Graft-versus-host disease | |
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Mouse colon impacted by acute graft-versus-host disease | |
Specialty | Emergency medicine ![]() |
Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.
White blood cells of the donor's immune system which remain within the donated tissue (the graft) recognize the recipient (the host) as foreign (non-self). The white blood cells present within the transplanted tissue then attack the recipient's body's cells, which leads to GvHD. This should not be confused with a transplant rejection, which occurs when the immune system of the transplant recipient rejects the transplanted tissue; GvHD occurs when the donor's immune system's white blood cells reject the recipient. The underlying principle (alloimmunity) is the same, but the details and course may differ.
GvHD can also occur after a blood transfusion, known as Transfusion-associated graft-versus-host disease or TA-GvHD if the blood products used have not been gamma irradiated or treated with an approved leukocyte reduction system. In contrast to organ/tissue transplant associated GvHD, the incidence of TA-GvHD is increased with HLA matching (first-degree or close relatives). [1]
In the clinical setting, graft-versus-host disease is divided into acute and chronic forms, and scored or graded on the basis of the tissue affected and the severity of the reaction. [3] [4]
In the classical sense, acute graft-versus-host disease is characterized by selective damage to the liver, skin (rash), 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 lungs in the form of immune-mediated pneumonitis. [5] Biomarkers can be used to identify specific causes of GvHD, such as elafin in the skin. [6] 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. [7]
Mucosal damage to the vagina can result in severe pain and scarring, and appears in both acute and chronic GvHD. This can result in an inability to have sexual intercourse. [8]
The acute or fulminant form of the disease (aGvHD) is normally observed within the first 10 to 100 days post-transplant, [9] [10] and is a major challenge to transplants owing to associated morbidity and mortality. [11] About one-third to one-half of allogeneic transplant recipients will develop acute GvHD. [10] It is less common in younger patients and in those with closer human leukocyte antigens (HLA) matches between donor and the patient. [10]
The first signs are usually a rash, burning, and redness of the skin on the palms and soles. This can spread over the entire body. Other symptoms can include nausea, vomiting, stomach cramps, diarrhea (watery and sometimes bloody), loss of appetite, jaundice, abdominal pain, and weight loss. [10]
Acute GvHD of the GI tract can result in severe intestinal inflammation, sloughing of the mucosal membrane, severe diarrhea, abdominal pain, nausea, and vomiting. [12] This is typically diagnosed via intestinal biopsy. Liver GvHD is measured by the bilirubin level in acute patients. [13] Skin GvHD results in a diffuse red maculopapular rash, [14] sometimes in a lacy pattern.
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 [12] as a result of the immunosuppression and may die of infection. However, a 2016 study found that the prognosis for patients with grade IV GvHD has improved in recent years. [15]
The chronic form of graft-versus-host disease (cGvHD) normally begins 90 to 600 days post-transplant. [10] The appearance of moderate to severe cases of cGVHD adversely influences long-term survival. [16]
The first symptom of cGvHD is commonly a rash on the palms of the hands or the soles of the feet, and the rash can spread and is usually itchy and dry. In severe cases, the skin may blister and peel, like a bad sunburn. A fever may also develop. Other symptoms of chronic GVHD can include: [10]
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 [17] in comparison to the classical oral lichen planus. Oral cancer associated with graft-versus-host disease may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-hematopoietic stem cell transplantation patients. [15]
Three criteria, known as the Billingham criteria, must be met in order for GvHD to occur. [18]
After bone marrow transplantation, T cells 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 cytokines, 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 (HLA). [20] However, graft-versus-host disease can occur even when HLA-identical siblings are the donors. [21] HLA-identical siblings or HLA-identical unrelated donors often have genetically different proteins (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. [22]
Antigens most responsible for graft loss are HLA-DR (first six months), HLA-B (first two years), and HLA-A (long-term survival). [23]
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 leukemias, donor T-cells have proven to have a valuable graft-versus-tumor effect. [24] 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. [25]
This type of GvHD is associated with transfusion 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. [26]
Thymus transplantation may be said to be able to cause a special type of GvHD because the recipient's thymocytes 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. [27] Autoimmune disease is a frequent complication after human allogeneic thymus transplantation, found in 42% of subjects over one year post-transplantation. [28] However, this is partially explained by the fact that the indication itself, that is, complete DiGeorge syndrome, increases the risk of autoimmune disease. [29]
A GvHD-like disease called thymoma-associated multiorgan autoimmunity (TAMA) can occur in patients with thymoma. In these patients rather than a donor being a source of pathogenic T cells, the patient's own malignant thymus produces self-directed T cells. This is because the malignant thymus is incapable of appropriately educating developing thymocytes to eliminate self-reactive T cells. The result is a disease virtually indistinguishable from GvHD. [30]
