Graft-versus-host disease is a life-threatening condition that develops after allogeneic bone marrow transplantation and can lead to severe damage to internal organs. Most often it occurs in patients with immunodeficiency. Recognition of the recipient's antigens by the donor's lymphocytes triggers an immune response, during which the recipient's cells are attacked by the donor's cytotoxic T-lymphocytes. A characteristic manifestation of graft-versus-host disease is severe pancytopenia.

A. Clinical picture. A maculopapular rash is typical on the earlobes, neck, palms, upper chest and back. Ulcers form on the oral mucosa, giving it the appearance of cobblestones; sometimes a white coating resembling lace appears. Fever is typical. In the early stages, hyperbilirubinemia is noted. Pancytopenia persists throughout the disease. In severe cases, profuse bloody diarrhea occurs. Patients die from liver failure, dehydration, metabolic disorders, malabsorption syndrome, blood loss and pancytopenia. Graft versus host disease develops in the following cases.

1. For transfusion of non-irradiated blood components in cases of immunodeficiency, for example, in case of malignant neoplasms (especially lymphogranulomatosis), primary immunodeficiencies and patients after organ transplantation. HIV infection does not increase the risk of graft-versus-host disease.

2. When transfusing non-irradiated blood components compatible with HLA antigens into patients with normal immunity, graft-versus-host disease rarely occurs. However, cases of graft-versus-host disease have been described after transfusion of parents with HLA-matched blood from their children. Apparently, in these cases, graft-versus-host disease is due to the fact that the parents are heterozygous for one of the HLA genes, and their children are homozygous.

3. Transplantation of internal organs. Most often, graft-versus-host disease occurs during liver transplantation, since it contains many lymphocytes. Graft-versus-host disease usually occurs when there is a high degree of similarity between the HLA antigens of the donor and recipient. Graft-versus-host disease rarely occurs in kidney and heart transplants.

4. Allogeneic bone marrow transplantation. Graft-versus-host disease is a common complication of allogeneic bone marrow transplantation. The damage to the internal organs of the recipient during the development of the reaction is similar to the damage to transplanted organs during their rejection. To prevent a reaction, cyclosporine, methotrexate and corticosteroids are prescribed. Despite prevention, the prevalence of mild graft-versus-host disease is about 30-40%, and moderate to severe disease is 10-20%. Graft-versus-host disease during allogeneic bone marrow transplantation is less often accompanied by suppression of hematopoiesis than during transplantation of other organs.

B. Diagnostics. Diagnosis is based on history and physical examination. Biopsy of the skin, liver, oral mucosa and gastrointestinal tract reveals lymphocytic infiltrates. In the gastrointestinal mucosa, a pattern of apoptosis is often observed. However, a diagnosis of graft-versus-host disease cannot be made based on biopsy data. Bone marrow examination reveals aplasia (unless the reaction is caused by a bone marrow transplant). If it is possible to obtain a sufficient number of lymphocytes from the lymphocytic infiltrate to determine HLA antigens, it is discovered that they are of donor origin and similar to the recipient's lymphocytes in HLA antigens. This confirms the diagnosis.

B. Prevention and treatment. Risk factors include chemotherapy and radiation therapy for malignant neoplasms, primary immunodeficiencies, previous organ transplantation, transfusion of blood components from close relatives, intrauterine transfusion of blood components. In the presence of risk factors, only irradiated red blood cells (30 Gy) are transfused to prevent graft-versus-host disease. Transfusions of blood components from siblings to immunocompromised patients should be avoided. If such a transfusion cannot be avoided, the blood components are irradiated. Treatment of graft-versus-host disease is ineffective; in most cases it ends in death: 84% of patients die within the first 3 weeks of the disease.

1. Antithymocyte and antilymphocyte immunoglobulins are ineffective in graft-versus-host disease caused by transfusion of blood components.

2. When carrying out immunosuppressive therapy to prevent graft-versus-host disease caused by internal organ transplantation, the following difficulties arise.

