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Immunoglobulin therapy is the use of a mixture of
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
(normal human immunoglobulin or NHIG) to treat several health conditions. These conditions include
primary immunodeficiency Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a ''primary'' immunodeficiency (PID), the cause of the immune deficiency must not be secondary in nature ( ...
,
immune thrombocytopenic purpura Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is a type of thrombocytopenic purpura defined as an isolated low platelet count with a normal bone marrow in the absence of othe ...
,
chronic inflammatory demyelinating polyneuropathy Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired autoimmune disease of the peripheral nervous system characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder is sometimes called c ...
,
Kawasaki disease Kawasaki disease is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. It is a form of vasculitis, where blood vessels become inflamed throughout the body. The fever typically lasts for more th ...
, certain cases of
HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
and measles, Guillain-Barré syndrome, and certain other infections when a more specific immunoglobulin is not available. Depending on the formulation it can be given by injection into muscle, a
vein Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated b ...
, or under the skin. The effects last a few weeks. Common side effects include pain at the site of injection, muscle pain, and
allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...
. Other severe side effects include
kidney problems Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
,
anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
,
blood clots A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
, and red blood cell breakdown. Use is not recommended in people with some types of IgA deficiency. Use appears to be relatively safe during
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...
. Human immunoglobulin is made from human
blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...
. It contains antibodies against many
viruses A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...
. Human immunoglobulin therapy first occurred in the 1930s and a formulation for injection into a vein was approved for medical use in the United States in 1981. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
. Each formulation of product is somewhat different. A number of
specific immunoglobulin Specific may refer to: * Specificity (disambiguation) * Specific, a cure or therapy for a specific illness Law * Specific deterrence, focussed on an individual * Specific finding, intermediate verdict used by a jury in determining the fina ...
formulations are also available including for
hepatitis B Hepatitis B is an infectious disease caused by the '' Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. ...
,
rabies Rabies is a viral disease that causes encephalitis in humans and other mammals. Early symptoms can include fever and tingling at the site of exposure. These symptoms are followed by one or more of the following symptoms: nausea, vomiting, vi ...
,
tetanus Tetanus, also known as lockjaw, is a bacterial infection caused by ''Clostridium tetani'', and is characterized by muscle spasms. In the most common type, the spasms begin in the jaw and then progress to the rest of the body. Each spasm usually ...
, varicella infection, and Rh positive blood exposure.


Medical uses

Immunoglobulin therapy is used in a variety of conditions, many of which involve decreased or abolished antibody production capabilities, which range from a complete absence of multiple types of antibodies, to IgG subclass deficiencies (usually involving IgG2 or IgG3), to other disorders in which antibodies are within a normal quantitative range, but lacking in quality – unable to respond to antigens as they normally should – resulting in an increased rate or increased severity of infections. In these situations, immunoglobulin infusions confer passive resistance to infection on their recipients by increasing the quantity/quality of
IgG Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
they possess. Immunoglobulin therapy is also used for a number of other conditions, including in many autoimmune disorders such as
dermatomyositis Dermatomyositis (DM) is a long-term inflammatory disorder which affects skin and the muscles. Its symptoms are generally a skin rash and worsening muscle weakness over time. These may occur suddenly or develop over months. Other symptoms may inc ...
in an attempt to decrease the severity of symptoms. Immunoglobulin therapy is also used in some treatment protocols for secondary immunodeficiencies such as
human immunodeficiency virus The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immun ...
(HIV), some autoimmune disorders (such as
immune thrombocytopenia Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is a type of thrombocytopenic purpura defined as an isolated low platelet count with a normal bone marrow in the absence of othe ...
and
Kawasaki disease Kawasaki disease is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. It is a form of vasculitis, where blood vessels become inflamed throughout the body. The fever typically lasts for more th ...
), some neurological diseases (
multifocal motor neuropathy Multifocal motor neuropathy (MMN) is a progressively worsening condition where muscles in the extremities gradually weaken. The disorder, a pure motor neuropathy syndrome, is sometimes mistaken for amyotrophic lateral sclerosis (ALS) because of t ...
,
stiff person syndrome Stiff-person syndrome (SPS), also known as stiff-man syndrome (SMS), is a rare neurologic disorder of unclear cause characterized by progressive rigidity and stiffness. The stiffness primarily affects the truncal muscles and is superimposed by s ...
,
multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
and myasthenia gravis) some acute infections and some complications of organ transplantation. Immunoglobulin therapy is especially useful in some acute infection cases such as
pediatric Pediatrics ( also spelled ''paediatrics'' or ''pædiatrics'') is the branch of medicine that involves the medical care of infants, children, adolescents, and young adults. In the United Kingdom, paediatrics covers many of their youth until the ...
HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
infection and is also considered the standard of treatment for some autoimmune disorders such as
Guillain–Barré syndrome Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain oft ...
. The high demand which coupled with the difficulty of producing immunoglobulin in large quantities has resulted in increasing global shortages, usage limitations and rationing of immunoglobulin.


