Graft-versus-host disease
Encyclopedia
Graft-versus-host disease (GVHD) is a common complication
after a stem cell transplant or bone marrow transplant from another person (an allogeneic transplant). Immune cells (white blood cells) in the donated marrow or stem cells (the graft) recognize the recipient (the host) as "foreign". The transplanted immune cells then attack the host's body cells. Graft versus host disease can also take place during a blood transfusion
under certain circumstances.
After bone marrow transplantation, T cell
s present in the graft
, either as contaminants or intentionally introduced into the host, attack the tissues
of the transplant recipient after perceiving host tissues as antigenically foreign. The T cells produce an excess of cytokine
s, including TNF-α and interferon-gamma
(IFNγ). A wide range of host antigens can initiate graft-versus-host-disease, among them the human leukocyte antigens (HLAs). However, graft-versus-host disease can occur even when HLA-identical siblings are the donors. HLA-identical siblings or HLA-identical unrelated donors often have genetically different protein
s (called minor histocompatibility antigens) that can be presented by Major histocompatibility complex
(MHC) molecules to the donor's T-cells, which see these antigens as foreign and so mount an immune response.
While donor T-cells are undesirable as effector cells of graft-versus-host-disease, they are valuable for engraftment by preventing the recipient's residual immune system
from rejecting the bone marrow graft (host-versus-graft). In addition, as bone marrow transplantation is frequently used to treat cancer
, mainly leukemia
s, donor T-cells have proven to have a valuable graft-versus-tumor
effect. A great deal of current research on allogeneic bone marrow transplantation involves attempts to separate the undesirable graft-vs-host-disease aspects of T-cell physiology from the desirable graft-versus-tumor effect.
forms.
This distinction is not arbitrary: Acute and chronic graft-versus-host-disease appear to involve different immune cell subsets, different cytokine
profiles, somewhat different host targets, and respond differently to treatment.
, skin
(rash), and mucosa, and the gastrointestinal tract
. Newer research indicates that other graft-versus-host-disease target organs include the immune system (the hematopoietic system
, e.g., the bone marrow
and the thymus
) itself, and the lung
s in the form of idiopathic pneumonitis
. Chronic graft-versus-host-disease also attacks the above organs, but over its long-term course can also cause damage to the connective tissue
and exocrine glands.
Acute GVHD of the GI tract can result in severe intestinal inflammation, sloughing of the mucosal membrane, severe diarrhea, abdominal pain, nausea, and vomiting. This is typically diagnosed via intestinal biopsy. Liver GVHD is measured by the bilirubin level in acute patients. Skin GVHD results in a diffuse maculopapular rash, sometimes in a lacy pattern.
It appears in both acute and chronic GVHD, mucosal damage to the vagina
can result in severe pain
and scarring. This can result in an inability to have sexual intercourse
.
Acute GVHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GVHD usually have a poor prognosis. If the GVHD is severe and requires intense immunosuppression involving steroids and additional agents to get under control, the patient may develop severe infections as a result of the immunosuppression and may die of infection.
In the oral cavity, chronic graft-versus-host-disease manifests as lichen planus with a higher risk of malignant transformation
to oral squamous cell carcinoma
in comparison to the classical oral lichen planus. Graft-versus-host-disease-associated oral cancer
may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-hematopoietic stem cell transplantation patients.
of un-irradiated blood to immunocompromised recipients. It can also occur in situations in which the blood donor is homozygous and the recipient is heterozygous for an HLA
haplotype
. It is associated with higher mortality (80-90%) due to involvement of bone marrow lymphoid tissue, however the clinical manifestations are similar to GVHD resulting from bone marrow transplantation. Transfusion-associated GVHD is rare in modern medicine. It is almost entirely preventable by controlled irradiation of blood products to inactivate the white blood cells (including lymphocytes) within.
may be said to be able to cause a special type of GVHD because the recipients thymocyte
s would use the donor thymus cells as models when going through the negative selection
to recognize self-antigens, and could therefore still mistake own structures in the rest of the body for being non-self. This is a rather indirect GVHD because it is not directly cells in the graft itself that causes it but cells in the graft that make the recipient's T cells act like donor T cells. It can be seen as a multiple-organ autoimmunity in xenotransplantation
experiments of the thymus between different species. Autoimmune disease is a frequent complication after human allogeneic thymus transplantation, found in 42% of subjects over 1 year post transplantation. However, this is partially explained by the fact that the indication itself, that is, complete DiGeorge syndrome
, increases the risk of autoimmune disease.