A. The use of corticosteroids, cytostatics, antilymphocyte immunoglobulin, muromonab-CD3 to suppress donor lymphocytes against the background of immunosuppression caused by graft-versus-host disease increases the risk of opportunistic infections.

B. The weakening of immunosuppression necessary for the rejection of donor lymphocytes can lead to rejection of the transplanted organ.

3. Graft-versus-host disease that occurs within the first 100 days after allogeneic bone marrow transplantation is treated with high doses of corticosteroids. If they are ineffective, antithymocyte immunoglobulin or muromonab-CD3 is prescribed. Chronic graft-versus-host disease, which develops no earlier than 100 days after transplantation, is treated with a combination of corticosteroids, azathioprine and cyclosporine. Over time, as the recipient develops immunological tolerance to the donor's antigens, graft-versus-host disease may spontaneously cease. In some cases it may even be useful. Thus, in patients with leukemia who develop graft-versus-host disease after allogeneic bone marrow transplantation, relapses are less likely to occur.

Tissue incompatibility reaction (graft versus host disease)

Graft-versus-host disease, or tissue incompatibility disease, develops when allogeneic mature T lymphocytes are transplanted into a recipient with a deficient immune system that is unable to fight foreign tissue and cause a rejection reaction (host-versus-graft disease). In such cases, the transplanted cells recognize the “host” (recipient) as foreign tissue and graft-versus-host disease begins. This reaction is observed in 10-80% of recipients with allogeneic bone marrow transplantation (depending on the degree of tissue incompatibility, the number of T-lymphocytes in the transplanted tissues, the age of the recipient and preventive measures). Graft-versus-host disease, although rare, does occur in organ transplants, especially the liver and small intestine, due to the large number of lymphocytes in these organs. As a rule, the target organs for the development of graft-versus-host disease are the immune system, skin, liver and small intestine of the recipient. The importance of early detection of graft-versus-host disease in patients with abdominal pain is that such cases do not require surgical intervention until severe complications such as intestinal perforation develop.

Acute graft-versus-host disease usually develops within the first two months after transplantation. First of all, the skin is affected. An itchy maculopapular rash appears, mainly on the skin of the palms, soles and ears. Erythroderma (redness and peeling) of the skin of the entire body gradually develops. Symptoms associated with damage to the gastrointestinal tract and liver appear later. Such patients gradually develop lack of appetite, vomiting, abdominal pain and bloating. Plain radiographs of the abdomen reveal signs of paralytic ileus. The liver is usually painless on palpation of the abdomen, but a biochemical blood test reveals hyperbilirubinemia, increased levels of alkaline phosphatase and aminotransferases. The recipient's immune system is "attacked" by foreign T-lymphocytes of the transplant, which leads to the development of a state of severe immunodeficiency, which is enhanced by the action of immunosuppressive drugs used to treat graft-versus-host disease. Such patients become susceptible to many opportunistic (opportunistic) infections, which can further complicate the course of the disease.

Chronic graft-versus-host disease usually develops later than two months after allogeneic bone marrow transplantation and can be either a continuation of an acute reaction or occur for the first time. In this case, the main clinical manifestations of the disease are skin lesions, cholestatic liver diseases and an immunodeficiency state. The gastrointestinal tract is rarely affected, with the exception of the development of dysphagia due to severe dry mouth (the so-called dry mucous membrane syndrome, or Sjögren's syndrome) and severe inflammation of the esophageal mucosa.

Finally, isologous, or syngeneic, graft-versus-host disease has been described in recipients who have undergone autologous bone marrow transplantation. This reaction is a form of autoimmune disease, tends to be self-limiting and manifests itself primarily as skin lesions. If such patients develop symptoms of gastrointestinal disease, they are usually manifestations of complications of the underlying disease, chemotherapy, or the development of opportunistic (opportunistic) infections.

Graft-versus-host disease is a complex multisystem lesion, in the mechanism of which both specific and nonspecific disorders play a role.

