OBAT DAN SISTEM IMMUNE

KULIAH PAKAR

BLOK IMUNOLOGI

PPD UNISMA

ANTIGEN DARI LUARDARI DALAM TUBUH PROTEIN ASING BAKTERIPROTEIN DARI DALAM

MASUK KEDALAM TUBUH MELALUI BERBAGAI ROUTEMULUT, JALAN NAPAS INJEKSI

MENYEBABKAN DISINTESANYA ANTI BODY OLEH SEL SEL LIMPOSIT

ANTIGEN

+

ANTIBODY

DIKELUARKANNYAMEDIATOR DARI SEL

REAKSI INFLAMASI

MEDIATOR MEDIATOR PADA REAKSI ALLERGI

MEDIATOR KIMIA YANG DIKELUARKAN OLEH SEL BASOPHIL DAN SEL MAST

PROTEIN DERIVED MEDIATOR HISTAMIN , SEROTONINEOSINOPHIL CHEMOTACTIC FACTORNEUTROPIL CHEMOTACTIC FACTORBRADIKININ GENERATING FACTOR

AG

IgE

SEL MAST /SEL BASOPHIL

LIPID DERIVED MEDIATORPROSTAGLANDINETROMBOXANELEUKOTRIENS

CONTOH EFEK HISTAMIN : SECRESI MUKUS, KONSTRIKSI BRONKUS KONTRAKSI OTOT POLOS USUS

PELEBARAN PEMBULUH DARAH KAPILER EFEK CEPAT 1-2 MENIT DAN EFEK HILANG SETELAH 15 MENIT

REAKSI TIPE 1ADA IgE SPESIFIK TERHADAP OBAT TERTENTU ATAU

BAGIAN DARI OBAT YANG DIKENAL SEBAGAI HAPTENE IgE SPESIFIKTERBENTUK SETELAH KONTAK PERTAMA DENGAN OBAT TERTENTUPADA PAPARAN ULANG OAT AKAN BERIKATAN DENGAN IgE DIPERMUKAAN MEMBRANE MAST SEL ATAU SEL BASOPHIL TERJADI RELEASE MEDIATOR INFLAMASI SEPERTI HISTAMIN, SEROTONIN, HEPARIN PROTEASE, LEUKOTRIENS TROMBOXANE DSB

REAKSI TIPE 1 INI MERUPAKAN IMMEDIATE HYPERSENSITIVITY ATAUREAKSI ANAPHYLAKSIS . REAKSI TYPE 1 DAPAT MENGENAI 1 ORGAN SEPERTI MUKOSA HIDUNG (RHINITIS) ACUT ASTMA, KULIT GASTROINTESTINAL ATAU DAPAT MENGENAI SELURUH ORGAN YANG DIKENALSEBAGAI ANAPHILAKSIS

ASMA BRONHIALE

PENYEMPITAN BRONKUS YANG TERJADI BERULANG YANG DILANDASI OLEH KKELAINAN INFLAMASI. PADA ASMA OK ALLERGI, ALLERGEN YANG DIHISAP BERIKATAN DENGAN IgE PADA MAST SEL DAN SEL BASOPIL . MENGHASILKAN REAKSI YANG MELIBATKAN SEL IMUNE DAN DIKELUARKANNYA MEDIATOR INFLAMASI PADA INTERSTTIAL SPACE YANG KEMUDIAN MEMPENGARUHI FUNGSI SEL PADA DINDING JALAN NAPAS.

