Therapeutic Immunology

25 Therapeutic Immunology antigen-presenting cells, activated T cells, macrophages, and B cells. The term also refers to the use of immunological reagents such as antibodies, T cells, or modifications of them in therapy. Both types have been applied to animal models of autoimmune diseases and attempts are in progress to apply immunotherapy to human autoimmune diseases. A principal goal of immunotherapy is to selectively diminish the unwanted immune response but retain protective immune mechanisms. Selective immunosuppression involves the induction of immunologic tolerance which is antigen-induced specific immunosuppression. Oral tolerance also shows promise. Trials are being conducted with peptide-induced tolerance, peptide–MHC complexes, and TCR peptides. Bystander suppression, nonspecific immune suppression, and antibody-dependent immunotherapy are other treatment modalities. Therapeutic antisera are serum antibody preparations employed to either protect against disease or for disease therapy. They are distinct from antibody or antisera preparations used for the serological identification of microorganisms. Therapeutic antisera, such as horse antitoxin against diphtheria, were widely used earlier in the 20th century. A few specific antisera such as tetanus antitoxin are still used. Tetanus antitoxin: Antibody raised by immunizing horses against Clostridium tetani exotoxin. It is a therapeutic agent to treat or prevent tetanus in individuals with contaminated lesions. Anaphylaxis or serum sickness (type III hypersensitivity) may occur in individuals receiving second injections because of sensitization to horse serum proteins following initial exposure to horse antitoxin. One solution to this has been the use of human antitetanus toxin of high titer. Treatment of the IgG fraction yields F(ab2) fragments which retain all of the toxin-neutralizing capacity but with diminished antigenicity of the antitoxin preparation. Diphtheria antitoxin is an antibody generated by the hyperimmunization of horses against Corynebacterium diphtheriae exotoxin with injections of diphtheria toxoid and diphtheria toxins. When used earlier in the 20th century to treat children with diphtheria, many of the recipients developed serum sickness. It may be employed for passive immunization to treat diphtheria or for short-term protection during epidemics. Presently, pepsin digestion of the serum globulin fraction of the antitoxin yields ANTIOXIDANTS AND IMMUNITY Immune function depends on a balance between free radical and the antioxidant status of the body. Exposure of healthy adults to high levels of oxidants leads to diminished immune responses. Exposure to low levels of dietary antioxidants also decreases immune responses such as delayed type hypersensitivity. There is increased oxidative stress and immune dysfunction in rheumatoid arthritis, aging, and cigarette smoking. This leads to damage to lipids and other cellular components by free radicals. Antioxidant status is reduced in arthritic patients and smokers compared with controls. Thus, supplemental antioxidants are useful in diminishing oxidative stress and improving immune function. Increased levels of antioxidants may be needed for elderly individuals to maintain delayed-type hypersensitivity responses. ARGININE AND IMMUNITY The dibasic nitrogen-rich amino acid arginine has a marked immunomodulatory function. It is critical for the maintenance of nitrogen balance and physiologic functions in humans. Supplemental administration of arginine in experimental animals has led to increased thymic size, lymphocyte count, and a lymphocyte mitogenic response to mitogens and antigens. There is enhanced IL-2 synthesis. It protects against posttraumatic thymic involution and the impairment of T cell function. It enhances delayed hypersensitivity reactions in animal studies and also promotes host antitumor responses. Arginine is essential for the function of various immunoregulatory proteins that include thymosin, thymopentin, and tuftsin. Arginine has a powerful effect on numerous cells and molecules of the immune system and may have future potential as a pharmacologic agent in the treatment of immunocompromised patients. Serotherapy is a form of treatment for an infectious disease developed almost a century ago in which antiserum raised by immunizing horses or