Classification

There are two forms of the disease:

• acute, which is usually observed between the 1st and 3rd weeks after transplantation, but can develop at a later date up to the end of the 3rd month. This form is observed in 25-50% of patients;
• chronic, which develops after 3 months and is observed in 40-50% of patients.

Main clinical manifestations

Damage to the oral mucosa is possible in both acute and chronic forms of the disease and is observed in 50-80% of cases. In the chronic form it is observed more often. In some patients it may be the only manifestation of the disease.

Damage to the oral mucosa

Acute form

• Diffuse erythema and painful lesions.
• Bleeding, xerostomia.
• Lichenoid lesions.
• Viral, bacterial and fungal infection.

Chronic form

• Diffuse lichenoid lesions.
• Multiple painful ulcers.
• Possible development of superficial mucous cysts, pyogenic granuloma and warty xanthoma
• Fibrosis and restriction of mouth opening.
• Viral, bacterial and fungal infection often develops.

Defeat of another localization

Acute form

• Fever with an increase in body temperature to high levels.
• Liver failure, gastrointestinal disorders.
• Generalized erythematous maculopapular rash.
• Sometimes the formation of blisters and detachment of the epidermis is possible.
• Infection.

Chronic form

• Damage to the liver, lungs, gastrointestinal tract, conjunctiva.
• Damage to the musculoskeletal system.
• Skin lesions resembling lichen planus.
• Skin lesions resembling systemic scleroderma.
• Skin hyperpigmentation.
• Severe infections.

Diagnosis

The diagnosis is mainly based on the history and clinical picture. If necessary, a biopsy and histological examination of the labial salivary glands and mucous membrane are performed.

Differential diagnosis

• Drug-induced stomatitis.
• Lichen planus.
• Systemic scleroderma.
• Polymorphous exudative erythema.
• Sjögren's syndrome.
• Pemphigus.
• Pemphigoid.
• Neutropenic mucositis.
• Radiation musosite.

Treatment

Basic principles

• Before undergoing a bone marrow transplant, patients should consult a dentist to check the condition of the teeth and the quality of the denture.
• The oral cavity should be scanned, loose and broken teeth removed, and sharp protruding edges of the dental filling should be ground down.
• An optimal oral care regimen for the patient is established.
• You should refrain from rinsing your mouth with solutions containing alcohol and flavorings due to the risk of increasing symptoms of the lesion.
• It is advisable to carefully remove plaque from the back of the tongue with a soft brush.
• When treating lesions of the oral mucosa after bone marrow transplantation, close cooperation between the dentist and the transplantologist is necessary.
• The main role in the treatment of graft-versus-host disease belongs to the transplantologist.

Standard treatment

• For rinsing the mouth, we can recommend a 0.9% solution of sodium chloride, as well as solutions of sodium bicarbonate and hydrogen peroxide.
• Some improvement is noted with the use of local anesthetics, such as 2% lidocaine or benzocaine.
• When ulcers form, local use of corticosteroids (ointments, elixirs, gels) is effective.
• Patients with xerostomia are recommended to use artificial saliva and are prescribed systemic agents that stimulate salivation.
• For severe ulcerative lesions and a chronic form of the disease, systemic corticosteroid therapy is indicated, which is carried out together with a specialist. If the patient is already receiving corticosteroids, then their dose is increased.
• Measures are needed to prevent and treat oral infections (viral, bacterial, fungal).
• Drugs prescribed prophylactically to prevent graft-versus-host disease include cyclosporine, tacrolimus, methotrexate, azathioprine, mycophenolate mofetil, and corticosteroids.

Graft-versus-host disease is a life-threatening condition that develops after allogeneic bone marrow transplantation and can lead to severe damage to internal organs. Most often it occurs in patients with immunodeficiency. Recognition of the recipient's antigens by the donor's lymphocytes triggers an immune response, during which the recipient's cells are attacked by the donor's cytotoxic T-lymphocytes. A characteristic manifestation of graft-versus-host disease is severe pancytopenia.