Asthma is associated with inflammation of the airway wall. Increased numbers of various types of inflammatory cells, most notably eosinophils but also basophils, mast cells, macrophages, and certain types of lymphocytes, can be found in airway wall biopsies and in bronchoalveolar lavage fluid from asthmatic patients. Inflammatory mediators and various cytokines also are increased in the airways of asthmatic subjects compared with healthy control subjects. How bronchial inflammation contributes to the asthmatic condition remains poorly understood. Even asthmatics with normal baseline lung function and no recent exacerbations of their asthma have increased numbers of inflammatory cells in their airways. Conversely, many individuals allergic to inhaled allergens have evidence of lower airway inflammation but suffer only from the symptoms of allergic rhinitis. The basis for this inflammation is not entirely clear. Many individuals with asthma are atopic and have clearly defined allergen exposures that are partially or substantially responsible for their asthmatic inflammation. Epidemiological studies show a strong correlation between increasing IgE levels and the prevalence of asthma regardless of atopic status Nonallergic individuals also can suffer from asthma, as is often seen in subjects in whom the onset of disease is later in life.

Asthma is a common disorder, accounting in the United States for 1% to 3% of all office visits, 500,000 hospital admissions per year, more pediatric hospital admissions than any other single illness, and more than 5000 deaths annually.

TERAPI ASMA DENGAN MENGGUNAAN OBAT UNTUK MENGURANGI INFLAMASI PADA JALAN NAPAS, (DENGAN OBAT ANTI INFLAMASI)Mengurangi spasme bronkhus (bronkodilator) yaitu:

b adrenergic receptor agonists, glucocorticoids, leukotriene inhibitors, chromones, methylxanthines, and inhibitors of immunoglobulin E (IgE).

DENGAN OBAT MENGENCERKAN DAHAK YANG BIASANYA KENTAL PADA PENDRRITA ASMA

The drugs available for the treatment of asthma are targeted at inhibiting the inflammatory responses and/or relaxing the bronchial smooth muscle. Letters denote the putative sites of action for the various classes of drugs used in treating asthma. b, b2 adrenergic agonists; cs, corticosteroids; l, leukotriene modifiers; m, muscarinic receptor antagonists; cr, cromolyn; t, theophylline; aI, anti-IgE therapy. The sunburst (     ) symbolizes an allergen.

Schematic representations of the disposition of inhaled drugs.

Inhalation therapy deposits asthma medications directly, but not exclusively, in the lungs. Distribution of inhaled drug between lungs and esophagus depends on particle size and efficiency of delivery to lungs. Most material, approximately 90%, will be swallowed and absorbed, entering the systemic circulation. Some drug also will be absorbed from the lungs. Optimal particle size for deposition in small airways is 1 to 5 mm.

REAKSI TIPE IIREAKSI ALLERGI INI ENYEBABKAN KERUSAKAN KAMATIAN

SEL HOST BIASANYA SEL DARAH. PADA AWALNYA OBATTERIKAT DENGAN KE SEL DARAH SEBAGAI HAPTENE MISALNYAPADA PLATELET ATAU ERITROSIT.ANTI BODI IgG ATAU IgM SPESIFIK UNTUK OBAT ATAU KOMPONEN PERMUKAAN SEL YANG TELAH DIRUBAH OLEH OBATBERKATAN DAN TERJADI AWAL DARI KERUSAKAN SEL MISALNYA KEHILANGAN INTEGRITAS MEMBRAN DAN SELANJUTNYA KEMATIAN SELKEMATIAN SEL JUGA TERJADI MELALUI PHAGOSITOSIS OLEH SELNETROPHIL MONOSIT ATAU MACROPHAGE SUATU PROSES YANG DIKENAL SEBAGAI OPSONISASI ATAU TERJADI PERUSAKAN SEL MELALUI ANTIBODI DEPENDENT CELLULAER CYTOTOXICITY.SEL YANG TERLIBAT ANTARA LAIN ERYTROSIT, LEUKOSIT DAN TROMBOSIT TERJADI HEMOLITIK ANAEMIA, AGRANULOCYTOSISATAU TOBOSITOPENIA.

