Intrauterine transplantation

In this issue of Blood, Liuba and colleagues provide important results in support of intrauterine transplantation for fetuses with X-SCID.

Using a congenic mouse model, Liuba and colleagues show that lymphoid-primed multipotent progenitors are superior to hematopoietic stem cells in providing rapid lymphoid reconstitution following intrauterine transplantation, with sustained polyclonal B-cell production.¹  Furthermore, they clearly demonstrate that in this model, intrauterine transplantation results in superior B-cell and T-cell reconstitution of X-linked severe combined immune deficiency (X-SCID) patients as compared to delaying transplantion until the neonatal or adolescent age range. Although caution must be executed when extrapolating these data to humans, the study is very interesting and important in regard to the potential for providing a cure for these children before birth.

Since Touraine et al published the first instance of intrauterine transplantation in a human fetus affected by bare lymphocyte syndrome (BLS) in 1989,²  we are aware of 4 X-SCID intrauterine transplantation cases.^3-5  All these fetuses survived and were chimeric at birth. Despite favorable results, the intrauterine approach was criticized by several authorities in this field who claimed that this approach did not offer any advantage over postnatal transplantation. The main arguments against intrauterine transplantation were that the fetal invasive procedure carried a certain additional risk, and if the mother was used as a donor, there might be an increased risk for graft-versus-host disease (GVHD), a condition which cannot be treated prenatally. Conversely, promoters of intrauterine transplantation claimed that reconstitution of the immune system before birth results in reduced susceptibility to infections in the neonatal period, and to an improved psychosocial situation for the family. Other potential advantages for an intrauterine approach include cost savings and a reduced risk of GVHD in the fetal environment.

Not surprisingly, these varied opinions on the risk-benefit balance of intrauterine transplantation were expressed by representatives from different fields of medicine. Those arguing against are usually transplantation clinicians comfortable with postnatal transplantation procedures, and those arguing in favor of intrauterine transplantation usually represent specialists in fetal medicine and fetal surgery. Thus, a consensus has been difficult to reach and fetal transplantation has not been widely adopted, despite the fact that cases treated in utero had outcomes comparable with the best reported with postnatal transplantation.

So far, 46 cases of intrauterine human transplantation for various indications have been reported.⁶  In 1 case, the fetus did not survive the procedure. A 2% complication rate is in agreement with the risk calculation performed by Liuba et al. Likely, the complication rate can be reduced further using a 22-gauge needle and modern ultrasonic guidance.

The lack of relevant animal models allowing direct comparisons between prenatal and postnatal transplantation has hampered further development in this field. The work by Liuba et al adds important information. It seems that the earlier the reconstitution of the immunologic system takes place, the better the results. This needs to be considered by those involved in the care of mothers carrying fetuses potentially affected by X-SCID.