A. Clinical picture. A maculopapular rash is typical on the earlobes, neck, palms, upper chest and back. Ulcers form on the oral mucosa, giving it the appearance of cobblestones; sometimes a white coating resembling lace appears. Fever is typical. In the early stages, hyperbilirubinemia is noted. Pancytopenia persists throughout the disease. In severe cases, profuse bloody diarrhea occurs. Patients die from liver failure, dehydration, metabolic disorders, malabsorption syndrome, blood loss and pancytopenia. Graft versus host disease develops in the following cases.

1. When transfusing non-irradiated blood components in cases of immunodeficiency, for example, malignant neoplasms (especially lymphogranulomatosis), primary immunodeficiencies and patients after organ transplantation. HIV infection does not increase the risk of graft-versus-host disease.

2. When transfusing non-irradiated HLA-matched blood components into patients with normal immunity, graft-versus-host disease rarely occurs. However, cases of graft-versus-host disease have been described after transfusion of parents with HLA-matched blood from their children. Apparently, in these cases, graft-versus-host disease is due to the fact that the parents are heterozygous for one of the HLA genes, and their children are homozygous.

3. Transplantation of internal organs. Most often, graft-versus-host disease occurs during liver transplantation, since it contains many lymphocytes. Graft-versus-host disease usually occurs when there is a high degree of similarity between the HLA antigens of the donor and recipient. Graft-versus-host disease rarely occurs in kidney and heart transplants.

4. Allogeneic bone marrow transplantation. Graft-versus-host disease is a common complication of allogeneic bone marrow transplantation. The damage to the internal organs of the recipient during the development of the reaction is similar to the damage to transplanted organs during their rejection. To prevent a reaction, cyclosporine, methotrexate and corticosteroids are prescribed. Despite prophylaxis, the prevalence of mild graft-versus-host disease is about 30-40%, and moderate to severe disease is 10-20%. Graft-versus-host disease during allogeneic bone marrow transplantation is less often accompanied by suppression of hematopoiesis than during transplantation of other organs.

B. Diagnostics. Diagnosis is based on history and physical examination. Biopsy of the skin, liver, oral mucosa and gastrointestinal tract reveals lymphocytic infiltrates. In the gastrointestinal mucosa, a pattern of apoptosis is often observed. However, a diagnosis of graft-versus-host disease cannot be made based on biopsy data. Bone marrow examination reveals aplasia (unless the reaction is caused by a bone marrow transplant). If it is possible to obtain a sufficient number of lymphocytes from the lymphocytic infiltrate to determine HLA antigens, it is discovered that they are of donor origin and similar to the recipient's lymphocytes in HLA antigens. This confirms the diagnosis.

IN. Prevention and treatment. Risk factors include chemotherapy and radiation therapy for malignant neoplasms, primary immunodeficiencies, previous organ transplantation, transfusion of blood components from close relatives, intrauterine transfusion of blood components. In the presence of risk factors, only irradiated red blood cells (30 Gy) are transfused to prevent graft-versus-host disease. Transfusions of blood components from siblings to immunocompromised patients should be avoided. If such a transfusion cannot be avoided, the blood components are irradiated. Treatment of graft-versus-host disease is ineffective; in most cases it ends in death: 84% of patients die within the first 3 weeks of the disease.

1. Antithymocyte And antilymphocyte immunoglobulins for graft-versus-host disease caused by transfusion of blood components, they are ineffective.

2. When carrying out immunosuppressive therapy to prevent graft-versus-host disease caused by internal organ transplantation, the following difficulties arise.

A. The use of corticosteroids, cytostatics, antilymphocyte immunoglobulin, muromonab-CD3 to suppress donor lymphocytes against the background of immunosuppression caused by graft-versus-host disease increases the risk of opportunistic infections.

b. The weakening of immunosuppression necessary for the rejection of donor lymphocytes can lead to rejection of the transplanted organ.

