions, mouse derived.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 36-4.)

TABLE 55-3 Characteristics of selected monoclonal antibodies (MAbs) and immunoglobulin-based agents.

MAb Characteristics and Clinical Uses Abatacept Extracellular domain of cytotoxic T-lymphocyte-associated antigen 4(CTLA-4) fused to human IgG Fc. Blocks T-cell activation by interfering with the interaction of T-cell CD28 to APC CD 80/86 (Figure 55-2). Used for severe rheumatoid arthritis Abciximab Antagonist of glycoprotein IIb1/IIIa receptor, preventing cross-linking reaction in platelet aggregation. Used post-angioplasty and in acute coronary syndromes Alefacept Fusion of a fragment of leukocyte-function-associated antigen-3 (LFA-3) to human IgG Fc region that prevents T-cell CD2 from binding to APC LFA-3. Approved for psoriasis Efalizumab MAb to CD-11a, the alpha subunit of T cell leukocyte-function-associated antigen-1 (LFA-1). Inhibits binding of LFA-1 to APC intercellular adhesion molecule-1 (ICAM-1; Figure 55-2). Approved for psoriasis Muromonab Antibody to the T3 (CD3) antigen on thymocytes. Used in acute renal allograft rejection Omalizumab Anti-IgE MAb used to treat severe asthma (See Chapter 20) Palivizumab Antibody to surface protein of respiratory syncytial virus (RSV). Used for prophylaxis and treatment of RSV infection Rituximab Binds to the CD20 antigen on B lymphocytes and recruits immune effector functions to mediate lysis. Used in B cell non-Hodgkin's lymphoma Trastuzumab Binds to the HER-2 protein on the surface of tumor cells. Cytotoxic for breast tumors that overexpress HER-2 protein

Muromonab-CD3

This MAb binds to the CD3 antigen on the surface of human thymocytes and mature T cells. It blocks the killing action of cytotoxic T cells and probably interferes with other T-cell functions. Muromonab-CD3 is used to manage renal, cardiac, and liver transplant rejection crises. Serious anaphylactic reactions can occur, especially with the first few doses. Neuropsychiatric and hypersensitivity reactions may also occur.

Daclizumab

Daclizumab is a highly specific MAb that binds to the alpha subunit of the IL-2 receptor displayed on the surface of T cells and prevents activation by IL-2. It is used in combination with other immunosuppressants to prevent renal transplant rejection. In contrast to cyclosporine, tacrolimus, or cytotoxic immunosuppressants, the adverse effects of daclizumab are equivalent to those of placebo. Basiliximab is a chimeric human-mouse IgG with an action that is equivalent to that of daclizumab.

Infliximab

This humanized MAb (Figure 55-3) is targeted against TNF-, a proinflammatory cytokine, and thereby decreases formation of interleukins and adhesion molecules involved in leukocyte activation. Infliximab induces remissions in treatment-resistant Crohn's disease. In combination with methotrexate, infliximab improves symptoms in patients with rheumatoid arthritis. It also is effective in the treatment of ulcerative colitis, ankylosing spondylitis, and psoriatic arthritis. Infusion reactions and an increased rate of infection may occur. Adalimumab (Figure 55-3) is a completely human IgG monoclonal antibody that binds to TNF- and is approved for treatment of rheumatoid arthritis. Though not a true MAb, etanercept (Figure 55-3) is an immunoglobulin-based agent that also binds with high affinity and thereby sequesters TNF-. It is a dimer of identical chains of a human TNF receptor fused to a human IgG constant region. Etanercept is used in arthritis, psoriasis, and ankylosing spondylitis, and is being investigated in other inflammatory diseases. Injection site reactions and hypersensitivity may occur. All of the anti-TNF-agents increase the risk of serious infection and lymphoma.

Immunomodulating Agents

Agents that stimulate immune responses represent a newer area in immunopharmacology with the potential for important therapeutic uses, including the treatment of immune deficiency diseases, chronic infectious diseases, and cancer.

Aldesleukin

Aldesleukin is recombinant interleukin-2 (IL-2), an endogenous lymphokine that promotes the production of cytotoxic T lymphocytes and activates NK cells (Table 55-1). Aldesleukin is indicated for the adjunctive treatment of renal cell carcinoma and malignant melanoma. It is investigational for possible efficacy in restoring immune function in AIDS and other immune deficiency disorders.