THE IMMUNE RESPONSE

The immune system evolved to discriminate self from nonself. Multicellular organisms were faced with the problem of destroying infectious invaders (microbes) or dysregulated self (tumors) while leaving normal cells intact. These organisms responded by developing a robust array of receptor-mediated sensing and effector mechanisms broadly described as innate and adaptive. Innate, or natural, immunity is primitive, does not require priming, and is of relatively low affinity, but is broadly reactive. Adaptive, or learned, immunity is antigen-specific, depends upon antigen exposure or priming, and can be of very high affinity. The two arms of immunity work closely together, with the innate immune system being most active early in an immune response and adaptive immunity becoming progressively dominant over time..

. The major effectors of innate immunity are complement, granulocytes, monocytes/macrophages, natural killer cells, mast cells, and basophils. The major effectors of adaptive immunity are B and T lymphocytes. B lymphocytes make antibodies; T lymphocytes function as helper, cytolytic, and regulatory (suppressor) cells. These cells are important in the normal immune response to infection and tumors, but also mediate transplant rejection and autoimmunity Immunoglobulins (antibodies) on the B lymphocyte surface are receptors for a large variety of specific structural conformations. In contrast, T lymphocytes recognize antigens as peptide fragments in the context of self major histocompatibility complex (MHC) antigens (called human leukocyte antigens [HLA] in human beings) on the surface of antigen-presenting cells, such as dendritic cells, macrophages, and other cell types expressing MHC class I (HLA-A, -B, and -C) and class II antigens (HLA-DR, -DP, and -DQ) in human beings. Once activated by specific antigen recognition via their respective clonally restricted cell-surface receptors, both B and T lymphocytes are triggered to differentiate and divide, leading to release of soluble mediators (cytokines, lymphokines) that perform as effectors and regulators of the immune response.

The impact of the immune system in human disease is enormous. Developing vaccines against emerging infectious agents such as human immunodeficiency virus (HIV) and Ebola virus is among the most critical challenges facing the research community. Immune system-mediated diseases are significant medical problems. Immunological diseases are growing at epidemic proportions that require aggressive and innovative approaches to develop new treatments. These diseases include a broad spectrum of autoimmune diseases such as rheumatoid arthritis, type I diabetes mellitus, systemic lupus erythematosus, and multiple sclerosis; solid tumors and hematologic malignancies; infectious diseases; asthma; and various allergic conditions. Furthermore, one of the great therapeutic opportunities for the treatment of many disorders is organ transplantation. However, immune system-mediated graft rejection remains the single greatest barrier to widespread use of this technology. An improved understanding of the immune system has led to the development of new therapies to treat immune system-mediated diseases.

IMMUNOSUPPRESSION

OBAT YANG MENEKAN SISTEMIMUNE BETUJUAN UNTUK MENURUNKAN RESPON IMUNE PADA TRANSPLANTASI ORGAN DAN PENYAKIT AUTOIMUNE. PADA TRANSPLANTASI OAT IMMNOSUPRESIVE YANG DIGUNAKAN ADLAH: (1) glucocorticoids,

(2) calcineurin inhibitors, (3) antiproliferative/antimetabolic agents, and (4) biologics (antibodies).

OBAT INI BERMANFAAT PADA IMUNE REJECTION YANG ACUT PADA TRANSPLANTASI ORGAN, DAN PENYAKIT AUTOIMUNE YANG NAMUN PENGOBATAN INI SERING ALI DIBUTUHKAN PENGGUNAAN YANG LAMA DAN DAPAT MENYEBABKAN PENEKANAN SELURUH SISTEM IMUNE. SEHINGGA BERISIKO TERJADINYA INFEKSI DAN KANKER Efek samping calcineurin dan glukocortikoid adalah nefrotksik dan diabetes

General Approach to Organ Transplantation Therapy

Organ transplant therapy is organized around five general principles. The first principle is careful patient preparation and selection of the best

available ABO blood type-compatible HLA match for organ donation. Second, a multitiered approach to immunosuppressive drug therapy,

similar to that in cancer chemotherapy, is employed. Several agents are used simultaneously, each of which is directed at a different molecular target within the allograft response Synergistic effects permit use of the various agents at relatively low doses, thereby limiting specific toxicities while maximizing the immunosuppressive effect.

