Graft-versus-host disease (GVHD) can be an unintentional consequence of blood transfusion or transplantation in severely immunocompromised or immunosuppressed patients. The degree of immunodeficiency in the host, rather than the number of transfused immunocompetent lymphocytes, determines whether GVHD will occur.
Etiology
When immunocompetent T lymphocytes are transfused from a donor to an immunodeficient or immunosuppressed recipient, the transfused or grafted lymphocytes recognize that the antigens of the host are foreign and react immunologically against them (Table 1). Instead of the usual transplantation reaction of host against graft, the reverse graft-versus-host reaction occurs and produces an inflammatory response.
Table1. Requirements for Potential Graft-versus-Host Disease
In a normal lymphocyte transfer reaction, the results of a GVHD are usually not serious because the recipient is capable of destroying the foreign lymphocytes. However, engraftment and multiplication of donor lymphocytes in an immunosuppressed recipient are a real possibility because lymphocytes capable of mitosis can be found in stored blood products. If the recipient cannot reject the transfused lymphocytes, the grafted lymphocytes may cause uncontrolled destruction of the host’s tissues and eventually death. A patient can develop chronic or acute GVHD. The stronger the antigen difference, the more severe is the reaction.
Epidemiology
It is now accepted that GVHD can occur whenever immunologically competent allogeneic lymphocytes are transfused into a severely immunocompromised host. Patients at risk include those who are immunodeficient or immunosuppressed with severe lymphocytopenia and bone marrow suppression. Despite chemotherapy at the time of bone marrow transplantation, patients are highly likely to develop acute GVHD and some of these immunocompromised patients will die of GVHD or associated infections.
Chronic GVHD affects 20% to 40% of patients within 6 months after transplantation. Two factors closely associated with the development of chronic GVHD are increasing age and a preceding episode of acute GVHD.
Cases of transfusion-related GVHD have increased significantly in the past 2 decades. This reaction has been reported subsequent to blood transfusion in bone marrow transplant recipients after total-body irradiation and in adults receiving intensive chemotherapy for hematologic malignancies. GVHD has also occurred in infants with severe congenital immunodeficiency and in those who received intrauterine transfusions followed by exchange transfusion. Almost 90% of patients with posttransfusion GVHD will die of acute complications of the disease. The usual cause of death is generalized infection.
Signs and Symptoms
GVHD causes an inflammatory response. Posttransfusion symptoms begin within 3 to 30 days after transfusion. Because of lymphocytic infiltration of the intestine, skin, and liver, mucosal destruction results, including ulcerative skin and mouth lesions, diarrhea, and liver destruction. Other clinical symptoms include jaundice, fever, anemia, weight loss, skin rash, and splenomegaly.
In bone marrow transplant patients, acute GVHD develops within the first 3 months of transplantation. The initial manifestations are lesions of the skin, liver, and gastrointestinal tract. An erythematous maculopapular skin rash, particularly on the palms and soles, is usually the first sign of GVHD. Disease progression is characterized by diarrhea, often with abdominal pain, and liver disease. Other signs and symptoms of complications related to therapy include fever, granulocytopenia, and bacteremia. Interstitial pneumonia, frequently associated with cytomegalovirus (CMV), can also occur.
Chronic GVHD resembles a collagen vascular disease, with skin changes such as erythema and cutaneous ulcers, and a liver dysfunction characterized by bile duct degeneration and cholestasis. Patients with chronic GVHD are susceptible to bacterial infections. For example, increasing age and preexisting lung disease increase the incidence of interstitial pneumonia.
Immunologic Manifestation
In immunocompromised patients, the transfused or grafted lymphocytes recognize the antigens of the host as foreign and react immunologically against them. Instead of the usual trans plantation reaction of host against graft, the reverse GVHD occurs.
Diagnostic Evaluation
Laboratory evidence of immunosuppression or immunodeficiency, such as a decreased total lymphocyte concentration, suggests that a patient may develop GVHD. Evidence of inflammation, such as an increased C-reactive protein (CRP) level, elevated leukocyte count with granulocytosis, and increased erythrocyte sedimentation rate (ESR), may suggest that GVHD has developed in GVHD candidates. Complications of anemia and liver disease, characterized by increased levels of bilirubin and blood enzymes (e.g., transaminases, alkaline phosphatase), and the presence of opportunistic pathogens (e.g., CMV) can further support the diagnosis.