, are the standard of care in acute GVHD and chronic GVHD. The use of these corticosteroids is designed to suppress the T-cell-mediated immune onslaught on the host tissues; however, in high doses, this immune-suppression raises the risk of infections and cancer relapse. Therefore, it is desirable to taper off the post-transplant high-level steroid doses to lower levels, at which point the appearance of mild GVHD may be welcome, especially in HLA mis-matched patients, as it is typically associated with a graft-versus-tumor effect.
The use of irradiated blood components prevent GVHD. The irradiation of blood eliminates the proliferative capacity of lymphocytes present in red cell, platelet and freshly collected plasma components. The penetrated photons of radiation beam into blood components cause the formation of electrically charged particles or secondary electrons. These electrons damage the DNA of lymphocytes either by direct interaction or by reacting initicially with cell water to form free radicals. The damaged lymphocytes are unable to proliferate in the host and therefore cannot mediate transfusion-associated GVHD.
Complication (medicine)
Complication, in medicine, is an unfavorable evolution of a disease, a health condition or a medical treatment. The disease can become worse in its severity or show a higher number of signs, symptoms or new pathological changes, become widespread throughout the body or affect other organ systems. A...
after a stem cell transplant or bone marrow transplant from another person (an allogeneic transplant). Immune cells (white blood cells) in the donated marrow or stem cells (the graft) recognize the recipient (the host) as "foreign". The transplanted immune cells then attack the host's body cells. Graft versus host disease can also take place during a blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
under certain circumstances.
Causes
According to the 1966 Billingham Criteria, 3 criteria must be met in order for GVHD to occur.- An immuno-competent graft is administered, with viable and functional immune cells.
- The recipient is immunologically disparate - histo-incompatible.
- The recipient is immuno-compromised and therefore cannot destroy or inactivate the transplanted cells.
After bone marrow transplantation, T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s present in the graft
Medical grafting
Grafting refers to a surgical procedure to move tissue from one site to another on the body, or from another person, without bringing its own blood supply with it. Instead, a new blood supply grows in after it is placed. A similar technique where tissue is transferred with the blood supply intact...
, either as contaminants or intentionally introduced into the host, attack the tissues
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
of the transplant recipient after perceiving host tissues as antigenically foreign. The T cells produce an excess of cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s, including TNF-α and interferon-gamma
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
(IFNγ). A wide range of host antigens can initiate graft-versus-host-disease, among them the human leukocyte antigens (HLAs). However, graft-versus-host disease can occur even when HLA-identical siblings are the donors. HLA-identical siblings or HLA-identical unrelated donors often have genetically different protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s (called minor histocompatibility antigens) that can be presented by Major histocompatibility complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
(MHC) molecules to the donor's T-cells, which see these antigens as foreign and so mount an immune response.
While donor T-cells are undesirable as effector cells of graft-versus-host-disease, they are valuable for engraftment by preventing the recipient's residual immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
from rejecting the bone marrow graft (host-versus-graft). In addition, as bone marrow transplantation is frequently used to treat cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, mainly leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
s, donor T-cells have proven to have a valuable graft-versus-tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
effect. A great deal of current research on allogeneic bone marrow transplantation involves attempts to separate the undesirable graft-vs-host-disease aspects of T-cell physiology from the desirable graft-versus-tumor effect.
Types
In the clinical setting, graft-versus-host-disease is divided into acute and chronicChronic (medicine)
A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature. The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS.In medicine, the...
forms.
- The acute or fulminant form of the disease (aGVHD) is normally observed within the first 100 days post-transplant, and is a major challenge to transplants owing to associated morbidity and mortality.
