Allogeneic hematopoietic stem cell transplantation (HSCT), commonly known as a bone marrow transplant, is a potentially curative treatment for many blood cancers and genetic disorders. This complex procedure involves replacing a patient’s diseased blood-forming system with healthy cells from a compatible donor. Success relies heavily on a close match of human leukocyte antigens (HLA), which are proteins the immune system uses to distinguish self from non-self. When multiple donors share an identical HLA type, other characteristics become important factors in selection. Donor gender plays a significant role among these secondary considerations, often leading to a preference for male donors due to immunological and quantitative differences that influence transplant outcomes.
The Risk of Alloimmunization in Female Donors
The general preference for male donors relates to a specific immune risk in female donors who have experienced pregnancy. A woman who has been pregnant is referred to as parous, and this history can lead to a state known as alloimmunization. This process occurs because the mother’s immune system is exposed to the fetus’s cells during pregnancy.
Fetal cells carry paternal HLA markers, which are foreign to the mother’s immune system. In response to this exposure, the mother may develop memory B and T cells that produce anti-HLA antibodies against these paternal markers. These antibodies can persist in the mother’s bloodstream for many years following the pregnancy.
When a parous woman donates stem cells, these circulating anti-HLA antibodies can transfer to the recipient. They may recognize and attack the patient’s tissues or the transplanted graft itself. The presence of these antibodies increases the risk of graft rejection, poor engraftment, and graft failure. Consequently, transplant centers often attempt to avoid using parous donors, especially for male recipients, to prevent these serious immunological complications.
Donor Gender and Graft-versus-Host Disease
Donor gender is a significant factor in the post-transplant complication known as Graft-versus-Host Disease (GVHD). GVHD occurs when the transplanted donor immune cells recognize the recipient’s body as foreign and launch an attack against the patient’s healthy tissues. The risk of this complication is particularly notable in transplants from a female donor to a male recipient (F→M).
This increased risk is connected to minor histocompatibility antigens (mHAs) encoded on the Y chromosome of the male recipient. Female cells lack a Y chromosome, so the donor’s immune system has never been exposed to these specific H-Y antigens. When the female donor’s T cells are introduced to the male recipient, they recognize these Y-chromosome antigens as foreign targets.
The resulting immune reaction against these H-Y antigens can trigger both acute and chronic GVHD, affecting the skin, liver, and gut. Studies have shown that the F→M combination is associated with a higher incidence of chronic GVHD compared to other gender combinations. This gender-specific immunological reaction makes the male donor a preferred choice to mitigate the risk of severe post-transplant complications.
Quantitative Advantages in Cell Yield
Beyond immunological factors, a practical reason for preferring male donors relates to the quantity of cells collected during the donation process. Male donors generally have a larger average body size and greater total circulating blood volume compared to female donors. This physiological difference allows a larger volume of blood to be processed during the collection of peripheral blood stem cells (PBSC).
This higher volume translates to a greater total yield of hematopoietic stem cells, specifically the crucial CD34+ cells, in the donated graft. A higher count of these stem cells is associated with more rapid and successful engraftment in the recipient. Rapid engraftment helps the patient’s new immune system establish itself more quickly, reducing vulnerability to life-threatening infections. This quantitative advantage tips the selection criteria toward male donors when all other factors are equal.
Situations Where Female Donors Are Preferred or Equal
Despite the general preference for male donors, a female donor may be considered equally suitable or even preferred in specific clinical situations.
Nulliparity
The most significant factor mitigating risks associated with female donors is the absence of prior pregnancy, or nulliparity. A nulliparous female donor has not been exposed to paternal HLA antigens, essentially eliminating the risk of alloimmunization and anti-HLA antibodies.
HLA Match Priority
Immunological risks are secondary to the primary need for an exact HLA match. If a female donor is the only available full HLA match, she will be selected over any male donor with a less-than-perfect match. Gender preference serves as a tiebreaker but never supersedes the requirement for high-resolution HLA compatibility.
Graft-versus-Leukemia (GVL) Effect
In cases involving blood cancer, the increased GVHD risk in a female-to-male transplant is sometimes tolerated due to the powerful “graft-versus-leukemia” (GVL) effect. The same donor T cells that attack healthy tissue may also aggressively target and eliminate residual cancer cells, leading to a lower risk of relapse. In these circumstances, a female donor may be intentionally chosen to maximize the anti-cancer effect, balancing the increased risk of GVHD against disease eradication.