Mother Donors Confer Protection Against Infectious Mortality after Haploidentical T Cell-Depleted Hematopoietic Transplantation
Authors: Ruggeri Loredana , Tosti Antonella , Mancusi Antonella , Topini Fabiana , Urbani Elena , Carotti Alessandra , Martelli Massimo Fabrizio , Velardi Andrea 
Published: November 2019

Abstract
Transplacental trafficking of maternal and fetal cells during pregnancy establishes long-term, reciprocal microchimerism in both mother and child because of exposure of the two immune systems to the non-self alloantigens (Maloney et al., J Clin Invest. 1999;104:41-47). Studies show the immune system in the mother is capable of being sensitized by paternal histocompatibility antigens. For example, antibodies directed against paternal HLA-antigens (van Rood et al., Nature. 1958;181:1735-1736) and T lymphocytes directed against paternal major (van Kampen et al., Hum Immunol. 2001;62:201-207) and minor histocompatibility antigens (Verdijk et al., Blood. 2004;103:1961-1964) are frequently detected in multiparous women. We previously demonstrated mother/child immune interactions positively influenced the outcome of mother to child HLA haploidentical T cell-depleted hematopoietic transplantation. In a series of adult and pediatric patients we demonstrated mother donors conferred protection against leukemia relapse and improved transplant related mortality (TRM), which was largely due to infection, and improved survival (Stern et al., Blood 2008, Oct 1;112:2990-5). However, in unmanipulated haploidentical transplantation, it has been recently shown that transplantation from mother donors increases the incidence of GvHD and decreases survival (Huang et al., EBMT 2014).
Here, we analyzed the outcomes of 238 adult acute leukemia patients after T cell-depleted haploidentical transplantation. When compared with transplantation from all other family members, transplantation from mother donors was associated with significantly lower TRM (largely infectious) (27% vs 50% from all other donors, P = 0.01). Multivariate analyses demonstrated transplantation from mother donors was an independent factor predicting improved survival (hazard ratio 0.41, 95% confidence interval 0.12 to 0.95, P = 0.03). In an attempt to elucidate the mechanism, we analyzed donor T cell repertoires that were specific for CMV antigens presented by recipient APCs (by ELISPOT and by limiting dilution cloning). Unlike all other donor/recipient pairs, mothers possessed CMV-specific CD8 cell clones that killed child’s and father’s CMV-pulsed dendritic cells (DCs). Such clones were non-alloreactive as they did not kill the child’s or father’s non-CMV-pulsed DCs. Mothers also possessed CD4 T cell clones that produced IFN-gamma in response to child’s and father’s CMV-loaded antigen-presenting cells (APCs). Such clones were non-alloreactive as they did not respond to child’s or father’s non-CMV-pulsed APCs. Thus, mothers possessed a T cell repertoire that recognized CMV antigens also when presented by the unshared, father’s, HLA haplotype. In fact, they showed twice as many T cells that recognized CMV antigens presented by the child’s APCs than all other donor/recipient pairs (p<0.05).
Apparently, therefore, pregnancy resulted in the generation of an additional T cell repertoire that specifically recognized pathogen antigens presented by the unshared paternal HLA haplotype antigens on the child’s APCs. Apparently, upon mother to child T cell-depleted hematopoietic transplantation, such repertoire expands over time and helps reduce infectious mortality. Further studies are needed to elucidate the mechanisms underlying mother T cell selection/education by paternal HLA haplotype antigens on the child’s APCs.

Disclosures
No relevant conflicts of interest to declare.