Microchimerism and tolerance following intrauterine transplantation and transfusion for alpha-thalassemia-1.

A fetus homozygous for alpha-thalassemia-1 was given haploidentical paternal CD34 cells at 13, 19 and 24 weeks' gestation and supported through pregnancy by blood transfusion. The fetal hematocrit ranged between 27 and 47% and between one half and three quarters of this hemoglobin was of recipient (Bart's) type. Intrauterine growth proceeded normally and no significant fetal hydrops was detected. Tests for donor HLA antigens, and alpha-globin DNA, were negative on fetal blood samples drawn before birth. A positive signal for alpha-globin DNA was obtained from cord blood and from marrow obtained at 3 months of age, suggesting that some donor stem cells had persisted in the recipient. The infant's blood mononuclear cells showed little proliferative and no cytotoxic response to the donor while responses to a third party were present. Additional paternal CD34 cells given at 3 months age did not reduce transfusion dependency in the subsequent 6 months. Our results show that repeated transfusions can support an alpha-thalassemia-1 fetus through pregnancy, in this instance without significant birth defects or apparent hypoxic tissue injury. The donor stem cells did not have a survival advantage compared with endogenous stem cells, but appeared to survive in the recipient as judged by the persistence of an alpha-globin DNA signal. In vitro studies of alloreactivity suggest tolerization of the host to the donor's MHC disparity. Future efforts will focus on exploiting this tolerance to improve the level of donor chimerism.