other animals against exotoxin, such as that produced by Corynebacterium diphtheriae , was administered to children with diphtheria. This antitoxin neutralized the injurious effects of the toxin. Thus, serotherapy was intended for prevention and treatment. Immunotherapy is a treatment mechanism in which therapy is the aim at targets of the immune system that include Copyright © 2004 by Taylor & Francis F(ab′)2 fragments of antibodies that retain their antigenbinding property but lose the highly antigenic Fc region. This process diminishes the development of serum sickness-type reactions and is called despecification. Gas gangrene antitoxin contains antibodies found in antisera against exotoxins produced by Clostridium perfringens, C. septicum, and C. oedematiens, bacteria, which may cause gas gangrene. In the past, this antiserum was used together with antibiotics and surgical intervention in the treatment of wounds where gas gangrene was possible. Intravenous immune globulin (IVIG) is an immunoglobulin preparation comprised principally of IgG derived from the blood plasma of about 1000 donors. This preparation may be effective against hepatitis A and B, cytomegalovirus, rubella, varicella-zoster, tetanus, and various other agents. IVIG is administered to children with common variable immunodeficiency, X-linked agammaglobulinemia, or other defects of the antibody limb of the immune system. Even though AIDS is a CD4+ T cell defect, IVIG may help to protect against microbial infection in HIV-I-infected children. It may also be effective in autoimmune or idiopathic thrombocytopenia, autoimmune neutropenia, or Kawasaki’s disease. IVIG may induce anaphylactic reactions and fever, as well as headache, muscle aches, and cardiovascular effects on blood pressure and heart rate. IVIG is the abbreviation for intravenous immunoglobulin. Immune serum is an antiserum containing antibodies specific for a particular antigen or immunogen. Such antibodies may confer protective immunity. Immune serum globulin is an injectable immunoglobulin that consists mainly of IgG extracted by cold ethanol fractionation from pooled plasma from up to 1000 human donors. It is administered as a sterile 16.5 ± 1.5% solution to patients with immunodeficiencies and as a preventive against certain viral infections including measles and hepatitis A. Human immune globulin (HIG) is a pooled globulin preparation from the plasma of donors who are negative for HIV that is used in the treatment of primary immunodeficiency, such as severe combined immunodeficiency, Bruton’s disease, and combined variable immunodeficiency, and in cases of idiopathic thrombocytopenic purpura. The method of production is extraction by cold ethanol fractionation at acid pH. Viruses are inactivated, which permits the safe administration of the HIG to patients without risk of HIV, HAV, HBV, or non-A, non-B hepatitis. HIG is the abbreviation for human immune globulin. HGG is the abbreviation for human γ globulin. HBIG (hepatitis B immunoglobulin) is a preparation of donor pool-derived antibodies against hepatitis B virus (HBV). It is heat treated and shown not to contain human immunodeficiency virus. HBIG is given at the time when individuals are exposed to HBV and 1 month thereafter. Low-titer (1:128) and high-titer (1:100,000) preparations are available. Monoclonal antibody (Mab) therapy refers to treatment with monoclonal antibodies to suppress immune function, kill target cells, or treat specific inflammatory diseases. Mab demonstrate highly specific binding to precise cellular or molecular targets. Since monoclonal antibodies are derived from mouse cells, they have the potential to induce allergic reactions in recepients. Monoclonal antibodies have multiple uses in health care. For example, Edrecolomab is used to treat solid tumors; Enlimomab is used to treat organ transplant rejection; Infliximab is used to treat Crohn’s disease and rheumatoid arthritis; OKT3 is used to treat organ transplant rejection; Palivizumab is used for respiratory syncytial virus; Rituxamab is used to treat leukemias and lymphomas; Rhumabvegf is used to treat solid tumors; and Transtuzumab is used to treat metastatic breast cancer. (Table 25.1) HAMA is human antimouse antibody. A group of murine monoclonal antibodies administered to selected cancer patients in research treatment protocols