3. Graft-versus-host disease, which occurs within the first 100 days after allogeneic bone marrow transplantation, is treated with high doses of corticosteroids. If they are ineffective, antithymocyte immunoglobulin or muromonab-CD3 is prescribed. Chronic graft-versus-host disease, which develops no earlier than 100 days after transplantation, is treated with a combination of corticosteroids, azathioprine and cyclosporine. Over time, as the recipient develops immunological tolerance to the donor's antigens, graft-versus-host disease may spontaneously cease. In some cases it may even be useful. Thus, in patients with leukemia who develop graft-versus-host disease after allogeneic bone marrow transplantation, relapses are less likely to occur.

Can donated material cause death? Why does graft versus host disease occur?

Graft-versus-host disease (GVHD) is a complication that occurs after a stem cell or bone marrow transplant as a result of the transplanted material attacking the recipient's body.

Reasons

The bone marrow produces various blood cells, including lymphocytes, which carry out the immune response. Normally, stem cells are found in the bone marrow.
Since only identical twins have exactly identical tissue types, the donor's bone marrow does not completely match the recipient's tissue. It is this difference that causes the donor's T-lymphocytes (a type of white blood cell) to perceive the recipient's body as foreign and attack it.

The acute form of GVHD usually develops within the first three months after surgery, while the chronic reaction occurs later and can last throughout the patient's life.

The risk of GVHD when receiving a transplant from a related donor is 30-40%; with an unrelated transplant it increases to 60-80%. The lower the compatibility index between donor and recipient, the higher the latter's risk of developing GVHD. After surgery, the patient is forced to take drugs that suppress the immune system: this helps reduce the chances of the disease occurring and reduce its severity.

Symptoms

Symptoms of acute and chronic GVHD vary in severity. In the acute form of GVHD the following are observed:

Abdominal pain and cramps
. Diarrhea
. Temperature rise
. Jaundice
. Skin rash
. Vomit
. Weight loss

In the chronic form of GVHD, the following symptoms are noted:

Dry eyes and xerostomia (dry mouth)
. Alopecia (baldness)
. Hepatitis
. Damage to the lungs and gastrointestinal tract
. Skin rash
. Thickening of the skin.

Diagnostics

Depending on the symptoms, the following tests and examinations are prescribed:

Gastrointestinal endoscopy (with or without biopsy)
. Liver function tests (AST, ALP and bilirubin levels will be elevated)
. Liver biopsy (if liver symptoms are present)
. X-ray of the lungs
. Skin biopsy

Treatment

Treatment for GVHD is aimed at suppressing the immune response without damaging the transplanted cells. Drugs used for this include methotrexate, cyclosporine, tacrolimus, sirolimus, antithymocyte immunoglobulin and alemtuzumab, alone or in combination.

In the acute form of the disease, the greatest effect is observed from the use of high doses of corticosteroids. If there is no response to steroids, anti-T-lymphocyte antibody drugs and other medications are prescribed.

Prednisolone (a steroid) alone or in combination with cyclosporine is used to treat chronic GVHD. Other drugs may also be available, such as mycophenolate mofetil (Cellcept), sirolimus (Rapamycin), and tacrolimus (Prograf).

Forecast

How the disease develops depends on its severity. In severe cases, death is possible.

In many cases, graft-versus-host disease can be successfully treated, although serious adverse reactions to treatment are possible.

Successful treatment of transplant rejection does not guarantee cure of the underlying disease.

Possible complications

Cholestasis
. Fatal outcome
. Damage to the liver, lungs or gastrointestinal tract
. Severe infection
. Severe pulmonary diseases

When to Seek Medical Help

You should contact your doctor immediately if you experience the following symptoms after a stem cell or bone marrow transplant:

Diarrhea
. Difficulty breathing
. Skin rash
. Stomach cramps
. Yellowing of the skin and whites of the eyes (jaundice)

Prevention

Histotyping and careful selection of a donor, who, if possible, is chosen from blood relatives, helps reduce the likelihood of developing GVHD. However, there is no absolute guarantee of preventing this complication.

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