Interferons

Interferon--2a inhibits cell proliferation and is used in hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, Kaposi's sarcoma, and hepatitis B and C. Interferon--1b has some beneficial effects in relapsing multiple sclerosis. Interferon--1b has greater immune-enhancing actions than the other interferons and appears to act by increasing the synthesis of TNF. The recombinant form is used to decrease the incidence and severity of infections in patients with chronic granulomatous disease.

Mechanisms of Drug Allergy

Immunologic reactions to drugs can fall into any of the 4 categories of hypersensitivity reactions.

Type I (Immediate) Drug Allergy

This form of drug allergy involves IgE-mediated reactions to animal and plant stings and pollens as well as to drugs. Such reactions include anaphylaxis, urticaria, and angioedema. When linked to carrier proteins, small drug molecules can act as haptens and initiate B-cell proliferation and formation of IgE antibodies. These antibodies bind to Fc receptors on tissue mast cells and blood basophils. On subsequent exposure, the antigenic drug cross-links the IgE antibodies on the surface of mast cells and basophils and triggers release of mediators of vascular responses and tissue injury, including histamine, kinins, prostaglandins, and leukotrienes. Drugs that commonly cause type I reactions include penicillins and sulfonamides.

Type II Drug Allergy

Type II allergy involves IgG or IgM antibodies that are bound to circulating blood cells. On reexposure to the antigen, complement-dependent cell lysis occurs. Type II reactions include autoimmune syndromes such as hemolytic anemia from methyldopa, systemic lupus erythematosus from hydralazine or procainamide, thrombocytopenic purpura from quinidine, and agranulocytosis from exposure to many drugs.

Type III Drug Allergy

Type III hypersensitivity is a complex type of drug allergy reaction that involves complement-fixing IgM or IgG antibodies and, possibly, IgE antibodies. Drug-induced serum sickness and vasculitis are examples of type III reactions; Stevens-Johnson syndrome (associated with sulfonamide therapy) may also result from type III mechanisms.

Type IV Drug Allergy

Type IV allergy is a cell-mediated reaction that can occur from topical application of drugs. It results in contact dermatitis.

Modification of Drug Allergies

Drugs that modify allergic responses to other drugs or toxins act at several steps of the immune mechanism. For example, corticosteroids inhibit lymphoid cell proliferation and reduce tissue injury and edema. However, most drugs that are useful in type I reactions (eg, epinephrine, H1 antagonists, corticosteroids) block mediator release or act as physiologic antagonists of the mediators.

Skill Keeper: Anaphylaxis and Sympathomimetic Drugs

(See Chapters 6 and 9)

In severe anaphylactic reactions, the life-threatening events commonly involve airway obstruction, laryngeal edema, and vascular collapse resulting from peripheral vasodilation and reduction in blood volume. Hypoxemia can contribute to cardiac events, including arrhythmias and myocardial infarction. Drugs used to treat anaphylaxis mainly target the receptors used by neurotransmitters of the sympathetic nervous system.

1. Why is epinephrine rather than norepinephrine used in anaphylaxis?

2. What other sympathomimetic drugs might be useful in the treatment of anaphylaxis?

The Skill Keeper Answers appear at the end of the chapter.

Skill Keeper Answers: Anaphylaxis and Sympathomimetic Drugs

(See Chapters 6 and 9)

1. Epinephrine activates all adrenoceptors, whereas norepinephrine has minimal agonist activity at 2 adrenoceptors. This difference is important in anaphylaxis because 2 adrenoceptor activation is needed to provide a bronchodilatory effect that will oppose the anaphylaxis-induced airway obstruction. The 1 adrenoceptor agonist effect of epinephrine opposes the anaphylaxis-induced vasodilation and, to some extent, the vascular leak (administration of fluid is also a cornerstone of the treatment of anaphylaxis), whereas the 1 adrenoceptor agonist effect helps maintain cardiac output.

2. If bronchospasm is predominant, then administration by inhalation of a 2-selective agonist such as albuterol may be useful. If cardiovascular collapse is predominant and does not respond adequately to fluid resuscitation, then vasopressor drugs may be helpful; these include  adrenoceptor agonists such as phenylephrine and 1-adrenoceptor agonists such as dobutamine or dopamine.

