Mismatched organ transplantation results in rejection that is mediated by T lymphocytes. What would happen if the T-lymphocytes cells were transplanted into an HLA-incompatible host? If the transplanted T-lymphocytes survive they are capable mounting an immune response against the host tissue. This is known as graft vs. host disease (GVHD) and is characterized by widespread tissue damage. Immune competent cells are transplanted under two circumstances, when cellular blood products are transfused and in patients receiving allogeneic stem cells. GVHD associated with transfusions (TA-GVHD) is a rare but almost fatal disease.
Incidence
The exact incidence of TA-GVHD is unknown but the disease is very rare. The annual incidence has been difficult to estimate but probably is in the low double figure. Irradiation of blood products and discontinuation of the practice of directed donation has reduced the incidence to almost zero indicating the preventable nature of disease. It is important to be aware about the disease as the number of predisposed patients is on the rise.
Products Causing TA-GVHD
All blood products stored unfrozen can cause GVHD. Fresh plasma has caused TA-GVHD. The process of freezing destroys T-lymphocytes. Fresh Frozen plasma and thawed erythrocytes are not associated with TA-GVHD.
Pathogenesis
GVHD can occur after transfusion as little as 4 X 103 T-lymphocytes/kg. The average number of leucocytes cellular blood products is as follows; red blood cells 2 X 109, random donor platelets 4 X 107 and apheresis platelets 1 X 108. Patients receiving transfusion of a cellular product are exposed to a dose of T lymphocytes capable of causing GVHD. The risk of TA-GVHD appears to be higher with the use of fresh blood. It is presumed that the number of lymphocytes and the number decreases with storage. The ability to eliminate HLA-incompatible T lymphocytes protects patients from development of TA-GVHD. The immunological mechanisms to eliminate non-HLA incompatible T lymphocytes must be exceedingly efficient because though almost every patient receiving blood products is exposed to a dose of lymphocytes capable of causing TA-GVHD, the disease remains rare even if precautions are not taken. TA-GVHD occurs when the host’s ability to eliminate transfused T lymphocytes is compromised. This may happen when there is T cell dysfunction and when the transfused lymphocytes evade the immune surveillance.
T cell dysfunction may be under the following circumstances:
- Severe congenital T cell immunodeficiencies immunodeficiencies
- Neonates and infants: Most cases of TA-GVHD have been reported in neonates who have undergone intrauterine transfusion. Infants who have undergone exchange transfusion are also at risk. In both these conditions the allogeneic cells have been shown to persist (6-8 weeks in case of exchange transfusion and 2-4 years in case of in utero transfusion). Maternal lymphocytes regularly cross over into foetal circulation but the foetus can eliminate these lymphocytes. In mixed lymphocyte cultures of foetal and maternal cells, foetal lymphocytes dominate. The protection is specific to the maternal lymphocytes and not other adult lymphocytes making the neonates prone to TA-GVHD
- Lymphomas: Virtually all the cases of TA-GVHD associated with lymphomas have been associated with Hodgkin’s lymphoma. The stage or treatment modality does not change the risk. Hodgkin’s lymphoma, unlike non-Hodgkin lymphoma, is associated with T cell dysfunction.
- Therapy induced T cell dysfunction: Purine analogues: Cladribine, deoxycoformycin and fludarabine cause a profound long lasting depletion of CD4 positive lymphocytes. The effects of bendamustine, clofarabine are less clear. Alemtuzumab and antithymocyte globulin (horse and rabbit) appear to carry a risk of TA-GVHD.
The most common cause of profound T cell deficiency, AIDS is for some reasons not associated with TA-GVHD.
Homology between donor and recipient HLAs appears to allow the transfused T lymphocyte to escape immunesurveillance and initiate TA-GVHD. HLA homology may be found in close blood relatives and in communities that are relatively homogenous for HLA. Transfusions from a family member increase the risk of TA-GVHD as patents are likely to share HLA epitopes with the host. The incidence of TA-GVHD in Japan, which has limited HAL-hetrogenity, is about 10-20 times higher Caucasians.
Manifestations
The median period between transfusion and onset of symptoms is 10 days but the may be as long as 4 weeks. Fever is usually the first manifestation and is soon followed, maculopapular skin rash, diarrhea and hepatitis. Pancytopenia differentiates TA-GVHD from GVHD following allogeneic stem cell transplant. Pancytopenia is seen in virtually every patient with TA-GVHD but is rare in GVHD associated with allogeneic stem cell transplant. The aim of allogeneic stem cell transplant is haematological reconstitution either for a failing marrow or following a high dose of chemotherapy. The transfused T-lymphocytes and the haemopoietic stem cells are HLA-identical. This spares the haemopoietic stem cells from attack by T lymphocytes and pancytopenia is rare. Unlike patients of GVHD, the haemopoietic stem cells ofpatients with TA-GVHD have an HLA type distinct from the transfused lymphocytes. This makes them susceptible to T-lymphocyte mediated cytotoxicity resulting in pancytopenia.
Diagnosis
TA-GVHD is diagnosed on clinical grounds. Donor lymphocytes may be detected in the blood.
Treatment
TA-GVHD has a very high mortality. The principles of treatment are the same as those of allogeneic stem cell transplant induced GVHD. Immunosuppressive therapies including high-dose steroids, azathioprine, methotrexate, cyclosporine and intravenous immunoglobulin have been used. Spontaneous remissions have been reported. The few successful cases included haploidentical transplant from the mother in an infant of X-linked severe combined immunodeficiency, infusion of patient lymphocytes and the use of anti-CD3 therapy with cyclosporine.
Prevention
TA-GVHS is a preventive disease. Most of the cases reported in the recent times have been in places where anti-GVHD measures are not strictly implemented.
Donor screening: Patients should not receive blood from first or second-degree blood relatives. If this is not avoidable then the blood should be irradiated.
γ-Irradiation: γ-Irradiation with 25Gy kills lymphocytes without affecting platelets or granulocytes. It does however shorten the shelf life of blood. The guidelines for irradiation vary from country to country. These take into account the risk of TA-GVHD, available infrastructure and the cost of irradiation. In Japan, the risk of TA-GVHD is higher and the guidelines more stringent. Generally speaking irradiation is recommended under the following circumstances:
- Transfusion from blood relatives
- Transfusions to patients with severe congenital T cell deficiencies
- Intrauterine transfusion
- Neonatal transfusions
- Transfusions in cardiac surgery
- Transfusions in patients who have received Cladribine, Deoxycoformycin, fludarabine and alemtuzumab
- Granulocyte transfusions
- Patients of allogeneic stem cell transfusion
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