United Kingdom

The United Kingdom's
National Health Service The National Health Service (NHS) is the umbrella term for the publicly funded healthcare systems of the United Kingdom (UK). Since 1948, they have been funded out of general taxation. There are three systems which are referred to using the " ...
recommends the routine use of immunoglobulin for a variety of conditions including primary immunodeficiencies and a number of other conditions, but recommends against the use of immunoglobulin in
sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
(unless a specific toxin has been identified), multiple sclerosis, neonatal sepsis, and pediatric
HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
.


United States

The
American Academy of Allergy, Asthma, and Immunology Founded in 1943, the American Academy of Allergy, Asthma & Immunology (AAAAI) is a professional medical membership organization of nearly 6,800 allergist/ immunologists and related professionals around the world with advanced training and experie ...
supports the use of
immunoglobulin An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
for primary immunodeficiencies, while noting that such usage actually accounts for a minority of usage and acknowledging that immunoglobulin supplementation can be appropriately used for a number of other conditions, including neonatal sepsis (citing a sixfold decrease in mortality), considered in cases of HIV (including pediatric HIV), considered as a second line treatment in relapsing-remitting multiple sclerosis, but recommending against its use in such conditions as chronic fatigue syndrome,
PANDAS Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a controversial hypothetical diagnosis for a subset of children with rapid onset of obsessive-compulsive disorder (OCD) or tic disorders. Sy ...
(pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) until further evidence to support its use is found (though noting that it may be useful in PANDAS patients with an autoimmune component), cystic fibrosis, and a number of other conditions. Brands include * Asceniv (immune globulin intravenous, human – slra) * Bivigam (immune globulin intravenous – human 10% liquid) * Gamunex-C, (immune globulin injection human) * Hizentra (immune globulin subcutaneous human) * Hyqvia (immune globulin 10 percent – human with recombinant human hyaluronidase) * Octagam (immune globulin intravenous, human) * Panzyga (immune globulin intravenous, human – ifas) * Xembify (immune globulin subcutaneous, human – klhw)


Canada

The National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services have also developed their own separate set of guidelines for the appropriate use of immunoglobulin therapy, which strongly support the use of immunoglobulin therapy in primary immunodeficiencies and some complications of HIV, while remaining silent on the issues of sepsis, multiple sclerosis, and chronic fatigue syndrome.


Australia

The Australian Red Cross Blood Service developed their own guidelines for the appropriate use of immunoglobulin therapy in 1997. Immunoglobulin is funded under the National Blood Supply and indications are classified as either an established or emerging therapeutic role or conditions for which immunoglobulin use is in exceptional circumstances only. Subcutaneous immunoglobulin access programs have been developed to facilitate hospital based programs. Human normal immunoglobulin (human immunoglobulin G) (Cutaquig) was approved for medical use in Australia in May 2021.


European Union

Brands include HyQvia (human normal immunoglobulin), Privigen (human normal immunoglobulin (IVIg)), Hizentra (human normal immunoglobulin (SCIg)), Kiovig (human normal immunoglobulin), and Flebogamma DIF (human normal immunoglobulin). In the EU human normal immunoglobulin (SCIg) (Hizentra) is used in people whose blood does not contain enough antibodies (proteins that help the body to fight infections and other diseases), also known as immunoglobulins. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. It is used to treat the following conditions: * primary immunodeficiency syndromes (PID, when people are born with an inability to produce enough antibodies); * low levels of antibodies in the blood in people with chronic lymphocytic leukaemia (a cancer of a type of white blood cell) or myeloma (a cancer of another type of white blood cell) and who have frequent infections; * low levels of antibodies in the blood in people before or after allogeneic haematopoietic stem cell transplantation (a procedure where the patient's bone marrow is cleared of cells and replaced by stem cells from a donor); * chronic inflammatory demyelinating polyneuropathy (CIDP). In this rare disease, the immune system (the body's defence system) works abnormally and destroys the protective covering over the nerves. It is indicated for replacement therapy in adults and children in primary immunodeficiency syndromes such as: * congenital agammaglobulinaemia and hypogammaglobulinaemia (low levels of antibodies); * common variable immunodeficiency; * severe combined immunodeficiency; * immunoglobulin-G-subclass deficiencies with recurrent infections; * replacement therapy in myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections. Flebogamma DIF is indicated for the replacement therapy in adults, children and adolescents (0–18 years) in: * primary immunodeficiency syndromes with impaired antibody production; Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. * hypogammaglobulinaemia (low levels of antibodies) and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (a cancer of a type of white blood cell), in whom prophylactic antibiotics have failed; * hypogammaglobulinaemia (low levels of antibodies) and recurrent bacterial infections in plateau-phase-multiple-myeloma (another cancer of a type of white blood cell) patients who failed to respond to pneumococcal immunisation; * hypogammaglobulinaemia (low levels of antibodies) in patients after allogenic haematopoietic-stem-cell transplantation (HSCT) (when the patient receives stem cells from a matched donor to help restore the bone marrow); * congenital acquired immune deficiency syndrome (AIDS) with recurrent bacterial infections. and for the immunomodulation in adults, children and adolescents (0–18 years) in: * primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count; * Guillain–Barré syndrome, which causes multiple inflammations of the nerves in the body; * Kawasaki disease, which causes multiple inflammation of several organs in the body.