- The chronic form of graft-versus-host-disease (cGVHD) normally occurs after 100 days. The appearance of moderate to severe cases of cGVHD adversely influences long-term survival.
This distinction is not arbitrary: Acute and chronic graft-versus-host-disease appear to involve different immune cell subsets, different cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
profiles, somewhat different host targets, and respond differently to treatment.
Clinical manifestation
In the classical sense, acute graft-versus-host-disease is characterized by selective damage to the liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
(rash), and mucosa, and the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
. Newer research indicates that other graft-versus-host-disease target organs include the immune system (the hematopoietic system
Haematopoiesis
Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells...
, e.g., the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
and the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
) itself, and the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s in the form of idiopathic pneumonitis
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
. Chronic graft-versus-host-disease also attacks the above organs, but over its long-term course can also cause damage to the connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...
and exocrine glands.
Acute GVHD of the GI tract can result in severe intestinal inflammation, sloughing of the mucosal membrane, severe diarrhea, abdominal pain, nausea, and vomiting. This is typically diagnosed via intestinal biopsy. Liver GVHD is measured by the bilirubin level in acute patients. Skin GVHD results in a diffuse maculopapular rash, sometimes in a lacy pattern.
It appears in both acute and chronic GVHD, mucosal damage to the vagina
Vagina
The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...
can result in severe pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
and scarring. This can result in an inability to have sexual intercourse
Sexual intercourse
Sexual intercourse, also known as copulation or coitus, commonly refers to the act in which a male's penis enters a female's vagina for the purposes of sexual pleasure or reproduction. The entities may be of opposite sexes, or they may be hermaphroditic, as is the case with snails...
.
Acute GVHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GVHD usually have a poor prognosis. If the GVHD is severe and requires intense immunosuppression involving steroids and additional agents to get under control, the patient may develop severe infections as a result of the immunosuppression and may die of infection.
In the oral cavity, chronic graft-versus-host-disease manifests as lichen planus with a higher risk of malignant transformation
Malignant transformation
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor....
to oral squamous cell carcinoma
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
in comparison to the classical oral lichen planus. Graft-versus-host-disease-associated oral cancer
Oral cancer
Oral cancer is a subtype of head and neck cancer, is any cancerous tissue growth located in the oral cavity. It may arise as a primary lesion originating in any of the oral tissues, by metastasis from a distant site of origin, or by extension from a neighboring anatomic structure, such as the...
may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-hematopoietic stem cell transplantation patients.
Transfusion-associated GVHD
This type of GVHD is associated with transfusionBlood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
of un-irradiated blood to immunocompromised recipients. It can also occur in situations in which the blood donor is homozygous and the recipient is heterozygous for an HLA
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
haplotype
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
. It is associated with higher mortality (80-90%) due to involvement of bone marrow lymphoid tissue, however the clinical manifestations are similar to GVHD resulting from bone marrow transplantation. Transfusion-associated GVHD is rare in modern medicine. It is almost entirely preventable by controlled irradiation of blood products to inactivate the white blood cells (including lymphocytes) within.
In thymus transplantation
Thymus transplantationThymus transplantation
Thymus transplantation is a form of organ transplantation where the thymus is moved from one body to another.-Indication:Thymus transplantation can be used to treat infants with DiGeorge syndrome, which results in an absent or hypoplastic thymus, in turn causing problems with the immune system's...
may be said to be able to cause a special type of GVHD because the recipients thymocyte
Thymocyte
Thymocytes are hematopoietic progenitor cells present in the thymus. Thymopoiesis is the process in the thymus by which thymocytes differentiate into mature T lymphocytes. The primary function of thymocytes is the generation of T lymphocytes . The thymus provides an inductive environment, which...
s would use the donor thymus cells as models when going through the negative selection
Negative selection
Negative selection may refer to:*Negative selection , in natural selection it refers to the selective removal of rare alleles that are deleterious...