The third principle is that greater immunosuppression is required to gain early engraftment and/or to treat established rejection than to maintain long-term immunosuppression. Therefore, intensive induction and lower-dose maintenance drug protocols are employed.

Fourth, careful investigation of each episode of transplant dysfunction is required, including evaluation for rejection, drug toxicity, and infection, keeping in mind that these various problems can and often do coexist. Organ-specific problems (e.g., obstruction in the case of kidney transplants) must also be considered. The fifth principle, which is common to all drugs, is that a drug should be reduced or withdrawn if its toxicity exceeds its benefit.

Biologic Induction Therapy. Induction therapy with polyclonal and monoclonal antibodies (mAbs) has been an important component of immunosuppression dating back to the 1960s, when Starzl and colleagues demonstrated the beneficial effect of antilymphocyte globulin (ALG) in the prophylaxis of rejection in renal transplant recipients. Over the past 40 years, several polyclonal antilymphocyte preparations have been used in renal transplantation; however, only 2 preparations are currently FDA approved: lymphocyte immune globulin (ATGAM) and antithymocyte globulin (THYMOGLOBULIN) Another important milestone in biologic therapy was the development of mAbs and the introduction of the murine anti-CD3 mAb (muromonab-CD3 or OKT3)

Maintenance Immunotherapy. The basic immunosuppressive protocols in most transplant centers use multiple drugs simultaneously. Therapy typically involves a calcineurin inhibitor, glucocorticoids, and mycophenolate mofetil (a purine metabolism inhibitor; see below), each directed at a discrete site in T-cell activation Glucocorticoids, azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus, and various monoclonal and polyclonal antibodies are all approved for use in transplantation. Glucocorticoid-free regimens have achieved special prominence in recent successes in using pancreatic islet transplants to treat patients with type I diabetes mellitus. Protocols employing steroid withdrawal or steroid avoidance are being evaluated in many transplant centers. Short-term results are good, but the effects on long-term graft function are unknown Recent data suggest that calcineurin inhibitors may shorten graft half-life by their nephrotoxic effects Protocols under evaluation include calcineurin dose reduction or switching from calcineurin to sirolimus-based immunosuppressive therapy at 3 to 4 months

Adrenocortical Steroids The introduction of glucocorticoids as immunosuppressive drugs in the 1960s played a key role in making organ transplantation possible. Their chemistry, pharmacokinetics, and drug interactions are described in Chapter 59. Prednisone, prednisolone, and other glucocorticoids are used alone and in combination with other immunosuppressive agents for treatment of transplant rejection and autoimmune disorders. Mechanism of Action. The immunosuppressive effects of glucocorticoids have long been known, but the specific mechanism(s) of their immunosuppressive action remains somewhat elusive. Glucocorticoids lyse (in some species) and induce the redistribution of lymphocytes, causing a rapid, transient decrease in peripheral blood lymphocyte counts. To effect longer-term responses, steroids bind to receptors inside cells; either these receptors, glucocorticoid-induced proteins, or interacting proteins regulate the transcription of numerous other genes Additionally, glucocorticoid-receptor complexes increase IkB expression, thereby curtailing activation of NF-kB, which increases apoptosis of activated cells Of central importance, key proinflammatory cytokines such as IL-1 and IL-6 are downregulated. T cells are inhibited from making IL-2 and proliferating. The activation of cytotoxic T lymphocytes is inhibited. Neutrophils and monocytes display poor chemotaxis and decreased lysosomal enzyme release. Therefore, glucocorticoids have broad antiinflammatory effects on multiple components of cellular immunity. In contrast, they have relatively little effect on humoral immunity.

