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Immune Globulin - The Miracle Product

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									Immune Globulin: The Miracle Product
Mark C. Hannibal, MD, PhD University of Washington School of Medicine Department of Pediatrics Division of Genetics and Developmental Medicine

• • • • Review of the immune system & antibodies Passive immunity History of immune globulin therapy Present state of immune globulin therapy:
– – – – Products Indications Adverse events Practical considerations

Immune Function
Two interrelated activities:
• Recognition • Response

Immune Response
• Starts when foreign structure (antigen) is recognized

• Involves a variety of cellular and humoral mediators • Process known as ―effector response‖

• Molecules foreign to blood and other body fluids • Stimulate production of antibodies (immunoglobulins)

• Combine specifically with the antibodies produced

Types of Immune Response
• Innate or inborn (nonspecific)
– Inherited defense mechanisms

• Adaptive or acquired (specific)
– Prior exposure to antigen necessary

• Passive
– Supplied via donor

Innate Immune Response
• First line of defense against pathogens
• Nonspecific immunity

• Present from birth • Defenses include:
– Physical barriers – Cellular mediators – Humoral mediators

Adaptive Immune Response
• Acquired in response to specific stimuli • Differs from innate response
– – – – Antigen specificity Diversity Immunologic memory Self and nonself recognition

• Defenses include:
– Cellular mediators – Humoral mediators

Adaptive Cellular Mediators
• B-lymphocytes • T-lymphocytes
– Helper cells – Suppressor cells – Cytotoxic cells

• Surface receptors recognize antigens
– Lymphocyte pool has ability to recognize up to 1016 antigens

Adaptive Humoral Mediators
• Cytokines
– Lymphokines

• Immunoglobulins (antibodies)
– – – – – IgG IgM IgA IgD IgE

Primary Adaptive Response
• First exposure to pathogen • Immune response often insufficient to combat disease

• Latent period of 5 to 10 days before measurable amounts of specific antibodies appear in blood

Secondary Adaptive Response
• Subsequent exposure to same antigen • Antibody production is much more rapid

• Provides long-lasting protection • Demonstrates memory of adaptive response

Primary and Secondary Immune Response
Secondary Response IgG
Plasma Antibody Concentration

Primary Response IgM

Time after exposure to antigen
Adapted from Wei-Chiang S, Louie SG. Immunology for Pharmacy Students. 1999.

Optimal Immune Response
• Both cellular and humoral mediators needed • Both innate and adaptive responses utilized

Immune Response

Adapted with permission from Playfair JHL. Immunology at a Glance. 6th ed. Malden, Mass: Blackwell Science, Ltd; 1996.

• Antigen-presenting cell – Presents antigen to T cells

• Derived from bone marrow CD34+ stem cells • Expresses only a single specific antibody
B Cell

• Major function is antibody production – Humoral immunity

B-Cell Activation
Two required steps
• Binding of antigen to surface immunoglobulin

• Secretion of B cell growth factors by activated CD4+ cells (IL-4, -5, -6)

Activated B Cells
Plasma cells
• Produce large amounts of antibody

Memory cells
• Respond to subsequent pathogen encounters • Quicker, more vigorous response

Target: Extracellular Organisms
Inflammatory CD4 Cell (T H2)




•Antibody Synthesis


Antigen-presenting cell (B Cell)


Adapted from Israels LG, Israels ED. Mechanisms in Hematology. 1996.

Adaptive Humoral Response

Adaptive Humoral Response
Cells involved in adaptive humoral response: • B cells • Plasma cells
– Activated B cells that secrete antibodies

Memory cells
– Adaptive immunity

Immunoglobulins (Ig)
• Also known as antibodies
– Neutralize and opsonize pathogens – Found in human serum

• Found in the gamma globulin class of plasma proteins, produced by B cells • Different Ig have different structures and specific functions • Bind to antigen

Ig Isotypes
• Immunoglobulin G (IgG)
• Immunoglobulin M (IgM)

• Immunoglobulin A (IgA)
• Immunoglobulin D (IgD)

• Immunoglobulin E (IgE)

Ig Production
• Activated B cell transforms into plasma cell • Plasma cell synthesizes Ig (2000/sec) • Synthesis of Ig:
– – – – Packed in endoplasmic reticulum Channeled through Golgi apparatus Glycosylated Transported to surface for secretion

Antibody Structure
• 4 polypeptide chains
– 2 light chains – 2 heavy chains

• Fab region
– Fab = fragment antigen binding – Specific binding site for antigen