The pathophysiology of GvHD includes three phases: [31]
Activation of APC occurs in the first stage of GvHD. Prior to haematopoietic stem cell transplantation, radiation or chemotherapy results in damage and activation of host tissues, especially intestinal mucosa. This allows the microbial products to enter and stimulate pro-inflammatory cytokines such as IL-1 and TNF-α. These proinflammatory cytokines increase the expression of MHC and adhesion molecules on APCs, thereby increasing the ability of APC to present antigen. [32] The second phase is characterized by the activation of effector cells. Activation of donor T-cells further enhances the expression of MHC and adhesion molecules, chemokines and the expansion of CD8 + and CD4 + T-cells and guest B-cells. In the final phase, these effector cells migrate to target organs and mediate tissue damage, resulting in multiorgan failure. [33]
Intravenously administered glucocorticoids, such as prednisone, are the standard of care in acute GvHD [11] and chronic GVHD. [41] The use of these glucocorticoids 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.[ citation needed ].While glucocorticoids remain the first line of treatment for acute GVHD, only about 50% of patients respond to treatment, otherwise having steroid-refractory GVHD (SR-GVHD). [42] An increasing number of recent treatment options for SR-GVHD have been investigated, such as extracorporeal photopheresis (ECP), mesenchymal stem cell (MSCs), fecal microbial transplantation (FMT), and the medication Ruxolitinib. [42]
Cyclosporine and tacrolimus are calcineurin inhibitors. The substances are structurally different but have the same mechanism of action. Cyclosporine binds to the cytosolic protein peptidyl-prolyl cis-trans isomerase A (known as cyclophilin), while tacrolimus binds to the cytosolic protein peptidyl-prolyl cis-trans isomerase FKBP12. These complexes inhibit calcineurin, block dephosphorylation of the transcription factor NFAT of activated T-cells and its translocation into the nucleus. [43] Standard prophylaxis involves the use of cyclosporine for six months with methotrexate. Cyclosporin levels should be maintained above 200 ng/ml. [44]
Other substances that have been studied for GvHD treatment include, for example: sirolimus, pentostatin, etanercept, and alemtuzumab. [44]
In August 2017, the US FDA approved ibrutinib to treat chronic GvHD after failure of one or more other systemic treatments. [45]
Given the complex systemic condition and immunosuppression of the chronic GVHD patients, non-drug therapies, are a significant advancement, and may be preferred whenever possible. Examples are photobiomodulation for GVHD-related oral mucosal ulcers, and electrostimulation for GVHD-related xerostomia. [46]
There are a large number of clinical trials either ongoing or recently completed in the investigation of graft-versus-host disease treatment and prevention. [47]
On May 17, 2012, Osiris Therapeutics announced that Canadian health regulators approved Prochymal, its drug for acute graft-versus-host disease in children who have failed to respond to steroid treatment. Prochymal is the first stem cell drug to be approved for a systemic disease. [48]
In January 2016, Mesoblast released results of a phase 2 clinical trial on 241 children with acute Graft-versus-host disease, that was not responsive to steroids. [49] The trial was of a mesenchymal stem cell therapy known as remestemcel-L or MSC-100-IV. Survival rate was 82% (vs 39% of controls) for those who showed some improvement after one month, and in the long term 72% (vs 18% of controls) for those that showed little effect after one month. [49]
Graft-versus-host disease has been implicated in eliminating several cases of HIV, including The Berlin Patient and six others in Spain. [50]
Aplastic anemia (AA) is a severe hematologic condition in which the body fails to make blood cells in sufficient numbers. Aplastic anemia is associated with cancer and various cancer syndromes. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood cells, white blood cells, and platelets.
Transplant 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.
Anti-thymocyte globulin (ATG) is an infusion of horse or rabbit-derived antibodies against human T cells and their precursors (thymocytes), which is used in the prevention and treatment of acute rejection in organ transplantation and therapy of aplastic anemia due to bone marrow insufficiency.
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce additional normal blood cells. HSCT may be autologous, syngeneic, or allogeneic.
Cell therapy is a therapy in which viable cells are injected, grafted or implanted into a patient in order to effectuate a medicinal effect, for example, by transplanting T-cells capable of fighting cancer cells via cell-mediated immunity in the course of immunotherapy, or grafting stem cells to regenerate diseased tissues.
X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.
Transfusion-associated graft-versus-host disease (TA-GvHD) is a rare complication of blood transfusion, in which the immunologically competent donor T lymphocytes mount an immune response against the recipient's lymphoid tissue. These donor lymphocytes engraft, recognize recipient cells as foreign and mount an immune response against recipient tissues. Donor lymphocytes are usually identified as foreign and destroyed by the recipient's immune system. However, in situations where the recipient is severely immunocompromised, or when the donor and recipient HLA type is similar, the recipient's immune system is not able to destroy the donor lymphocytes. This can result in transfusion associated graft-versus-host disease. This is in contrast with organ/tissue transplant associated GvHD, where matching HLA reduces the incident of the complication.