Checklist

When you complete this chapter, you should be able to:

 Describe the primary features of cell-mediated and humoral immunity.

 Name 7 immunosuppressants and, for each, describe the mechanism of action, clinical uses, and toxicities.

 Describe the mechanisms of action, clinical uses, and toxicities of antibodies used as immunosuppressants.

 Identify the major cytokines and other immunomodulating agents and know their clinical applications.

 Describe the different types of allergic reactions to drugs.

Drug Summary Table: Drugs that Modulate Immune Function

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions Glucocorticoids Prednisone Activation of glucocorticoid receptor leads to altered gene transcription Many inflammatory conditions, organ transplantation, hematologic cancers Duration of activity is longer than pharmacokinetic half-life of drug owing to gene transcription effects Adrenal suppression, growth inhibition, muscle wasting, osteoporosis, salt retention, glucose intolerance, behavioral changes Many other glucocorticoids available for oral and parenteral use. See Chapter 39 Immunophilin ligandsCyclosporine The complex of cyclosporine-cyclophilin inhibits calcineurin Organ transplantation, graft-versus-host disease, some autoimmune diseases Metabolized by CYP450 system; many drug-drug interactions Renal dysfunction, hypertension, neurotoxicity Tacrolimus: Like cyclosporine but inhibits calcineurin by binding to FK506 immunophilin Sirolimus: Its binding to cyclophilin inhibits the IL-2 signaling pathway; toxicity effects include hypertriglyceridemia, hepatotoxicity, diarrhea, and myelosuppression Purine antagonist Mycophenolate mofetil Blocks de novo GTP synthesis by inhibiting inosine monophosphate dehydrogenase Organ transplantation, graft-versus-host disease, some autoimmune diseases Oral, parenteral Gastrointestinal disturbances, myelosuppression Miscellaneous Thalidomide Complex immune effects including reduction in TNF- production Erythema nodosum leprosum, multiple myeloma Oral Teratogen, somnolence, peripheral neuropathy, neutropenia CD-2 receptor antagonist Alefacept Binds to T-cell CD2 receptor and blocks its association with LFA-3 Psoriasis Recombinant protein; parenteral Reduced T cell count, hepatotoxicity, hypersensitivity reaction, infection, malignancy Immunosuppressive antisera Antithymocyte globulin Binds to T cells and triggers complement-based cytotoxicity Transplantation Parenteral Hypersensitivity reaction, injection site reaction, malignancy Antilymphocyte globulin: Like antithymocyte globulin Anti-Rho(D) antibody RhoGAM

Prevents Rh sensitization by binding to Rho(D) antigens

Administered to Rho(D)-negative mothers who carry a Rho(D)-positive fetus

Parenteral Injection-site reactions, hemolysis if given to Rh-positive person CD3 antagonist Muromonab-CD3 MAb that inhibits cytotoxic T cells by binding to CD3 Allograft rejection Parenteral Anaphylactic reactions, neuropsychiatric effects, hypersensitivity reactions IL-2 antagonists Daclizumab MAb that blocks the T-cell IL-2 receptor Renal transplantation Parenteral Hypersensitivity reactions, infection, malignancy Basiliximab: Chimeric MAb similar to daclizumab Anti-TNF- agents Infliximab MAb binds to TNF- and prevents it from activating TNF- receptor Inflammatory bowel disease, rheumatoid arthritis, , ankylosing spondylitis, psoriatic arthritis Parenteral Hypersensitivity reactions, infection, malignancy Adalimumab: Human MAb similar to daclizumab Etanercept: Dimer of human TNF receptor fused to IgG constant region Recombinant IL-2 Aldesleukin Activates IL-2 receptors on T, B, and NK cells Renal cell carcinoma, melanoma Parenteral Capillary leak syndrome, exacerbation of preexisting inflammatory/autoimmune diseases, hypersensitivity reactions Interferons (IFNs) Interferon--2a Enhances immune responses by activating IFN- receptors Leukemia, melanoma, hepatitis B and C Parenteral Interferon--1b: Used for multiple sclerosis Interferon--1b: Used for chronic granulomatous disease.

GTP, guanosine triphosphate; LFA, lymphocyte-associated antigen; MAb, monoclonal antibody; TNF, tumor necrosis factor.



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