Pathologic features include lymphocytic and monocytic infiltration into perivascular spaces in the dermis and dermo epidermal junction of the skin and into the epithelium of the oropharynx, tongue, and esophagus. Infiltration can also be observed into the base of the intestinal crypts of the small and large bowels and into the periportal area of the liver, with secondary necrosis of cells in infiltrated tissues.
Prevention
The incidence of GVHD can be minimized by depletion of mature lymphocytes from the marrow by using monoclonal antibodies or physical methods. The risk of GVHD can be minimized, if not eliminated, by irradiation of the marrow transplant or blood products. Blood product irradiation is believed to be the most efficient and probably the most economical method available for the prevention of posttransfusion GVHD.
No cases of posttransfusion GVHD have been reported after the administration of irradiated blood products irradiated with an effective and appropriate radiation dose. Several categories of patients possess the clinical indications for the use of irradiated products.
High-Risk Patients
Patients at the highest risk with an absolute need for irradiated blood products include the following:
• Recipients of autologous or allogeneic bone marrow grafts. Recipients of autologous bone marrow may be expected to have the same risk of posttransfusion GVHD as patients receiving allogeneic bone marrow.
• Children with severe congenital immunodeficiency syndromes involving T lymphocytes. The degree of immunodeficiency in the host, rather than the number of transfused immunocompetent cells, determines whether GVHD will occur.
Intermediate-Risk Patients
Patients considered to be at a lower risk of developing GVHD include the following:
• Infants receiving intrauterine transfusions, followed by exchange transfusions, and possibly infants receiving only exchange transfusions. The immune mechanism of the fetus and newborn may not be sufficiently mature to reject foreign lymphocytes and prior transfusions may induce a state of immune tolerance in the newborn. Transfused lymphocytes may continue to circulate for a prolonged period in some immunologically tolerant hosts without the development of GVHD. There is insufficient evidence to recommend irradiation of blood given to all premature infants.
• Patients receiving total-body radiation or immunosuppressive therapy for disorders such as lymphoma and acute leukemia. Although routine irradiation of blood products given to these patients can be justified, it cannot be regarded as absolutely indicated because the risk of developing GVHD is so low. Blood product irradiation, however, is advised for selected patients with hematologic malignancies, especially when transfusions are given during or near the time of sustained and severe therapy-induced immunosuppression.
Low-Risk Patients
Patients also at risk but considered the least susceptible include the following:
• Patients with solid tumors. The incidence of the development of GVHD in these patients is difficult to determine. However, it has developed in nonhematologic malignancies such as neuroblastoma. In one case, GVHD developed after infusion of a single unit of packed red blood cells (RBCs).
• Patients with aplastic anemia receiving antithymocyte globulin theoretically may be at increased risk of posttransfusion GVHD during therapy-induced periods of lymphocytopenia.
• Although a theoretical risk of posttransfusion GVHD may exist in patients with acquired immunodeficiency syndrome (AIDS), the disease has not actually been observed in this disorder. The routine use of irradiated blood is not recommended.
Effects of Radiation on Specific Cellular Components
Lymphocytes. Ionizing radiation is known to inhibit lymphocyte mitotic activity and blast transformation. Irradiation of normal donor lymphocytes with 1500 rad from a cesium-137 source results in a 90% reduction in mitogen-stimulated 14C-thymidine incorporation. An 85% reduction in mitogen induced blast transformation after exposure to 1500 rad and a 97% to 98.5% reduction in mitogenic response have been noted after an appropriate exposure to radiation.
Granulocytes. Ionizing radiation may impair granulocyte function in a dose-dependent manner. The degree of actual damage to granulocytes is controversial. Chemotactic activity decreased linearly with increasing doses of irradiation from 500 to 120,000 rad, but the reduction only reached statistical significance at 10,000 rad. A linear dose-response curve demonstrates that granulocyte locomotion is affected by very small doses of irradiation. An appropriate dose of radiation is likely to eliminate lymphocytic mitotic activity and prevent GVHD without causing significant damage to granulocytes or altering their chemotactic or bactericidal ability. Irradiation before transfusion has been demonstrated to contribute to defective oxidative metabolism, but this effect is highly variable.