• Fc region
– Fc = fragment crystalline – Interacts with Fc receptor

• Hinge region
– Flexibility for Ag binding

Antibody Domain Function
• V domain (VL - VH)
– Antigen binding

• C1 domain (CL - CH1)
• CH2

– Coupling of L and H chains

– Interacts with complement – Attaches to Fc receptors – Activates • Macrophages • PMN • Platelets

• CH3

• Most prevalent antibody (80% serum antibody) • Four subclasses
– IgG1 and IgG3 • Primarily recognize protein antigens

– IgG2 and IgG4 • Bind carbohydrate antigens

• Only antibody that crosses placenta • Produced on second antigen exposure

• Found on B-cell surface • Pentamer (5 monomers)
– No Fc portions exposed – Phagocytic cells can’t bind pathogens opsonized by IgM

• Excellent activator of complement cascade
– Classic pathway

• Produced during first exposure to antigen

• Found in fluid secretions
– – – – Tears Saliva Nasal solution GI mucus

• Dimeric form
– Linked with secretory component

• Secreted in breast milk

• Function not fully understood
• Found on B-cell surface during different stages of maturation

• Possible involvement in cell differentiation

• Least common serum isotype
• Most IgE bound to IgE Fc receptor on mast cells • Antigen binding to IgE releases inflammatory substances
– Histamine – Pathogenesis of hay fever, allergic asthma

Ig Subclass Comparison

Characteristics of Ig Classes

Adapted with permission from Wick M, Wick M, Heberger S, Simon H, Fateh-Moghadam A. Infusionsther Transfusionmed. 1996;23(Suppl 4):55-59.

Antibody Class Switch
• Primary response to antigen is IgM
– Naïve B cells

• Secondary antibody response is IgG
– Memory cells

• Class switch provides IgG and IgA antibodies
– IgG moves outside intravascular space – IgG crosses placenta – IgA transported to mucosal surfaces

Passive Immunity
• Immune protection produced by transfer of antibodies to a recipient from a donor • Donor has been actively immunized • Occurs naturally from mother to fetus during pregnancy and mother to infant during nursing • Short-lived protection

Immune Globulin: Drug name for passive immunity products
• • • • • • History of passive immunity transfer Current brands and production FDA-approved use—‖On-Label‖ ―Off-Label‖ use and evidence for efficacy Safety and side effects Practical considerations

History of Transfer of Passive Immunity
• Late 19th Century, von Behring and Kitasato demonstrate antitoxin effect of blood drawn from rabbits immune to tetanus toxins • This was soon applied to humans • By 1938, immunoglobulins were being isolated from pooled human serum

Cohn Cold-Ethanol Fractionation
• Large scale plasma fractionation during World War II allowed stable storage • Plasma cooled to 0°C, ethanol and buffer added, and four protein fractions were precipitated out of solution • Cohn fraction II contained most antibodies • Intramuscular administration protected against measles and hepatitis A

Immune Globulin Treatment for Primary Immunodeficiency
• 1952 Bruton describes agammaglobulinemia

Swiss Red Cross Laboratories
• 1960’s Barundun and others prepared IgG for intravenous use • low pH (acidic) and traces of pepsin protease to inhibit reaggregation

• Prevent anaphylactic reactions to IVIG

1980’s: FDA Approval of IVIG
Initial three forms of IVIG: • Sandoglobulin (Sandoz-Novartis): fractionated and lyophilized at low pH 4 • Gamimune N (Cutter-Bayer): fractionated at pH 4.25 and stabilized with maltose • Gammagard (Baxter-Travenol): cold ethanol fractionation then ion-exchange chromatography

Growth of IVIG Usage
• From 1992 to 2003, production tripled from 19.4 to 52.6 tons • Up to 8 different products available • Changing product line as Red Cross got out of the market, Octapharma entered, phase out of old products and introduction of new ones by established manufacturers

Carimune NF: ZLB-Behring
• Descendent of Sandoglobulin • Labeled for Primary Immune Deficiency, Acute and Chronic ITP • USA donors • pH 4 with pepsin, nanofiltration • 5% sucrose (3% IgG reconstitution) • Lyophilized

Gamunex: Talecris
• Labeled for Primary Humoral Immunodeficiency and ITP • USA donors • Caprylate and chromatography purified • No sugar content • 10% IgG Liquid

Gammagard Liquid: Baxter
• Labeled for Primary Immune Deficiency • Paid donor pool • Solvent/detergent treated, nanofiltration, low pH • No added sugar • Latex free packaging • 10% IgG Liquid