stimulate synthesis of antimouse antibody in the human recipient. The murine monoclonal antibodies are specific for the human tumor cell epitopes. The antimouse response affects the continued administration of the monoclonal antibody preparation. The hypersensitivity induced can be expressed as anaphylaxis, subacute allergic reactions, delayed-type hypersensitivity, rash, urticaria, flu-like symptoms, gastrointestinal disorders, dyspnea, hypotension, and renal failure. Campath-1 (CD52) CAMPATH-1M is a rat IgM monoclonal antibody against the CD52 antigen. It is able to lyse cells using human complement, making no other manipulation necessary to deplete T cells other than to add donor serum. This has been used to deplete T cells to prevent GVHD. CD52 is a lipid-anchored glycoprotein with a very small peptide constituent. Anti-CD52 antibodies are potent lytic agents, killing cells in vitro with human complement as well as in vivo. These antibodies have been used for therapy of leukemia, bone marrow transplantation, organ transplantation, rheumatoid arthritis, vasculitis, and multiple sclerosis. CAMPATH-1H (human IgG1) was the first monoclonal antibody to be humanized. It was formed by transplanting complementarity-determining regions of campath-1G into human heavy and light chain genes. Even though initial binding affinity was decreased, this was corrected by modifying framework residues. Patients receiving this humanized antibody developed a Copyright © 2004 by Taylor & Francis TABLE 25.1 Antibody Name Abciximab (ReoPro®) ABX-CBL ABX-EGF ABX-IL8 AcuTect™ AFP-ScanTM Alemtuzumab (Campath®) Apolizumab (RemitogenTM) Arcitumomab (CEA-Scan®) Technetium99m-labeled Anti-CD11a hu1 124 Basiliximab (Simulect®) Bectumomab Bevacizumab (AvastinTM) Capromab Pendetide (Prostascint®) Indium-111 labeled Cetuximab CEACideTM Daclizumab (Zenapax®) Edrecolomab (Panorex®) Efalizumab (XanelimTM) Enlimomab Epratuzumab (LymphoCide™) Gemtuzumab ozogamicin Mylotarg® Hu23F2G (LeukArrest™) Hu1124 Ibritumomab tiuxetan (ZevalinTM) Igovomab (Indimacis 125®) Imciromab pentetate (Myoscint®) IMC-C225 (ERBITUXTM) Infliximab (Remicade®) Inolimomab LDP-01 LDP-02 LeuTech® 99cTc-Anti-CD15 Anti-Granulocyte Antibody Lerdelimumab Lym-1 Yttrium-90 labeled LymphoScan® MAK-195F MDX-33 MDX-H210 MDX-447 Mitumomab (BEC2) Muromonab (Orthoclone OKT®3) Natalizumab (Antegren®) Nebacumab (Centoxin®) Nofetumomab (Verluma®) OctreoScan® Indium-111 labeled Target Antigen Glycoprotein IIbIIIa receptor CD147 EGFr IL-8 AFP CD52 1D10 antigen Carcinoembryonic antigen CD11a CD25 (IL-2 receptor) VEGF Prostate membrane specific antigen (PMSA) EGFr Carcinoembryonic antigen CD25 (IL-2 receptor) 17-1A cell surface antigen CD11a CD54 (ICAM-1) CD22 CD33 calicheamicin CD11/18 (leukointegrin) CD11a CD20 Tumor-associated antigen CA125 Human cardiac myosin EGFR TNF-α IL-2 receptor β2 integrin α4β7 integrin receptor CD15 Conditions Treated/Prevented Complications of coronary angioplasty GVHD EGF-dependent human tumor Rheumatoid arthritis, psoriasis Diagnoses of acute venous thrombosis Detection of liver and germ cell cancers B cell chronic lymphocytic leukemia, multiple sclerosis, kidney transplant rejection B cell Non-Hodgkin’s lymphoma, solid tumors Presence, location, and detection of recurrent and metastatic colorectal cancer Psoriasis Allograft rejection Non-Hodgkin’s lymphoma Metastatic renal cell carcinoma Radioimmunoscintigraphy for prostate cancer Head and neck, breast, pancreatic, colorectal cancers Colorectal cancer Allograft rejection Colorectal cancer Rheumatoid arthritis Organ transplant rejection Non-Hodgkin’s lymphoma Acute myeloid leukemia Ischemic stroke Psoriasis B cell non-Hodgkin’s lymphoma Detection of ovarian adenocarcinoma Myocardial infarction imaging EGF-dependent human tumor Crohn’s disease, rheumatoid arthritis Organ transplant rejection Stroke, kidney transplant rejection Crohn’s disease, ulcerative colitis Imaging infection sites TGFb2 HLA-DR CD22 TNF-α CD64 Bispecific HER2 × CD64 Bispecific EGFR × CD64 GD3-idiotypic CD3 α-4 integrin (VLA-4) Bacterial endotoxins Carcinoma-associated antigen Somatostatin receptor Glaucoma, cataract Non-Hodgkin’s lymphoma Detection of B cell non-Hodgkin’s lymphoma Hyperinflammatory response in sepsis syndrome Idiopathic thrombocytopenia purpura Breast, colorectal, kidney, ovarian, prostate cancers Head, neck, renal cancers