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 atransplant 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 ablood transfusion, known asTransfusion-associated graft-versus-host disease orTA-GvHD if theblood products used have not beengamma irradiated or treated with an approvedleukocyte 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]
Micrographs of grades of skin graft-versus-host disease: Ranging from grade I GvHR (with minimal vacuolization in the epidermis) to grade II GvHR (with vacuolization and dyskeratotic bodies) to grade III GvHR (with sub epidermal cleft formation) and finally to grade IV GvHR (with separation of the dermis from the epidermis)[2]
In the clinical setting, graft-versus-host disease is divided intoacute andchronic 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 theliver,skin (rash),mucosa, and thegastrointestinal tract. Newer research indicates that other graft-versus-host disease target organs include the immune system (thehematopoietic system, e.g., thebone marrow and thethymus) itself, and thelungs in the form of immune-mediatedpneumonitis.[5] Biomarkers can be used to identify specific causes of GvHD, such aselafin 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 theconnective tissue andexocrine glands.[7]
Mucosal damage to thevagina can result in severepain andscarring, and appears in both acute and chronic GvHD. This can result in an inability to havesexual intercourse.[8]
Theacute orfulminant 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 ofallogeneic transplant recipients will develop acute GvHD.[10] It is less common in younger patients and in those with closerhuman 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 theGI 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 diffuseredmaculopapular 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]
Thechronic 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]
Decreased appetite
Diarrhea
Abdominal cramps
Weight loss
Yellowing of the skin and eyes (jaundice)
Enlarged liver
Bloated abdomen
Pain in the upper right part of the abdomen
Increased levels of liver enzymes in the blood (seen on blood tests)
Skin that feels tight
Dry, burning eyes
Dryness or painful sores in the mouth
Burning sensations when eating acidic foods
Bacterial infections
Blockages in the smaller airways of the lungs
In theoral cavity, chronic graft-versus-host disease manifests aslichen planus with a higher risk ofmalignant transformation to oralsquamous 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]
Animmuno-competent graft is administered, with viable and functional immune cells.
The recipient is immunologically different from the donor –histo-incompatible.
The recipient isimmunocompromised and therefore cannot destroy or inactivate the transplanted cells. In particular, it involves an inability of the recipient'scell-mediated immunity to destroy or inactivate viablelymphocytes from the donor.[19]
After bone marrow transplantation,T cells present in thegraft, either as contaminants or intentionally introduced into the host, attack thetissues of the transplant recipient after perceiving host tissues as antigenically foreign. The T cells produce an excess ofcytokines, includingTNF-α andinterferon-gamma (IFNγ). A wide range of hostantigens can initiate graft-versus-host disease, among them thehuman 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 differentproteins (calledminor histocompatibility antigens) that can be presented bymajor 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 areHLA-DR (first six months),HLA-B (first two years), andHLA-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 residualimmune system from rejecting the bone marrow graft (host-versus-graft). In addition, as bone marrow transplantation is frequently used to treatcancer, mainlyleukemias, donor T-cells have proven to have a valuable graft-versus-tumor effect.[24] A great deal of current research onallogeneic bone marrow transplantation involves attempts to separate the undesirable graft-vs-host disease aspects of T-cell physiology from the desirablegraft-versus-tumor effect.[25]
This type of GvHD is associated withtransfusion of un-irradiated blood to immunocompromised recipients. It can also occur in situations in which the blood donor ishomozygous and the recipient isheterozygous for anHLAhaplotype. 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'sthymocytes would use the donor thymus cells as models when going through thenegative 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 inxenotransplantation 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, completeDiGeorge syndrome, increases the risk of autoimmune disease.[29]
A GvHD-like disease calledthymoma-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 efferent phase: activation, proliferation, differentiation and migration of effector cells
The effector phase: target tissue destruction
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 asIL-1 andTNF-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]
DNA-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.[34]
The T-cells of umbilical cord blood (UCB) have an inherent immunological immaturity,[35] and the use of UCB stem cells in unrelated donor transplants has a reduced incidence and severity of GvHD.[36]
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,[39] and generalimmunodeficiency, resulting in a patient more susceptible toviral,bacterial, andfungalinfection. In a multi-center study, disease-free survival at three years was not different between T cell-depleted and T cell-replete transplants.[40]
Intravenously administeredglucocorticoids, such asprednisone, 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]
Cyclosporine andtacrolimus arecalcineurin 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]
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 arephotobiomodulation for GVHD-related oral mucosal ulcers, and electrostimulation for GVHD-relatedxerostomia.[48]
There are a large number of clinical trials either ongoing or recently completed in the investigation of graft-versus-host disease treatment and prevention.[49]
On 17 May 2012, Osiris Therapeutics announced that Canadian health regulators approvedProchymal, its drug for acute graft-versus-host disease in children who have failed to respond to steroid treatment. Prochymal is the firststem cell drug to be approved for a systemic disease.[50]
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.[51] The trial was of a mesenchymal stem cell therapy known asremestemcel-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.[51]
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^Tsukada S, Itonaga H, Taguchi J, Miyoshi T, Hayashida S, Sato S, et al. (2019). "[Gingival squamous cell carcinoma diagnosed on the occasion of osteonecrosis of the jaw in a patient with chronic GVHD]".[Rinsho Ketsueki] the Japanese Journal of Clinical Hematology.60 (1):22–27.doi:10.11406/rinketsu.60.22.PMID30726819.{{cite journal}}: CS1 maint: overridden setting (link)
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^Bonifazi F, Solano C, Wolschke C, Sessa M, Patriarca F, Zallio F, et al. (February 2019). "Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study".The Lancet. Haematology.6 (2):e89–e99.doi:10.1016/S2352-3026(18)30214-X.hdl:10138/311714.PMID30709437.S2CID73449161.{{cite journal}}: CS1 maint: overridden setting (link)
^Wadhera A, Maverakis E, Mitsiades N, Lara PN, Fung MA, Lynch PJ (October 2007). "Thymoma-associated multiorgan autoimmunity: a graft-versus-host-like disease".Journal of the American Academy of Dermatology.57 (4):683–9.doi:10.1016/j.jaad.2007.02.027.PMID17433850.
^Roncarolo MG, Battaglia M (August 2007). "Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans".Nature Reviews. Immunology.7 (8):585–98.doi:10.1038/nri2138.PMID17653126.S2CID7043844.
^Hale G, Waldmann H (May 1994). "Control of graft-versus-host disease and graft rejection by T cell depletion of donor and recipient with Campath-1 antibodies. Results of matched sibling transplants for malignant diseases".Bone Marrow Transplantation.13 (5):597–611.PMID8054913.
^Wagner JE, Thompson JS, Carter SL, Kernan NA (2005). "Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II-III trial".Lancet.366 (9487):733–41.doi:10.1016/S0140-6736(05)66996-6.PMID16125590.S2CID33732870.
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