To the editor:

An earlier report by Bucher et al1  indicated a better stem cell transplant (SCT) outcome with younger sibling donors (YSD). Transmaternal cell flow during pregnancy2  might explain this observation. Notably, cord blood comprises minor H antigen experienced T cells that are not only directed against maternal foreign minor H antigens.3,4  This observation prompted us to investigate the role of minor H antigens in the birth order effect in HLA identical SCT.

Hereto, we made use of a large database of 10/10 HLA allele-matched and minor H antigen–typed SCT donor/recipient pairs (Spierings et al, submitted), collected under the auspices of the International Histocompatibility and Immunogenetics Workshop and Conference. Additional relevant family information was included for 311 10/10 HLA allele–matched sibling donor/recipient pairs.

In the whole cohort of 311 pairs, overall survival, graft versus host disease (GVHD) incidence, GVHD-related mortality, and GVHD-free survival were not statistically significantly different in SCT with older sibling donors (OSD, n = 143) compared with SCT with YSD (n = 168; Figure 1A).

Figure 1

Influence of birth order on overall survival and GVHD incidence. (A) Overall survival and GVHD incidence in recipients with a YSD (n = 168) compared with recipients with an OSD (n = 143) are not statistically significantly different. (B) Female donors with female recipients have a higher non-GVHD death incidence (ie, relapse) in YSD compared with OSD (hazard ratio = 3.76, P = .094). (C) Adult YSD are subdivided by gender. Female donors in female recipients have a significantly (P = .008) reduced GVHD incidence compared with M→M.

Figure 1

Influence of birth order on overall survival and GVHD incidence. (A) Overall survival and GVHD incidence in recipients with a YSD (n = 168) compared with recipients with an OSD (n = 143) are not statistically significantly different. (B) Female donors with female recipients have a higher non-GVHD death incidence (ie, relapse) in YSD compared with OSD (hazard ratio = 3.76, P = .094). (C) Adult YSD are subdivided by gender. Female donors in female recipients have a significantly (P = .008) reduced GVHD incidence compared with M→M.

The sample size of 311 appeared too small to analyze the effect of either single or multiple autosomally or of single Y chromosome–encoded minor H antigen(s). However, the effect of gender mismatch5  on the birth order effect appeared feasible to investigate. Interaction analyses of birth order and gender mismatch showed a statistically significant interaction for non-GVHD, which is merely relapse-related, death (P < .05; data not shown). Subsequent analysis in female recipients of female donors (F→F; Figure 1B) showed lower, nonsignificant non–GVHD-related death in the YSD group (hazard ratio = 3.76, P = .094).

The study cohort comprised pediatric and adult SCT pairs. The number of pediatric pairs (n = 40) was too small to analyze separately. Analysis of the adult SCT pairs revealed a significant reduced GVHD incidence in the YSD group as opposed to the OSD group by comparing F→F transplantation with male donors to male recipients (M→M) transplantation (hazard ratio = 0.337, P = .008; Figure 1C). Furthermore, GVHD-free survival was significantly better in F→F compared with M→M SCT (hazard ratio = 0.547, P = .043; data not shown).

In summary, we support the existence of a birth order effect as reported before.1,6  Additionally, we show that gender might be one of the causal factors. Interestingly, the birth order effect was significant in the adult female donor/female recipient SCT pairs. Our current plausible explanation is the intrauterine exposure to sibling antigens occurring during pregnancy, leading to minor H antigen experienced T-cell responses in women.4  These responses might lead to immune regulation.7  Subsequent (re-)exposure to fetal antigens during pregnancy of the donor herself explains the favorable younger female SCT donor in combination with the female recipient.

To get a clearer picture of the influence of minor H antigens on the birth order effect, we suggest a much larger cohort of HLA-identical sibling SCT with detailed information regarding family and obstetric history of both patient and donor.

Contribution: M.D., E.S., and E.G. designed the research and drafted the manuscript; A.C., H.D., J.-F.E., J.E., T.G., B.K., D.L., P.L., and R.S. provided data; M.D., E.S., and M.H. collected data; and M.D., E.S., R.B., and E.G. analyzed results and prepared figures.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Eric Spierings, Laboratory for Translational Immunology, University Medical Center Utrecht, F03.821, Postbox 85500, 3508 GA, Utrecht, Netherlands; e-mail: e.spierings@umcutrecht.nl.

1
Bucher
 
C
Stern
 
M
Buser
 
A
, et al. 
Role of primacy of birth in HLA-identical sibling transplantation.
Blood
2007
, vol. 
110
 
1
(pg. 
468
-
469
)
2
Gammill
 
HS
Guthrie
 
KA
Aydelotte
 
TM
Adams Waldorf
 
KM
Nelson
 
JL
Effect of parity on fetal and maternal microchimerism: interaction of grafts within a host?
Blood
2010
, vol. 
116
 
15
(pg. 
2706
-
2712
)
3
Mommaas
 
B
Stegehuis-Kamp
 
JA
van Halteren
 
AG
, et al. 
Cord blood comprises antigen-experienced T cells specific for maternal minor histocompatibility antigen HA-1.
Blood
2005
, vol. 
105
 
4
(pg. 
1823
-
1827
)
4
Dierselhuis
 
MP
Blokland
 
EC
Pool
 
J
Schrama
 
E
Scherjon
 
SA
Goulmy
 
E
Transmaternal cell flow leads to antigen-experienced cord blood.
Blood
2012
, vol. 
120
 
3
(pg. 
505
-
510
)
5
Loren
 
AW
Bunin
 
GR
Boudreau
 
C
, et al. 
Impact of donor and recipient sex and parity on outcomes of HLA-identical sibling allogeneic hematopoietic stem cell transplantation.
Biol Blood Marrow Transplant
2006
, vol. 
12
 
7
(pg. 
758
-
769
)
6
Dobbelstein
 
C
Ahn
 
KW
Haagenson
 
M
, et al. 
Birth order and transplant outcome in HLA-identical sibling stem cell transplantation: an analysis on behalf of the Center for International Blood and Marrow Transplantation (CIBMTR).
Biol Blood Marrow Transplant
2013
, vol. 
19
 
5
(pg. 
741
-
745
)
7
van Halteren
 
AGS
Jankowska-Gan
 
E
Joosten
 
A
, et al. 
Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members.
Blood
2009
, vol. 
114
 
11
(pg. 
2263
-
2272
)