Small cell lung cancer, melanoma Allograft rejection Multiple sclerosis, Crohn’s disease Gram-negative bacteria sepsis Detection of small-cell lung cancer Immunoscintigraphic localization of primary and metastatic neuroendocrine tumors that contain somatostatin receptors (Continued) Copyright © 2004 by Taylor & Francis TABLE 25.1 Antibody Name (Continued) Target Antigen Ig-E HLA-DA IgE Tumor-associated antigen CA125 CD4 Antigenic site of the F protein of respiratory syncytial virus (F gp) Complement C5 CD4 Cytomegalovirus (CMV) CD20 Tumor-associated glycoprotein-72 Cytomegalovirus (CMV) CD2 CD33 Surface granulocyte nonspecific cross-reacting antigen High molecular weight melanomaassociate antigen B lymphocyte surface protein Her2/neu CD3 αvβ3 integrin Cytokeratin tumor-associated antigen GPIIb/IIIa CD5, ricin A-chain toxin Conditions Treated/Prevented Allergic asthma, allergic rhinitis B cell non-Hodgkin’s lymphoma Allergic asthma, allergic rhinitis Ovarian cancer CD4-mediated autoimmune diseases, allograft rejection Respiratory syncytial virus infection AMI, UA, CPB, PTCA Crohn’s disease, multiple sclerosis Acute CMV disease Non-Hodgkin’s lymphoma Detection of colorectal and ovarian cancers Prevention of CMV infection in bone marrow transplant patients Acute GVHD, psoriatic arthritis Acute myeloid leukemia, myelodysplastic syndrome Detection of osteomyelitis, acute atypical appendicitis Diagnosis of cutaneous melanoma lesions Non-Hodgkin’s lymphoma Her2 positive metastatic breast cancer GVHD, ulcerative colitis Solid tumors Detection of carcinoma of colon and rectum Prevention of platelet aggregation GVHD Olizumab rhuMAb-E25 Oncolym® (131Lym-1) iodine131 labeled Omalizumab (XolairTM) Oregovomab (OvaRex ®) ORTHOCLONE OKT4A Palivizumab (Synagis®) Pexelizumab (5G1.1-SC) Priliximab Regavirumab Rituximab (Rituxan®) Satumomab pendetide (OncoScint® CR/OV) Sevirumab (Protovir®) Siplizumab (MEDI-507) SmartTM M195 Sulesomab (LeukoScan®) Technicium-99m labeled Tecnemab K1 Tositumomab (Bexxar®) Iodine 131 attached Trastuzumab (Herceptin®) Visilizumab (Nuvion™, SmartTM antiCD3) VitaxinTM Votumumab (Humaspect®) YM-337 Zolimomab Notes: GVHD: graft-vs.-host disease; EGFr: epidermal growth factor receptor; IL-2: interleukin-2; IL-8: interleukin-8; AFP: α fetoprotein; VEGF: vascular endothelial growth factor; ICAM-1: intercellular adhesion molecule-1; TNF-α: tumor necrosis factor-α; TGFb2-transforming growth factor b2; HLA: human leukocyte antigen; VLA-4: very late antigen-4; AMI: acute myocardial infarction; UA: unstable angina; CPB: cardiopulmonary bypass; PTCA: percutaneous transluminal coronary angioplasty; GPIIb/IIIa: glycoprotein IIbIIIa. very low antiglobulin response compared with the original rat antibody. The CD52 antigen is a glycoprotein with only 12 amino acids. It is a complex carbohydrate consisting of sialylated polylactosamine units with fucosylated mannose core. It is attached to Asn3 at the C-terminus as a glycosylphosphatidylinositol (GPI) anchor. The CAMPATH-1 epitope is comprised of the C-terminal amino acids and part of the GPI anchor, which means that the antibodies bind near the cell membrane which facilitates cell lysis. The antigen is expressed abundantly on all lymphocytes except for plasma cells, and also on monocytes, macrophages, and eosinophils. It is not found on any other tissues except the male reproductive tract where it is expressed strongly on epithelial cells lining the epididymis, vas deferens, and seminal vesicle. The CD52 antigen is a principal membrane protein of sperm. Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively binds with high affinity in a cell-based assay to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. The antibody is an IgG1 kappa that contains human framework regions with the complementarity-determining regions of a murine antibody (4D5) that binds to HER2. Commercially distributed as Herceptin®. Herceptin®: See Trastuzumab. REMICADE® (infliximab) is a chimeric IgGlk monoclonal antibody with an approximate mol wt of 149,100 Da. It is composed of human constant and murine variable regions. I nfliximab binds specifically to human tumor necrosis factor alpha (TNFα) with an association constant of 1010 M−1. Infliximab is produced by a recombinant cell Copyright © 2004 by Taylor & Francis line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses. ReoPro® (abciximab) is