Minor histocompatibility antigen are peptides presented on the cellular surface of donated organs that are known to give an immunological response in some organ transplants. They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides. These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules's antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities' proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.
Juvenile myelomonocytic leukemia (JMML) is a rare form of chronic leukemia that affects children, commonly those aged four and younger. The name JMML now encompasses all diagnoses formerly referred to as juvenile chronic myeloid leukemia (JCML), chronic myelomonocytic leukemia of infancy, and infantile monosomy 7 syndrome. The average age of patients at diagnosis is two (2) years old. The World Health Organization has included JMML as a subcategory of myelodysplastic and myeloproliferative disorders.
Donor lymphocyte infusion (DLI) or buffy coat infusion is a form of adoptive immunotherapy used after hematopoietic stem cell transplantation.
Transplantable organs and tissues may refer to both organs and tissues that are relatively often transplanted, as well as organs and tissues which are relatively seldom transplanted. In addition to this it may also refer to possible-transplants which are still in the experimental stage.
Thymus transplantation is a form of organ transplantation where the thymus is moved from one body to another. It is used in certain immunodeficiencies, such as DiGeorge Syndrome.
TK is an experimental cell therapy which may be used to treat high-risk leukemia. It is currently undergoing a Phase III clinical trial to determine efficacy and clinical usefulness.
Graft-versus-tumor effect (GvT) appears after allogeneic hematopoietic stem cell transplantation (HSCT). The graft contains donor T cells that can be beneficial for the recipient by eliminating residual malignant cells. GvT might develop after recognizing tumor-specific or recipient-specific alloantigens. It could lead to remission or immune control of hematologic malignancies. This effect applies in myeloma and lymphoid leukemias, lymphoma, multiple myeloma and possibly breast cancer. It is closely linked with graft-versus-host disease (GvHD), as the underlying principle of alloimmunity is the same. CD4+CD25+ regulatory T cells (Treg) can be used to suppress GvHD without loss of beneficial GvT effect. The biology of GvT response is still not fully understood but it is probable that the reaction with polymorphic minor histocompatibility antigens expressed either specifically on hematopoietic cells or more widely on a number of tissue cells or tumor-associated antigens is involved. This response is mediated largely by cytotoxic T lymphocytes (CTL) but it can be employed by natural killers as separate effectors, particularly in T-cell-depleted HLA-haploidentical HSCT.
Microtransplantation (MST) is an advanced technology to treat malignant hematological diseases and tumors by infusing patients with granulocyte colony-stimulating factor (G-CSF) mobilized human leukocyte antigen (HLA)-mismatched allogeneic peripheral blood stem cells following a reduced-intensity chemotherapy or targeted therapy. The term "microtransplantation" comes from its mechanism of reaching donor cell microchimerism.
Guo Mei is a hematologist and associate director of 307th Hospital of Chinese People’s Liberation Army and deputy director of Radiation Research Institute.
T-cell depletion (TCD) is the process of T cell removal or reduction, which alters the immune system and its responses. Depletion can occur naturally or be induced for treatment purposes. TCD can reduce the risk of graft-versus-host disease (GVHD), which is a common issue in transplants. The idea that TCD of the allograft can eliminate GVHD was first introduced in 1958. In humans the first TCD was performed in severe combined immunodeficiency patients.
Belumosudil, sold under the brand name Rezurock among others, is a medication used for the treatment of chronic graft versus host disease (cGvHD). It is in the class of drugs known as serine/threonine kinase inhibitors. Specifically, it is an inhibitor of Rho-associated coiled-coil kinase 2. Belumosudil binds to and inhibits the serine/threonine kinase activity of ROCK2. This inhibits ROCK2-mediated signaling pathways which play major roles in pro- and anti-inflammatory immune cell responses. A genomic study in human primary cells demonstrated that the drug also has effects on oxidative phosphorylation, WNT signaling, angiogenesis, and KRAS signaling.
In the immune system, veto cells are white blood cells that have a selective immunomodulation properties. Veto cells were first described in 1979 as cells that “can prevent generation of cytotoxic lymphocytes by normal spleen cells against self-antigens”. Hence, veto cells delete T cells that recognize the veto cells.
Shimon Slavin is an Israeli professor of medicine. He pioneered immunotherapy mediated by allogeneic donor lymphocytes and innovative methods for stem cell transplantation to cure hematological malignancies and solid tumors. He also used hematopoietic stem cells to induce transplantation tolerance to bone marrow and organ allografts.
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