Gammagard S/D: Baxter
• Labeled for Primary Immune Deficiency, ITP, Chronic Lymphocytic Leukemia, Kawasaki syndrome (disease) • Paid donor pool • Solvent/detergent treated, ultrafiltration, ion-exchange chromatography • 4% glucose (10% IgG reconstitution) sugar content • Lyophilized • Packaging contains latex • Lowest IgA content of immune globulins

Flebogamma: Grifols
• Labeled for Primary Immune Deficiency Disorders • USA donors • PEG precipitation, ion-exchage chromatography, pasteurization • 5% D-Sorbitol sugar alcohol content • 5% IgG Liquid

Octagam: Octapharma
• • • • • Labeled for Primary Immune Deficiency USA non-remunerated donors Solvent/Detergent, pH 4 treatment 10% Maltose sugar content 5% IgG Liquid

Vivaglobin: ZLB Behring
• Labeled for Primary Immune Deficiency • 16% IgG liquid for subcutaneous use • Glycine stabilized; no sugar

GamaSTAN S/D: Talecris
• Formerly Baygam produced by Bayer • Labeled for Hepatitis A, measles, rubella and varicella prophylaxis, and hypogammaglobulinemia and agammaglobulinemia • 16% IgG liquid for intramuscular use • Glycine-stabilized; no sugar • Can be used subcutaneously (off-label)

FDA-Approved Indications for IVIG
• • • • • • Primary Immune Deficiency Idiopathic Thrombocytopenic Purpura Kawasaki Disease B-cell Chronic Lymphocytic Leukemia HIV Infection Bone Marrow Transplantation

Immune Globulin Use in Primary and Secondary Immune Deficiency
• Definitely Beneficial: – Primary immune defects with absent B cells – Hypogammaglobulinuria and impaired specific antibody production • Probably Beneficial: – Chronic Lymphocytic Leukemia with low IgG and history of infections – Prevention of infections in HIV-infected children – Primary immune defects with normogammaglobulinemia and impaired specific antibody production

Immune Globulin Use in Primary and Secondary Immune Deficiency
• Might Provide Benefit:
– Prevention of neonatal sepsis

• Unlikely to be Beneficial:
– Isolated IgA deficiency – Isolated IgG4 deficiency

Immune Globulin Use in Autoimmunity
• Definitely Beneficial: – Graves ophthalmopathy – Idiopathic thrombocytopenic purpura • Probably Beneficial: – Dermatomyositis and polymyositis – Autoimmune uveitis

Immune Globulin Use in Autoimmunity
• Might Provide Benefit:
– – – – – – – – – – Severe rheumatoid arthritis Autoimmune diabetes mellitus Posttransfusion purpura Vasculitides and antineutrophil antibody syndromes Autoimmune neutropenia Autoimmune hemolytic anemia Autoimmune hemophilia Systemic lupus erythematosus Fetomaternal alloimmune thrombocytopenia Neonatal isoimmune hemolytic jaundice

• Unlikely to be Beneficial:
– Inclusion body myositis – Antiphospholipid antibody syndrome

Immune Globulin Use in Neuroimmunologic Disorders
• Definitely Beneficial: – Guillain-Barré syndrome – Chronic inflammatory demyelinating polyneuropathy – Multifocal motor neuropathy • Probably Beneficial: – Lambert-Eaton myasthenic syndrome – IgM antimyelin-associated glycoprotein paraprotein-associated peripheral neuropathy – Myasthenia gravis – Stiff-man syndrome

Immune Globulin Use in Neuroimmunologic Disorders
• Might Provide Benefit:
– – – – – – – – – – – – Monoclonal gammopathy multiple sclerosis Intractable childhood epilepsy Rasmussen syndrome Acute disseminated encephalomyelitis HTLV-1-associated encephalomyelitis Cerebral infarction with antiphospholipid antibodies Demyelinative brainstem encephalitis Lumbosacral or brachial plexitis Paraproteinemic neuropathy Opsoclonus myoclonus Postinfectious cerebellar ataxia Acute idiopathic dysautonomia

Immune Globulin Use in Neuroimmunologic Disorders
• Unlikely to be Beneficial: – Demyelinating neuropathy associated with monoclonal IgM – Adrenoleukodystrophy – Amyotrophic lateral sclerosis – Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome – Paraneoplastic cerebellar degeneration, sensory neuropathy or encephalopathy

Immune Globulin Use in Infectious and Infection-Related Diseases
• Definitely Beneficial: – Kawasaki disease – CMV-induced pneumonitis in solid organ transplants • Probably Beneficial:
– Neonatal sepsis – Rotoviral enterocolitis – Bacterial infections in lymphoproliferative diseases – Streptococcal toxic shock – Enteroviral meningoencephalitis