the Fab fragment of the chimeric human–murine monoclonal antibody 7E3. Abciximab binds to the glycoprotein (GP) IIb/IIIa (αIIbβ3) receptor of human platelets and inhibits platelet aggregation. Abciximab also binds to the vitronectin (αvβ3) receptor found on platelets and vessel wall endothelial and smooth muscle cells. The chimeric 7E3 antibody is produced by continuous perfusion in mammalian cell culture. The 47,615-Da Fab fragment is purified from cell culture supernatant by a series of steps involving specific viral inactivation and removal procedures, digestion with papain, and column chromatography. E5 is a murine monoclonal IgM antibody to endotoxin that has proven safe and capable of diminishing mortality and helping to reverse organ failure in patients with Gramnegative sepsis who are not in shock during therapy. E5 may recognize and combine with lipid A epitope. HA-1A is a human monoclonal IgM antibody specific for the lipid A domain of endotoxin. It can prevent death of laboratory animals with Gram-negative bacteremia and endotoxemia. In clinical trials, HA-1A has proven safe and effective for the treatment of patients with sepsis and Gram-negative bacteremia, whether or not they are in shock, but not in those with focal Gram-negative infection. Rituxan (rituximab) is an anticancer monoclonal antibody that serves as a type of biotherapy by binding to tumor cells and triggering the immune system to kill target tumor cells rather than using toxic chemicals to accomplish this result. The antibody has been approved by the FDA for use in patients with non-Hodgkin’s lymphoma. Simulect© (basiliximab) is a chimeric (murine/human) monoclonal antibody (IgG1k), produced by recombinant DNA technology, that functions as an immunosuppressive agent, specifically binding to and blocking the interleukin2 receptor α-chain (IL-2Rα, also known as CD25 antigen) on the surface of activated T-lymphocytes. Based on the amino acid sequence, the calculated mol wt of the protein is 144 kDa. It is a glycoprotein obtained from fermentation of an established mouse myeloma cell line genetically engineered to express plasmids containing the human heavy and light chain constant region genes and mouse heavy and light chain variable region genes encoding the RFT5 antibody that binds selectively to the 11,2Rα. The active ingredient, basiliximab, is water soluble. The drug product, Simulect, is a sterile lyophilisate which is available in 6-ml colorless glass vials. Each vial contains 20 mg basiliximab, 7.21 mg monobasic potassium phosphate, 0.99 mg disodium hydrogen phosphate (anhydrous), 1.61 mg sodium chloride, 20 mg sucrose, 80 mg mannitol, and 40 mg glycine, to be reconstituted in 5 ml of Sterile Water for Injection, USP. No preservatives are added. Tumor immunotherapy: Immunological surveillance, first proposed by Paul Ehrlich 100 years ago, is believed to be a protective mechanism against the development of neoplasia in intact healthy subjects. Significant suppression of the immune system from any cause may favor tumor development. Contemporary attempts at therapeutic modification of the immune response include the use of immune response modifiers, monoclonal antibodies, cancer vaccines, and gene therapy. Genetically engineered cytokines such as IL-2 and interferon-α have been used to activate the immune system. Early hopes for success have now abated. Interferons have some proven efficacy in the management of melanoma, renal cell carcinoma, and hairy cell leukemia, and as adjuvant therapy in certain hematological malignancies such as low-grade lymphoma and myeloma. Although IL-2 has been used in the past to treat renal cell carcinoma and melanoma with the generation of tumor-infiltrating lymphocytes and lymphokineactivated killer cells, it has toxic physiologic effects. Monoclonal antibodies as anticancer agents are promising but have problems of delivery to targets, reactions to murine antibodies, and difficulties in linking therapeutic warheads to these “smart bombs.” Bispecific antibodies have been used to crosslink targets to immune effector cells to activate a cell-mediated antitumor response. Current cancer vaccines include autologous cell lines, allogeneic cell lines, genetically modified tumor cells, glycoproteins, stripped glycoproteins, peptides, antitumor idiotypes, and polynucleotides encoding tumor