Mature Red Blood Cells. Mature RBCs appear to be highly resistant to radiation damage. After RBCs were exposed to 10,000 rad, 52Cr-labeled in vivo RBC survival was the same as that of untreated controls. Stored erythrocytes can be treated with up to 20,000 rad without changing their viability or in vitro properties, including adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) levels, plasma hemoglobin (Hb), and potassium ions (K+).
Platelets. Ionizing radiation may impair platelet function. Although this impairment is dose-dependent, the effects of irradiation on platelets have been difficult to characterize. Several studies have demonstrated unchanged in vivo platelet survival after exposure to 5000 to 75,000 rad. A 33% decrease in the expected platelet count increase was noted after transfusion of platelets exposed to 5000 rad, and similarly irradiated autologous platelets had a diminished ability to correct the bleeding times in a small number of volunteers who had consumed aspirin.
Immunologic Tolerance
The importance of tolerance to self antigens was recognized early in the study of immunology. Immunologic tolerance is the acquisition of nonreactivity toward particular antigens. Self-recognition (tolerance) is a critical process, and the failure to recognize self antigens can result in autoimmune disease.
Various pathways to immunologic tolerance have been recognized. It has been suggested that T and B cells are affected independently and differently and may be tolerated under certain circumstances. Several mechanisms may operate simultaneously in a single host. During fetal development of the immune system and during the first few weeks of neonatal life, none of the cells of the immune system has reached maturity. For this reason, the entire immune system is particularly susceptible to tolerance induction at this stage of development.
T Cell Tolerance
T cells do not show a marked difference in tolerance at different stages of maturation. The antigen required to produce tolerance and the circumstance of its presentation are specific for each individual T cell subset. At least three pathways have been recognized for T cell tolerance:
1. Clonal abortion. Immature T cell clones may be aborted in a manner similar to that of B cells.
2. Functional deletion. The subsets of a mature T cell may be individually deleted, leading to the loss of only one of the functions of the T cell group.
3. T cell suppression. T cell suppressors actively suppress the actions of other T cell subsets or B cells.
B Cell Tolerance
As a B cell matures, it becomes less susceptible to tolerization. In addition, during B cell maturation, the forms of antigen presentation that will produce tolerance also vary. Four pathways have been established for the induction of B cell tolerance. Therefore, the mode of tolerance depends on the maturity of the cell, antigen, and manner of antigen presentation to the immune system. The pathways of B cell tolerance are as follows:
1. Clonal abortion. A low concentration of multivalent antigen may cause the immature clone to abort. Tolerance of immature B cells by this mechanism is high.
2. Clonal exhaustion. Repeated antigen challenge with a T-independent antigen may remove all mature functional B cell clones. Tolerance of mature B cells is moderate.
3. Functional deletion. The combined absence of the helper T subset and presence of T-dependent antigen (or with T suppressor cells), or an excess of T-independent antigen, prevents mature B cells from functioning normally. The ability to tolerize B cells by this mechanism is moderate.
4. Antibody-forming cell blockade. An excess of T independent antigen interferes with the secretion of antibody by antibody-forming cells. B cell tolerance by this mechanism is low.
Immune Response Gene–Associated Antigens
The specific immune responses to a variety of antigenic sub stances are now known to be regulated by an immune response (Ir) gene. Ir gene control is considered genetically dominant. T he homology of the HLA-D region with the animal I region suggests that the human Ir gene might be linked to the HLA complex. Evidence for the existence of the Ir gene has been obtained from family and population studies. Additional evidence for the presence of Ir genes comes from HLA-linked disease susceptibility genes and HLA-disease associations. It is believed that individuals who lack this gene are unresponsive.
The generally accepted concept is that the Ir gene is responsible for the interaction of T cells with B cells and macrophages, which are necessary for T cell activation. Activation of T cells is required for the following:
• Conversion to active helper function
• Production of lymphokines
Mediation of delayed and contact hypersensitivity, as the proliferative response to antigen, depends on the interaction of a T cell with an APC, usually macrophage-monocytes. Helper function also depends on T cell interaction with precursors of antibody-secreting cells. T cells interact with these cells by recognizing specific antigen bound to macrophages or to B cells and the I region gene products expressed on the surface of these cells. T cells are able to recognize the precise details of antigen structure and distinguish between two closely related Ir gene–associated molecules expressed on the surface of these APCs or on the B cell.
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