Graft-versus-Host Disease in two Newborns After Repeated Blood Transfusions Because of Rhesus Incompatibility

Fatal GVHD developed in two male newborn babies, who had been treated by repeated intrauterine (only case 2) and exchange blood transfusions because of severe Rhesus incompatibility. The clinical manifestations of the disease were fever, enlargement of liver and spleen, diarrhea, exanthema, anemia, and blood eosinophilia. Both babies died at the age of three weeks. In case 2 identical HL-A antigens were found in the blood of the last donor and in the lymphocytes of the baby obtained shortly after death.

Autopsy and histologic examinations disclosed a marked atrophy of the lymphatic organs with depletion of lymphocytes, together with an hypoplastic bone marrow. Around blood vessels in the systemic connective tissue and in many organs infiltrates of eosinophilic granulocytes, histiocytes, lymphocytes and lympho-monocytoid blasts were found. The gastro-intestinal tract, the liver and the skin were predominantly affected. In addition we observed hemorrhagic necroses of lymph nodes with extreme dilatation of lymph vessels, which were occupied by mature and immature erythroid and monocytoid cells. Ringshaped fibrinoid and hemorrhagic necroses were also found in the spleen around the Malpighian corpuscles. These inflammatory and necrotizing tissue damages are attributed to local immune reactions between proliferating T-lymphocytes of the donor and tissue antigens of the host.

No primary defect of the immune system of the babies could be verified. It is therefore postulated that intrauterine transfusions (or an accidental materno-fetal transfusion via the placenta) induced a state of nonspecific immune tolerance by exhaustion of the immature cellular immune defence mechanisms of the fetus, thus allowing subsequent implants of immune competent cells not to be rejected but to proliferate and inhabit the lymphatic organs of the host. This hypothesis is supported by two facts: 1. Intrauterine and subsequent exchange transfusions are usually required to induce GVHD in primary immunologically normal babies (with Hassal's corpuscles and immune globulines shown to be present). 2. Only lymphocytes of the exchange transfusion donors and non of the intrauterine donors were found in the blood of the GVHD babies.

Both these requirements were also met in the cases of Naiman et al. (1969) and Parkman et al. (1974).

Our case 1 may have been caused by a slightly different mechanism in that instead of intrauterine transfusions, maternal blood cells had crossed the placenta and had induced a state of nonspecific fetal immune tolerance. This, however, could not be directly proven because no immunological and cytogenetic studies were performed in this case.