to recognize self-antigens, and could therefore still mistake own structures in the rest of the body for being non-self. This is a rather indirect GVHD because it is not directly cells in the graft itself that causes it but cells in the graft that make the recipient's T cells act like donor T cells. It can be seen as a multiple-organ autoimmunity in xenotransplantation
Xenotransplantation
Xenotransplantation , is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenografts or xenotransplants...
experiments of the thymus between different species. Autoimmune disease is a frequent complication after human allogeneic thymus transplantation, found in 42% of subjects over 1 year post transplantation. However, this is partially explained by the fact that the indication itself, that is, complete DiGeorge syndrome
DiGeorge syndrome
22q11.2 deletion syndrome, which has several presentations including DiGeorge syndrome , DiGeorge anomaly, velo-cardio-facial syndrome, Shprintzen syndrome, conotruncal anomaly face syndrome, Strong syndrome, congenital thymic aplasia, and thymic hypoplasia is a syndrome caused by the deletion of a...
, increases the risk of autoimmune disease.
Prevention
- DNADNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
-based tissue typing allows for more precise HLA matching between donors and transplant patients, which has been proven to reduce the incidence and severity of GVHD and to increase long-term survival. - The T-cells of umbilical cord blood (UCB) have an inherent immunological immaturity, and the use of UCB stem cells in unrelated donor transplants has a reduced incidence and severity of GVHD.
- MethotrexateMethotrexateMethotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
, ciclosporinCiclosporinCiclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
and tacrolimusTacrolimusTacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
are common drugs used for GVHD prophylaxis. - Graft-versus-host-disease can largely be avoided by performing a T-cell-depleted bone marrow transplant. However, these types of transplants come at a cost of diminished graft-versus-tumor effect, greater risk of engraftment failure, or cancer relapse, and general immunodeficiencyImmunodeficiencyImmunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
, resulting in a patient more susceptible to viralVirusA virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
, bacterial, and fungalFungusA fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
infectionInfectionAn infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
. In a multi-center study, disease-free survival at 3 years was not different between T cell-depleted and T cell-replete transplants.
Treatment of GVHD
Intravenously administered corticosteroids, such as prednisonePrednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
, are the standard of care in acute GVHD and chronic GVHD. The use of these corticosteroids is designed to suppress the T-cell-mediated immune onslaught on the host tissues; however, in high doses, this immune-suppression raises the risk of infections and cancer relapse. Therefore, it is desirable to taper off the post-transplant high-level steroid doses to lower levels, at which point the appearance of mild GVHD may be welcome, especially in HLA mis-matched patients, as it is typically associated with a graft-versus-tumor effect.
The use of irradiated blood components prevent GVHD. The irradiation of blood eliminates the proliferative capacity of lymphocytes present in red cell, platelet and freshly collected plasma components. The penetrated photons of radiation beam into blood components cause the formation of electrically charged particles or secondary electrons. These electrons damage the DNA of lymphocytes either by direct interaction or by reacting initicially with cell water to form free radicals. The damaged lymphocytes are unable to proliferate in the host and therefore cannot mediate transfusion-associated GVHD.
Investigational therapies for graft-versus-host disease
There are a large number of clinical trials either ongoing or recently completed in the investigation of graft-versus-host disease treatment and prevention.See also
- Organ transplantOrgan transplantOrgan transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
- Transplant rejectionTransplant rejectionTransplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
- Transplant rejection
- ImmunologyImmunologyImmunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
- ImmunosuppressionImmunosuppressionImmunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
- Immunosuppression
- CancerCancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
Further reading
- Ferrara JLM, Deeg HJ, Burakoff SJSteven J. BurakoffSteven J. Burakoff, MD, is a cancer specialist and the author of both Therepeutic Immunology and Graft-Vs.-Host Disease: Immunology, Pathophysiology, and Treatment .-Biography:...
. Graft-Vs.-Host Disease: Immunology, Pathophysiology, and Treatment. Marcel Dekker, 1990 ISBN 0-8247-9728-0 - Polsdorfer, JR Gale Encyclopedia of Medicine: Graft-vs.-host disease