Side effects

Although immunoglobulin is frequently used for long periods of time and is generally considered safe, immunoglobulin therapy can have severe adverse effects, both localized and systemic. Subcutaneous administration of immunoglobulin is associated with a lower risk of both systemic and localized risk when compared to intravenous administration (hyaluronidase-assisted subcutaneous administration is associated with a greater frequency of adverse effects than traditional subcutaneous administration but still a lower frequency of adverse effects when compared to intravenous administration). Patients who are receiving immunoglobulin and experience adverse events are sometimes recommended to take acetaminophen and
diphenhydramine Diphenhydramine (DPH) is an antihistamine and sedative mainly used to treat allergies, insomnia, and symptoms of the common cold. It is also less commonly used for tremor in parkinsonism, and nausea. It is taken by mouth, injected into ...
before their infusions to reduce the rate of adverse effects. Additional premedication may be required in some instances (especially when first getting accustomed to a new dosage),
prednisone Prednisone is a glucocorticoid medication mostly used to suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium due to cancer and ad ...
or another oral steroid. Local side effects of immunoglobulin infusions most frequently include an injection site reaction (reddening of the skin around the injection site), itching, rash, and hives. Less serious systemic side effects to immunoglobulin infusions include an increased heart rate, hyper or hypotension, an increased body temperature, diarrhea, nausea, abdominal pain, vomiting, arthralgia or myalgia, dizziness, headache, fatigue, fever, and pain. Serious side effects of immunoglobulin infusions include chest discomfort or pain,
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
,
tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...
,
hyponatremia Hyponatremia or hyponatraemia is a low concentration of sodium in the blood. It is generally defined as a sodium concentration of less than 135  mmol/L (135  mEq/L), with severe hyponatremia being below 120 mEq/L. Symptoms can be a ...
,
hemolysis Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...
,
hemolytic anemia Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonly ...
,
thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (t ...
,
hepatitis Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pa ...
,
anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
, backache,
aseptic meningitis Aseptic meningitis is the inflammation of the meninges, a membrane covering the brain and spinal cord, in patients whose cerebral spinal fluid test result is negative with routine bacterial cultures. Aseptic meningitis is caused by viruses, my ...
,
acute kidney injury Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both. Causes of AKI are c ...
, hypokalemic
nephropathy Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can b ...
,
pulmonary embolism Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain p ...
, and
transfusion related acute lung injury Transfusion-related acute lung injury (TRALI) is the serious complication of transfusion of blood products that is characterized by the rapid onset of excess fluid in the lungs. It can cause dangerous drops in the supply of oxygen to body tiss ...
. There is also a small chance that even given the precautions taken in preparing immunoglobulin preparations, an immunoglobulin infusion may pass a virus to its recipient. Some immunoglobulin solutions also contain isohemagglutinins, which in rare circumstances can cause hemolysis by the isohemagglutinins triggering phagocytosis. In the case of less serious side effects, a patient's infusion rate can be adjusted downwards until the side effects become tolerable, while in the case of more serious side effects, emergency medical attention should be sought. Immunoglobulin therapy also interferes with the ability of the body to produce a normal immune response to an attenuated live virus vaccine for up to a year, can result in falsely elevated blood glucose levels, and can interfere with many of the IgG-based assays often used to diagnose a patient with a particular infection.