antigens. Gene therapy may be used to modify tumor cells to express costimulatory molecules such as B7-1 to help initiate a cell-mediated response against the neoplasm. Altered peptide ligands (APL) are peptides that may closely resemble an agonist peptide in amino acid sequence. They induce only a partial response from T lymphocytes specific for the agonist peptide. Altered peptide ligands are analogs of immunogenic peptides in which the T cell receptor contact sites have been altered, usually by substitution with another amino acid. Even though these peptides fail to stimulate T cell proliferation, they active some T cell receptor-mediated functions. Antagonist peptides specifically downmodulate the agonist-induced response. APL can act therapeutically by modulating the cytokine pattern of T cells or they may induce a form of anergy in T cells. They stimulate a partial response from T lymphocytes specific for the agonist peptide. Autolymphocyte therapy (ALT) is an unconfirmed immunotherapeutic treatment for metastatic renal carcinoma. Leukocytes from the patient are isolated and activated with Copyright © 2004 by Taylor & Francis monoclonal antibodies to induce the leukocytes to synthesize and secrete cytokines. Cytokines produced in the supernatant are combined with a sample of the patient’s own lymphocytes and reinjected. Preliminary reports claim success, but these are not confirmed. Dendritic cell immunotherapy: The lack of detectable tumor-specific immune responses in humans led to the use of autologous dendritic cells in active immunotherapy. Dendritic cells are expanded from progenitors ex vivo, charged with tumor antigens, and reinfused. Methods are being sought to genetically modify dendritic cells with antigens encoded by viral and nonviral vectors. Dendritic cells might also be used to vaccinate humans at the time a primary tumor is resected. This would permit an immune response to be available to act against metastases not detectable at the time the primary tumor is identified. Despecification is a method to reduce the antigenicity of therapeutic antisera prepared in one species and used in another. To render immunoglobulin molecules less immunogenic in the heterologous recipient, they may be treated with pepsin to remove the molecules’ most immunogenic portion, i.e., the Fc fragment, but leave intact the antigenbonding regions, i.e., F(ab′)2 fragments which retain their antitoxic properties. Had such a treatment been available earlier in the 20th century, serum sickness induced by horse antitoxin administered to human patients as a treatment for diphtheria would have been greatly reduced. Biologicals are substances used for therapy that include antitoxins, vaccines, products prepared from pooled blood plasma, and biological response modifiers (BRM). BRMs are prepared by recombinant DNA technology and include lymphokines such as interferons, interleukins, tumor necrosis factor, etc. Monoclonal antibodies for therapeutic purposes also belong in this category. Biologicals have always presented problems related to chemical and physical standardization to which drugs are subjected. They are regulated by the Food and Drug Administration (FDA) within the U.S. Immunomodulation describes therapeutic alteration of the immune system by the administration of biological response modifiers such as lymphokines or antibodies against cell surface markers bound to a toxin such as ricin. Biological response modifiers (BRM) include a broad spectrum of molecules, such as cytokines, that alter the immune response. They include substances such as interleukins, interferons, hematopoietic colony-stimulating factors, tumor necrosis factor, B lymphocyte growth and differentiating factors, lymphotoxins, and macophageactivating and chemotactic factors, as well as macrophage inhibitory factor, eosinophils chemotactic factor, osteoclast activating factor, etc. BRM may modulate the immune system of the host to augment antirecombinant DNA technology and are available commercially. An example is α interferon used in the therapy of hairy cell leukemia. Inosiplex (Isoprinosine) is an immunomodulating agent that increases natural kill (NK) cell cytotoxicity as well as T cell and monocyte functional activites. It has produced slight benefit in AIDS patient and has been used in Europe to treat diverse immunodeficiency diseases