Calcineurin Inhibitors

Perhaps the most effective immunosuppressive drugs in routine use are the calcineurin inhibitors, cyclosporine and tacrolimus, which target intracellular signaling pathways induced as a consequence of T-cell-receptor activation (Although they are structurally unrelated and bind to distinct, albeit related molecular targets, they inhibit normal T-cell signal transduction essentially by the same mechanism Cyclosporine and tacrolimus do not act per se as immunosuppressive agents. Instead, these drugs bind to an immunophilin (cyclophilin for cyclosporine or FKBP-12 for tacrolimus), resulting in subsequent interaction with calcineurin to block its phosphatase activity. Calcineurin-catalyzed dephosphorylation is required for movement of a component of the nuclear factor of activated T lymphocytes (NFAT) into the nucleus NFAT, in turn, is required to induce a number of cytokine genes, including that for interleukin-2 (IL-2), a prototypic T-cell growth and differentiation factor.

Cyclosporine. Chemistry. Cyclosporine (cyclosporin A), a cyclic polypeptide consisting of 11 amino acids, is produced by the fungus species Beauveria nivea. Of note, all amide nitrogens are either hydrogen bonded or methylated, the single D-amino acid is at position 8, the methyl amide between residues 9 and 10 is in the cis configuration, and all other methyl amide moieties are in the trans form Because cyclosporine is lipophilic and highly hydrophobic, it is formulated for clinical administration using castor oil or other strategies to ensure solubilization.

Mechanism of Action. Cyclosporine suppresses some humoral immunity, but is more effective against T-cell-dependent immune mechanisms such as those underlying transplant rejection and some forms of autoimmunity It preferentially inhibits antigen-triggered signal transduction in T lymphocytes, blunting expression of many lymphokines including IL-2, and the expression of antiapoptotic proteins. Cyclosporine forms a complex with cyclophilin, a cytoplasmic receptor protein present in target cells. This complex binds to calcineurin, inhibiting Ca2+-stimulated dephosphorylation of the cytosolic component of NFAT

Clinical indications for cyclosporine are kidney, liver, heart, and other organ transplantation; rheumatoid arthritis; and psoriasis. Cyclosporine generally is recognized as the agent that ushered in the modern era of organ transplantation, increasing the rates of early engraftment, extending kidney graft survival, and making cardiac and liver transplantation possible. Cyclosporine usually is combined with other agents, especially glucocorticoids and either azathioprine or mycophenolate mofetil, and most recently, sirolimus.

Tacrolimus. Tacrolimus (PROGRAF, FK506) is a macrolide antibiotic produced by Streptomyces tsukubaensis

Mechanism of Action. Like cyclosporine, tacrolimus inhibits T-cell activation by inhibiting calcineurin Tacrolimus binds to an intracellular protein, FK506-binding protein-12 (FKBP-12), an immunophilin structurally related to cyclophilin. A complex of tacrolimus-FKBP-12, Ca2+, calmodulin, and calcineurin then forms, and calcineurin phosphatase activity is inhibited. As described for cyclosporine and depicted in, the inhibition of phosphatase activity prevents dephosphorylation and nuclear translocation of NFAT and inhibits T-cell activation. Thus, although the intracellular receptors differ, cyclosporine and tacrolimus target the same pathway for immunosuppression

TOLERANCE

Introduction

Immunosuppression has concomitant risks of opportunistic infections and secondary tumors. Therefore, the ultimate goal of research on organ transplantation and autoimmune diseases is to induce and maintain immunologic tolerance, the active state of antigen-specific nonresponsiveness Tolerance, if attainable, would represent a true cure for conditions discussed above without the side effects of the various immunosuppressive therapies. The calcineurin inhibitors prevent tolerance induction in some, but not all, preclinical models In these same model systems, sirolimus does not prevent tolerance and may even promote tolerance induction Several other promising approaches are being evaluated in clinical trials. Because they remain experimental, they are discussed only briefly here.