Immune Globulin Use in Infectious and Infection-Related Diseases
• Might Provide Benefit: – Postoperative sepsis – RSV lower respiratory tract infection – Pseudomembranous colitis – Campylobacter species-induced enteritis

• Unlikely to be Beneficial: – Chronic fatigue syndrome – Acute rheumatic fever – Viral load in HIV infection

Miscellaneous Use of Immune Globulin
• Definitely Beneficial: – None • Probably Beneficial:
– Toxic epidermal necrolysis – Stevens-Johnson syndrome

• Might Provide Benefit: – Severe, persistent, high dose steroid dependent asthma – Prevention of infection and acute GVHD after bone marrow transplantation – Prevention of acute humoral rejection after renal transplantation – Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections – Delayed pressure urticaria – Treatment of acute humoral rejection after renal transplantation – Autoimmune blistering skin diseases and manifestations of systemic diseases – Chronic urticatria – Autoimmune liver disease – Acute myocarditis

Miscellaneous Use of Immune Globulin

Miscellaneous Use of Immune Globulin
• Unlikely to be Beneficial: – Prevention of spontaneous recurrent abortions* – Nonsteroid-dependent asthma – Dilated cardiomyopathy – Chronic fatigue syndrome – Prevention of chronic GVHD after bone marrow transplantation – Atopic dermatitis – Autistic disorders

Safety and Efficacy of Immune Globulin
• Produced from paid plasmapheresis donors or plasma of whole blood donors • Recommended large pool of donors to make product: 15,000 to 60,000 • Tested for
– Hepatitis B surface antigen – HIV p24 antigen – Antibodies to syphilis, HIV-1, HIV-2, Hepatitis C

Adverse Events of Immune Globulin Therapy
2002 Immune Deficiency Foundation survey of more than 1000 patients – 44% reported reactions not related to the rate of infusion – 34% of reactions occurred during the first infusion Most reactions were mild: • Back or abdominal aching or pain • Nausea • Rhinitis • Asthma • Chills • Low grade fever • Myalgias (muscle aches) • Headaches

Managing Mild-Moderate Reactions
• Slow or stop infusion for 15-30 minutes • Diphenhydramine, acetominophen, ibuprofen or aspirin • Hydrocortisone 50-100 mg for adults, 5 mg/kg for children • Intravenous hydration with normal saline • To prevent reactions, pretreatment with any of the above may help

Severe Adverse Events with Immune Globulin
• Anaphylaxis and Anaphlylactoid reactions • Hypotension, Steven-Johnson syndrome, myocardial infarction, thrombosis, cytopenia, hemolysis, stroke, seizure, loss of consciousness, acute respiratory distress syndrome, pulmonary edema, acute bronchospasm, transfusion associated lung injury, aseptic meningitis

Severe Adverse Events with Immune Globulin
Events not related in time to infusion • Acute renal failure
– More common in sucrose containing products

• Neurodegeneration • Risk of transmitted infection
– Theoretical since more than 100 people infected with Hepatitis C in the 1990’s

Practical Considerations in the Use of Immune Globulin
• Definitely Beneficial: – Subcutaneous therapy to reduce systemic adverse events – Maintain IgG troughs >500 mg/dl to reduce infections – Expert monitoring to manage adverse events of immune globulin therapy

Practical Considerations in the Use of Immune Globulin
• Probably Beneficial:
– Home based therapy for low risk patients can improve quality of life – Use of low IgA content IVIG for IgA deficient patients with IgG anti-IgA antibodies – Product changes might improve adverse event profiles – Premedication can improve mild adverse events – Matching particular IVIG products to patients to reduce adverse events – Stopping or slowing infusion to help manage adverse events

Practical Considerations in the Use of Immune Globulin
• Might Provide Benefit: – Subcutaneous therapy can improve quality of life for patients receiving IVIG – Maintenance of IgG trough >800 reduces infectious consequences • Unlikely to be Beneficial: – Placement of indwelling catheters or ports for IVIG administration – Making IVIG dosing and treatment decisions for antibody replacement therapy in PID solely upon IgG trough levels – Routinely testing IgG trough levels more frequently than every 6 months

Acknowledgments & References
• Bayer (immune system slides)

• Orange JS et al. J Allergy Clin Immunol 117:S525-53, 2006 • Siegel J. Pharmacotherapy 25:78S-84S, 2005 • Good RA & Lorenz E. Cancer 68:1415-21, 1991

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