Why are male donors preferred over female donors for stem cell transplants?

Dr Lucille Sarah Singh answers the question of why male donors are preferred over female donors for stem cell transplants.

Let’s get started by stating upfront that  this has nothing to do with misogyny. The reasons are all tied up in biology and, more specifically, the remarkable changes that occur in a woman’s immune system when she becomes pregnant. 

Haematopoietic stem cells (harvested from the blood or bone marrow of donors) may carry with them antibody-producing immune cells which could cause short- and long-term complications after a transplant. Women who have been pregnant at any point in their life may carry high levels of these potentially problematic antibodies. 

What changes in a woman’s immune system when she becomes pregnant?

All foetuses get 50% of their DNA from their mother and 50% from their father. During pregnancy, foetal cells can cross the placenta and enter the mother’s bloodstream. This can stimulate the mother’s immune system to produce antibodies to certain proteins on the surface of the foetal cells which the mother’s immune system recognise as foreign. 

These foreign proteins represent proteins from the father. The mother’s immune system makes antibodies against these invaders in much the same way it would against viruses or bacteria. This process is called alloimmunization and is a natural response from a healthy and functional immune system. Even if the pregnancy was an ectopic pregnancy or resulted in a miscarriage, termination, or stillbirth, evidence of the foetal cells and DNA can be detected in the mother’s blood and tissues for many decades or perhaps even lifelong. 

Why is this important in stem cell transplantation?

When analysing data from thousands of transplants worldwide, there is a clear association between an increased risk of graft-versus-host disease (GVHD) in recipients who receive stem cells from female donors who have had pregnancies. 

This is thought to be due to pregnancy-induced immune memory in the transplanted cells from the donor. Ongoing production of allo-antibodies occurs which then attack the stem cell recipient’s tissues and organs. GVHD causes inflammation and dysfunction to one or more organ systems. It commonly affects the skin, liver, and gut. At best this is a manageable short-term illness and at its worst, GVHD can turn into a chronic debilitating disease with resultant organ dysfunction and even death. 

Is there an upside to having these antibodies in the transplant setting?

Interestingly, yes, as the same enhanced immune response may also increase the graft-versus-leukaemia effect. This means that these antibodies may have a role to play in destroying leukaemia cells. Again, the data supports this by showing a slightly reduced risk of relapse when donor cells from females who have been pregnant are used.

What’s the bottom line? 

Would you choose a female donor who has been pregnant? 

The selection of the best donor for a particular patient is a nuanced and considered decision. It’s guided by the urgency of the transplant, the underlying disease or cancer that the patient is being transplanted for, and a multitude of other logistical factors. 

The ideal donor would be a healthy identical twin, but this type of donation is exceedingly rare. A 10/10 sibling donor is the next preferable option, but every sibling carries only a 25% chance of being a 10/10 match even with the same biological parents. 

When searching donor registries for potential unrelated matches, there is a hierarchy of factors that are considered. Younger donors trump older donors. Male donors trump female donors for the reasons detailed. Female donors who haven’t been pregnant trump females who have been pregnant. These choices are all risk mitigating measures. 

When the donor is a woman who has previously been pregnant and no alternative donor is available, the transplant can still proceed. The type of immune suppression post-transplant may be increased or optimised to decrease the chances of developing GVHD. 

In conclusion, females who have had children can absolutely become stem cell donors. Thousands of successful transplants occur  every year using stem cells from donors who have been pregnant. 

Dr Lucille Sarah Singh is a physician and clinical haematologist in private practice at Albert’s Cellular Therapy (ACT) based at Netcare Pretoria East Hospital.  She serves on the executive committees of the South African Clinical Haematology Association (SACHAS) and South African Bone Marrow Registry (SABMR) and is Director of the ACT Haematology Clinical Trial Unit at Netcare Pretoria East Hospital.

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