IMMUNOSTIMULATION

General Principles

In contrast to immunosuppressive agents that inhibit the immune response in transplant rejection and autoimmunity, a few immunostimulatory drugs have been developed with applicability to infection, immunodeficiency, and cancer. Problems with such drugs include systemic (generalized) effects at one extreme or limited efficacy at the other.

Immunostimulants

Levamisole. Levamisole (ERGAMISOL) was synthesized originally as an anthelmintic but appears to "restore" depressed immune function of B lymphocytes, T lymphocytes, monocytes, and macrophages. Its only clinical indication is as adjuvant therapy with 5-fluorouracil after surgical resection in patients with Dukes' stage C colon cancer where it occasionally has been associated with fatal agranulocytosis.

Thalidomide. Thalidomide (THALOMID) is best known for the severe, life-threatening birth defects it caused when administered to pregnant women For this reason, it is available only under a restricted distribution program and can be prescribed only by specially licensed physicians who understand the risk of teratogenicity if thalidomide is used during pregnancy. Thalidomide should never be taken by women who are pregnant or who could become pregnant while taking the drug. Nevertheless, it is indicated for the treatment of patients with erythema nodosum leprosum and also is used in conditions such as multiple myeloma. Its mechanism of action is unclear Reported immunologic effects vary substantially under different conditions. For example, thalidomide has been reported to decrease circulating TNF-a in patients with erythema nodosum leprosum, but to increase it in patients who are HIV-seropositive Alternatively, it has been suggested that the drug affects angiogenesis The anti-TNF-a effect has led to its evaluation as a treatment for severe, refractory rheumatoid arthritis

Bacillus Calmette-Guerin (BCG). Live bacillus Calmette-Guerin (BCG; TICE BCG, THERACYS) is an attenuated, live culture of the bacillus of Calmette and Guerin strain of Mycobacterium bovis, that induces a granulomatous reaction at the site of administration. By unclear mechanisms, this preparation is active against tumors and is indicated for treatment and prophylaxis of carcinoma in situ of the urinary bladder and for prophylaxis of primary and recurrent stage Ta and/or T1 papillary tumors after transurethral resection Adverse effects include hypersensitivity, shock, chills, fever, malaise, and immune complex disease.

Recombinant Cytokines. Interferons. Although interferons (alpha, beta, and gamma) initially were identified by their antiviral activity, these agents also have important immunomodulatory activities The interferons bind to specific cell-surface receptors that initiate a series of intracellular events: induction of certain enzymes, inhibition of cell proliferation, and enhancement of immune activities, including increased phagocytosis by macrophages and augmentation of specific cytotoxicity by T lymphocytes Recombinant interferon alfa-2b (IFN-alpha 2, INTRON A) is obtained from Escherichia coli by recombinant expression. It is a member of a family of naturally occurring small proteins with molecular weights of 15,000 to 27,600 daltons, produced and secreted by cells in response to viral infections and other inducers. Interferon alfa-2b is indicated in the treatment of a variety of tumors, including hairy cell leukemia, malignant melanoma, follicular lymphoma, and AIDS-related Kaposi's sarcoma, It also is indicated for infectious diseases, chronic hepatitis B, and condylomata acuminata. In addition, it is supplied in combination with ribavirin (REBETRON) for treatment of chronic hepatitis C in patients with compensated liver function not treated previously with interferon alfa-2b or who have relapsed after interferon alfa-2b therapy. Adverse experiences involving the cardiovascular system (hypotension, arrhythmias, and rarely cardiomyopathy and myocardial infarction) and CNS (depression, confusion) are less-frequent side effects.

