Sensitization to HY-Antigen in Female Donors Was Not Associated with the Post-Transplant HY-IgG Development Nor Clinical Outcomes in Sex-Mismatched Transplantation

Background:

Transplant of male recipients from female donors (F>M HCT) is well known as a risk factor for developing chronic graft-versus-host disease (cGVHD).  We have so far suggested that B cell response against minor histocompatibility antigens encoded on the Y chromosome, called H-Y antigens, develops following F>M HCT and associates with cGVHD. Here, we hypothesize that pre-sensitization to HY-antigen in a female donor may affect the post-HCT HY-IgG development and clinical outcomes following F>M HCT. This study uses our novel HY microarray to determine the prevalence and impact of donor HY-IgG.

Methods:

We measured IgG against 5 HY antigens (DBY, UTY, ZFY, EIF1AY, & RBS4Y) in 289 female donors (age:18-60) of high resolution 8/8 HLA-matched HCT facilitated by the NMDP between 1990-2002 and assessed the impact of HY seropositivity on cumulative cGVHD incidence and other clinical outcomes.

In addition, we studied 90 Stanford adult female donors and their corresponding male recipients between 2005 and 2012 who survived without relapse for at least 3m post-HCT and assessed the association of HY-IgG development between pre- and post-HCT. The cut-off value for seropositivity was defined as Q3 + 2xIQR, determined from plasma of 60 maledonors. HY-score was defined as the cumulative number of targeted HY antigens.

Results:

Prevalence of HY-IgGs in female donors is shown in Table1. Half of female donors had at least one of 5 HY-IgG(s).

Table1	DBY	UTY	ZFY	EIF1AY	RPS4Y	Any-HY
NMDP (n=289)	63 (22%)	112 (39%)	22 (8%)	7 (2%)	42 (15%)	143 (49%)
Stanford (n=90)	20 (22%)	32 (36%)	4 (4%)	1 (1%)	8 (9%)	46 (51%)

Univariate analyses of NMDP cohort showed that individual HY-IgGs in female donors were not associated with cGVHD. Focusing on increasing HY-score, we did not detect association with cGVHD nor other clinical outcomes (Table 2). This absence of association was also observed in Stanford cohort.

Table2 (NMDP)	cGVHD		aGVHD		Relapse		TRM		OS
HY-score	HR	P	HR	P	HR	P	HR	P	HR	P
0 (n=146)	1	-	1	-	1		1	-	1	-
1 (n=75)	1.34	0.15	1.17	0.46	1.22	0.54	0.85	0.44	0.98	0.89
2 (n=39)	1.12	0.65	1.25	0.39	0.63	0.31	0.62	0.078	0.81	0.39
3 to 4 (n=29)	1.32	0.37	1.64	0.064	1.85	0.19	1.3	0.34	1.48	0.099

Further, we were unable to show the adoptive transfer of HY seropositivity from female donors to male recipients (Table3).

Table 3		DonorDBY			DonorUTY			DonorZFY			DonorEIF1AY			DonorRPS4Y
		-	+	P	-	+	P	-	+	P	-	+	P	-	+	P
Recipient	-	38	7	0.2	31	13	0.28	55	4	0.29	56	1	>0.99	44	5	0.72
post-HCT	+	32	13		27	19		31	0		33	0		38	3

Conclusion:

Half of female donors were HY-seropositive, but there were no enough evidence to suggest that the HY sensitization can predict clinical outcome. In fact, we provided little evidence of adoptive HY B-cell immunity transfer. On-going studies will relate female HY sensitization to parity and age. The absence of adoptive immune transfer might raise a concern for the efficacy of donor vaccination strategies to augment GVL benefit.