Routes of administration


1950s – intramuscular

After immunoglobulin therapy's discovery and description in ''
Pediatrics Pediatrics ( also spelled ''paediatrics'' or ''pædiatrics'') is the branch of medicine that involves the medical care of infants, children, adolescents, and young adults. In the United Kingdom, paediatrics covers many of their youth until th ...
'' in 1952, weekly
intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...
s of immunoglobulin (IMIg) were the norm until intravenous formulations (IVIg) began to be introduced in the 1980s. During the mid and late 1950s, one-time IMIg injections were a common public health response to outbreaks of
polio Poliomyelitis, commonly shortened to polio, is an infectious disease caused by the poliovirus. Approximately 70% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe s ...
before the widespread availability of vaccines. Intramuscular injections were extremely poorly tolerated due to their extreme pain and poor efficacy – rarely could intramuscular injections alone raise plasma immunoglobulin levels enough to make a clinically meaningful difference.


1980s – intravenous

Intravenous formulations began to be approved in the 1980s, which represented a significant improvement over intramuscular injections, as they allowed for a sufficient amount of immunoglobulin to be injected to reach clinical efficacy, although they still had a fairly high rate of adverse effects (though the addition of stabilizing agents reduced this further).


1990s – subcutaneous

The first description of a subcutaneous route of administration for immunoglobulin therapy dates back to 1980, but for many years subcutaneous administration was considered to be a secondary choice, only to be considered when peripheral venous access was no longer possible or tolerable. During the late 1980s and early 1990s, it became obvious that for at least a subset of patients the systemic adverse events associated with intravenous therapy were still not easily tolerable, and more doctors began to experiment with subcutaneous immunoglobulin administration, culminating in an ''ad hoc'' clinical trial in Sweden of 3000 subcutaneous injections administered to 25 adults (most of whom had previously experienced systemic adverse effects with IMIg or IVIg), where no infusion in the ''ad hoc'' trial resulted in a severe systemic adverse reaction, and most subcutaneous injections were able to be administered in non-hospital settings, allowing for considerably more freedom for the people involved. In the later 1990s, large-scale trials began in Europe to test the feasibility of subcutaneous immunoglobulin administration, although it was not until 2006 that the first subcutaneous-specific preparation of immunoglobulin was approved by a major regulatory agency ( Vivaglobin, which was voluntarily discontinued in 2011). A number of other trade names of subcutaneous immunoglobulin have since been approved, although some small-scale studies have indicated that a particular cohort of patients with common variable immunodeficiency (CVID) may develop intolerable side effects with subcutaneous immunoglobulin (SCIg) that they do not with intravenous immunoglobulin (IVIg). Although intravenous was the preferred route for immunoglobulin therapy for many years, in 2006, the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) approved the first preparation of immunoglobulin that was designed exclusively for subcutaneous use.


Mechanism of action

The precise mechanism by which immunoglobulin therapy suppresses harmful
inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
is likely multifactorial. For example, it has been reported that immunoglobulin therapy can block Fas-mediated cell death. Perhaps a more popular theory is that the immunosuppressive effects of immunoglobulin therapy are mediated through IgG's Fc glycosylation. By binding to receptors on
antigen presenting cells An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
, IVIG can increase the expression of the inhibitory Fc receptor, FcgRIIB, and shorten the half-life of auto-reactive antibodies. The ability of immunoglobulin therapy to suppress pathogenic immune responses by this mechanism is dependent on the presence of a sialylated glycan at position CH2-84.4 of IgG. Specifically, de-sialylated preparations of immunoglobulin lose their therapeutic activity and the anti-inflammatory effects of IVIG can be recapitulated by administration of recombinant sialylated IgG1 Fc. Sialylated-Fc-dependent mechanism was not reproduced in other experimental models suggesting that this mechanism is functional under a particular disease or experimental settings. On the other hand, several other mechanisms of action and the actual primary targets of immunoglobulin therapy have been reported. In particular, F(ab')2-dependent action of immunoglobulin to inhibit activation of human dendritic cells, induction of autophagy, induction of COX-2-dependent PGE-2 in human dendritic cells leading to expansion of regulatory T cells, inhibition of pathogenic Th17 responses, and induction of human basophil activation and IL-4 induction via anti-IgE autoantibodies. Some believe that immunoglobulin therapy may work via a multi-step model where the injected immunoglobulin first forms a type of
immune complex An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen o ...
in the patient. Once these immune complexes are formed, they can interact with Fc receptors on
dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...
, which then mediate anti-inflammatory effects helping to reduce the severity of the autoimmune disease or inflammatory state. Other proposed mechanisms include the possibility that donor antibodies may bind directly with the abnormal host antibodies, stimulating their removal; the possibility that IgG stimulates the host's complement system, leading to enhanced removal of all antibodies, including the harmful ones; and the ability of immunoglobulin to block the antibody receptors on immune cells (
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s), leading to decreased damage by these cells, or regulation of macrophage
phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
. Indeed, it is becoming more clear that immunoglobulin can bind to a number of membrane receptors on
T cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
,
B cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...
, and monocytes that are pertinent to autoreactivity and induction of tolerance to self. A recent report stated that immunoglobulin application to activated
T cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
leads to their decreased ability to engage microglia. As a result of immunoglobulin treatment of T cells, the findings showed reduced levels of
tumor necrosis factor-alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
and
interleukin-10 Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti- inflammatory cytokine. In humans, interleukin 10 is encoded by the ''IL10'' gene. IL-10 signals through a receptor complex consisting of two IL-10 ...
in T cell-microglia co-culture. The results add to the understanding of how immunoglobulin may affect inflammation of the central nervous system in autoimmune inflammatory diseases.