Interleukin-2. Human recombinant interleukin-2 (aldesleukin, PROLEUKIN; des-alanyl-1, serine-125 human IL-2) is produced by recombinant DNA technology in E. coli This recombinant form differs from native IL-2 in that it is not glycosylated, has no amino terminal alanine, and has a serine substituted for the cysteine at amino acid 125 The potency of the preparation is represented in International Units in a lymphocyte proliferation assay such that 1.1 mg of recombinant IL-2 protein equals 18 million International Units. Aldesleukin has the following in vitro biologic activities of native IL-2: enhancement of lymphocyte proliferation and growth of IL-2-dependent cell lines; enhancement of lymphocyte-mediated cytotoxicity and killer cell activity; and induction of interferon-g activity In vivo administration of aldesleukin in animals produces multiple immunologic effects in a dose-dependent manner. Cellular immunity is profoundly activated with lymphocytosis, eosinophilia, thrombocytopenia, and release of multiple cytokines (e.g., TNF, IL-1, interferon-g). Aldesleukin is indicated for the treatment of adults with metastatic renal cell carcinoma and melanoma. Administration of aldesleukin has been associated with serious cardiovascular toxicity resulting from capillary leak syndrome, which involves loss of vascular tone and leak of plasma proteins and fluid into the extravascular space. Hypotension, reduced organ perfusion, and death may occur. An increased risk of disseminated infection due to impaired neutrophil function also has been associated with aldesleukin treatment.

Immunization

Immunization may be active or passive. Active immunization involves stimulation with an antigen to develop immunologic defenses against a future exposure. Passive immunization involves administration of preformed antibodies to an individual who is already exposed or is about to be exposed to an antigen.

Vaccines. Active immunization, vaccination, involves administration of an antigen as a whole, killed organism, attenuated (live) organism, or a specific protein or peptide constituent of an organism. Booster doses often are required, especially when killed (inactivated) organisms are used as the immunogen. In the United States, vaccination has sharply curtailed or practically eliminated a variety of major infections, including diphtheria, measles, mumps, pertussis, rubella, tetanus, Haemophilus influenzae type b, and pneumococcus

Although most vaccines have targeted infectious diseases, a new generation of vaccines may provide complete or limited protection from specific cancers or autoimmune diseases Because T cells optimally are activated by peptides and costimulatory ligands that both are present on antigen-presenting cells (APCs), one approach for vaccination has consisted of immunizing patients with APCs expressing a tumor antigen. The first generation of anticancer vaccines used whole cancer cells or tumor-cell lysates as a source of antigen in combination with various adjuvants, relying on host APCs to process and present tumor-specific antigens These anticancer vaccines resulted in occasional clinical responses and are being tested in prospective clinical trials. Second generation anticancer vaccines utilized specific APCs incubated ex vivo with antigen or transduced to express antigen and subsequently reinfused into patients.

Immune Globulin. Passive immunization is indicated when an individual is deficient in antibodies because of a congenital or acquired immunodeficiency, when an individual with a high degree of risk is exposed to an agent and there is inadequate time for active immunization (e.g., measles, rabies, hepatitis B), or when a disease is already present but can be ameliorated by passive antibodies (e.g., botulism, diphtheria, tetanus). Passive immunization may be provided by several different products Nonspecific immunoglobulins or highly specific immunoglobulins may be provided based upon the indication. The protection provided usually lasts from 1 to 3 months. Immune globulin is derived from pooled plasma of adults by an alcohol-fractionation procedure. It contains largely IgG (95%) and is indicated for antibody-deficiency disorders, exposure to infections such as hepatitis A and measles, and specific immunologic diseases such as immune thrombocytopenic purpura and Guillain-Barre syndrome In contrast, specific immune globulins ("hyperimmune") differ from other immune globulin preparations in that donors are selected for high titers of the desired antibodies. Specific immune globulin preparations are available for hepatitis B, rabies, tetanus, varicella-zoster, cytomegalovirus, and respiratory syncytial virus. Rho(D) immune globulin is a specific hyperimmune globulin for prophylaxis against hemolytic disease of the newborn due to Rh incompatibility between mother and fetus. All such plasma-derived products carry the theoretical risk of transmission of infectious disease.