but is not yet approved for use in the U.S. Roquinimex is an immunomodulating drug capable of augmenting NK cell numbers and reactivity and stimulating various T and B cell functions. It has been used to stimulate immune function in post-bone marrow transplant patients. By contrast, it prevents relapses of chronic relapsing allergic encephalomyelitis in animal models of that disease. It also reduces relapses, disease activity, and disease progression in multiple sclerosis patients. If confirmed in further studies, this immunomodulator will have a significant future role in clinical medicine. B lymphocyte Stimulator (BlyS) is a naturally occurring protein that stimulates the immune system to produce antibodies. It is being tested as a potential drug for the treatment of immunodeficiency that occurs in higher than normal levels in rheumatoid arthritis (RA) and lupus (SLE) patients and could account for their immune systems becoming overeactive and attacking joints in RA or connective tissues in SLE. Immunoaugmentive therapy (IAT) describes an approach to tumor therapy practiced by selected individuals in Mexico, Germany, and the Bahama Islands that is not based on scientific fact and is of unproven efficacy or safety. Concoctions of tumor cell lysate and blood serum from tumor-bearing patients as well as from normal individuals is injected into cancer patients ostensively for the two to provide tumor antibody and “blocking” and “deblocking” proteins. The method is not based upon any scientifically approved protocol and is of very doubtful value. The treatment preparations are often contaminated with microorganisms. An immunoprotein is an immunologically active protein such as one that serves as a target for immunological probes or therapy. Immunoablation is the deliberate destruction of a patient’s immune competence to condition the patient for organ transplantation or to treat refractory autoimmune diseases. Bombesin is a neuropeptide of 14 residues that is analogous to a gastrin-releasing peptide that is synthesized in the gastrointestinal tract and induces GI smooth muscle contraction and the release of stomach acid and the majority of GI hormones with the exception of secretin. Bombesin Copyright © 2004 by Taylor & Francis injection into the brain may induce hyperglucagonemia, hyperglycemia, analgesia, and hypothermia. Bombesin facilitates bronchial epithelial cell proliferation, and pancreatic and small-cell carcinoma. Antibombesin antibodies might prove useful in the future for the treatment of smallcell lung carcinoma whose cells bear bombesin receptors. Botulinum toxin is formed by Clostridium botulinum. The 150-kDa type A toxin is available in purified form and is employed to treat a neuromuscular junction disease such as dystonias. It acts by combining with the presynaptic cholinergic nerve terminals where it is internalized and prevents exocytosis of acetylcholine. Subsequently, sprouting takes place, and new terminals are formed which reinnervate the muscle. Avionics®: Interferon-β-1a preparation approved for the treatment of multiple sclerosis. Cimetidine is an H2-receptor antagonist that is capable of over 90% reduction in food-stimulated and nocturnal secretion of gastric acid after a single dose. This histamine H2-receptor antagonist is of interest to immunologists because of its efficacy in treating common variable immunodeficiency, possibly through suppressor T lymphocyte inhibition. It also has an immunomodulating effect by reducing the activity of suppressor lymphocytes. Other drug immunomodulators include low-dose cyclophosphamide given prior to immunization with a tumor vaccine, which can augment the immune response in both animals and humans. Indomethacin can nullify the effects of suppressor macrophages. Levamisole is an antihelminthic drug used extensively in domestic animals and birds that was found to also produce immunostimulant effects. The drug may potentiate or restore the function of T lymphocytes and other leukocytes. This agent increases the magnitude to the delayed-type hypersensitivity or T cell-medicated immunity in humans. Although it has some efficacy in the treatment of RA, Levamisole induces severe agranular cytosis, which requires discontinuation of use. It also potentiates the action of fluorouracil in adjuvant therapy of colorectal cancer. Hydroxychloroquine (2-[[4-[7-chloro-4-quinolyl]amino] ethyl-amino]ethanol sulfate). An antimalarial drug that has also been used in therapy of the connective tissue diseases, such as SLE and RA. Chlorambucil (4-[bis(2-chloroethyl)amino-phenylbutyric acid) is an alkylating and cytotoxic drug. Chlorambucil is not as toxic as is cyclophosphamide and has served as an effective therapy for selected immunological diseases such as rheumatoid arthritis, SLE, Wegener’s granulomatosis, essential cryoglobulinemia, and cold agglutinin hemolytic anemia. Although it produces bone marrow suppression, it has not produced hemorrhagic cystitis and is less irritating to the GI tract than is cyclophosphamide. Chlorambucil increases the likelihood of opportunistic infections and the incidence of some tumors. Aminophylline: See theophylline. An antihistamine is a substance that links to histamine receptors, thereby inhibiting histamine action. Antihistamine drugs derived from ethylamine block H1 histamine receptors, whereas those derived from thiourea block the H2 variety. α Naproxen (2-naphthaleneacetic acid, 6-methoxy-αmethyl) is an antiinflammatory drug used in the treatment of arthritis, especially RA of children and adults, as well as ankylosing spondylitis. Naprosyn is a nonsteroidal antiinflammatory drug (NSAID). Nonsteroidal antiinflammatory drugs (NSAIDs) are a category of drugs used in the treatment of rheumatoid arthritis (RA), gouty arthritis, ankylosing spondylitis, and osteoarthritis. The drugs are weak organic acids. They block prostaglandin synthesis by inhibiting cyclooxygenase and lipooxygenase. They also interrupt membranebound reactions such as NADPH oxidase in neutrophils, monocyte phospholipase C, and processes regulated by G protein. They also exert a number of other possible activities such as diminished generation of free radicals and superoxides, which may alter intracellular cAMP levels, diminishing vasoactive mediator release from granulocytes, basophils, and mast cells. Salicylates and other similar drugs are used to treat rheumatic disease through their capacity to suppress the signs and symptoms of inflammation. These drugs also exert antipyretic and analgesic effects. Their antiinflammatory properties make then most useful in the management of disorders in which pain is related to the intensity of the inflammatory process. NSAIDs used for special indications include indomethacin and ketorolac. Gastric irritation caused by some of the original NSAIDs led to the introduction of newer NSAIDs that include phenylbutazone and a host of other compounds for use and treatment of such conditions as RA or osteoarthritis. NSAIDs, including aspirin, are employed mainly for their antiinflammatory, analgesic, and antipyretic effects. NSAIDs are widely used but are not always completely safe considering their gastrointestinal tract and kidney toxicity. All of these drugs are able to inhibit the enzyme cyclooxygenase that is the principal means by which they diminish pain, inflammation, and fever. Cyclooxygenase catalyzes arachidonic acid conversion to prostaglandins (GH). Copyright © 2004 by Taylor & Francis Propylthiouracil is an antithyroid drug that blocks TPO activity. Phenylbutazone (4-butyl-1,2-diphenyl-3,5-pyrazolidenedione) is a drug that prevents synthesis of prostaglandin and serves as a powerful antiinflammatory drug. It is used in therapy of RA and ankylosing spondylitis. β ′ Quinidine (β-quinine; 6′-methoxycinchonan-9-ol) is a stereoisomer of quinine recognized for its cardiac antiarrhythmic effects. Tolmetin (1-methyl-5-p-toluoylpyrrole-2-acetic acid) is an antiinflammatory agent effective in the therapy of arthritis, including juvenile RA, RA, and ankylosing spondylitis. Vinblastine is a chemotherapeutic alkaloid that leads to lysis of rapidly dividing cells by disruption of the mitotic spindle microtubules. It is used for therapy of leukemia, Hodgkin’s disease, lymphoproliferative disorders, and malignancies. Vincristine is a chemotherapeutic alkaloid that lyses proliferating cells through disruption of the mitotic spindle. It is used in the therapy of leukemia and other malignancies. Intolerance refers to adverse reactivity following the administration of normal doses of a drug. L-phenlyalanine mustard is a nitrogen mustard that is employed for therapy of multiple myeloma patients. Copyright © 2004 by Taylor & Francis