Hyperimmune globulin

Hyperimmune globulins are a class of
immunoglobulin An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
s prepared in a similar way as for ''normal human immunoglobulin'', except that the donor has high titers of
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
against a specific organism or
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...
in their plasma. Some agents against which hyperimmune globulins are available include
hepatitis B Hepatitis B is an infectious disease caused by the '' Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. ...
,
rabies Rabies is a viral disease that causes encephalitis in humans and other mammals. Early symptoms can include fever and tingling at the site of exposure. These symptoms are followed by one or more of the following symptoms: nausea, vomiting, vi ...
,
tetanus Tetanus, also known as lockjaw, is a bacterial infection caused by ''Clostridium tetani'', and is characterized by muscle spasms. In the most common type, the spasms begin in the jaw and then progress to the rest of the body. Each spasm usually ...
toxin,
varicella-zoster Varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3, HHV3) or ''Human alphaherpesvirus 3'' (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting chil ...
, etc. Administration of hyperimmune globulin provides "passive" immunity to the patient against an agent. This is in contrast to
vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...
s that provide "active" immunity. However, vaccines take much longer to achieve that purpose while hyperimmune globulin provides instant "passive" short-lived immunity. Hyperimmune globulin may have serious
side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s, thus usage is taken very seriously. Hyperimmune serum is blood plasma containing high amounts of an antibody. It has been hypothesised that hyperimmune serum may be an effective therapy for persons infected with the
Ebola virus ''Zaire ebolavirus'', more commonly known as Ebola virus (; EBOV), is one of six known species within the genus ''Ebolavirus''. Four of the six known ebolaviruses, including EBOV, cause a severe and often fatal hemorrhagic fever in humans and ot ...
.


Society and culture


Economics

In the United Kingdom a dose cost the
NHS The National Health Service (NHS) is the umbrella term for the publicly funded healthcare systems of the United Kingdom (UK). Since 1948, they have been funded out of general taxation. There are three systems which are referred to using the " ...
between 11.20 and 1,200.00 pounds depending on the type and amount.


Brand names

As biologicals, various trade names of immunoglobulin products are ''not'' necessarily interchangeable, and care must be exercised when changing between them. Trade names of intravenous immunoglobulin formulations include Flebogamma, Gamunex, Privigen, Octagam and Gammagard, while trade names of subcutaneous formulations include Cutaquig, Cuvitru, HyQvia, Hizentra, Gamunex-C, and Gammaked.


Supply issues

The United States is one of a handful of countries that allow plasma donors to be paid, meaning that the US supplies much of the plasma-derived medicinal products (including immunoglobulin) used across the world, including more than 50% of the European Union's supply. The Council of Europe has officially endorsed the idea of not paying for plasma donations for both ethical reasons and reasons of safety, but studies have found that relying on entirely voluntary plasma donation leads to shortages of immunoglobulin and forces member countries to import immunoglobulin from countries that do compensate donors. In Australia, blood donation is voluntary and therefore to cope with increasing demand and to reduce the shortages of locally produced immunoglobulin, several programs have been undertaken including adopting plasma for first time blood donors, better processes for donation, plasma donor centres and encouraging current blood donors to consider plasma only donation.


Research

Experimental results from a small
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
in humans suggested protection against the progression of
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, but no such benefit was found in a subsequent phase III clinical trial. In May 2020, the US approved a phase three clinical trial on the efficacy and safety of high-concentration intravenous immune globulin therapy in severe
COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
.


References


External links

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