Clinical relevance of feto-maternal microchimerism in (hematopoietic stem cell) transplantation

Abstract

Toleration of a semi-allogeneic fetus in the mother's uterus as well as tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) appear to share some immunologic concepts. The existence of microchimeric cells, and the original idea of a bidirectional cell trafficking between mother and child during pregnancy have been known for decades. Today, origins and mechanisms of persistence of microchimeric cells are intensively being elucidated. Both, the translation of the phenomenon of feto-maternal immune tolerance to donor choice or prevention of graft-versus-host disease (GvHD) in HSCT, and the implications of microchimeric cells in and for HSCT are highly intriguing. Yet, differences in detection methods of microchimeric cells, as well as in transplantation protocols impede the comparison of larger cohorts, and limit potential clinical advice. Still, matching of non-inherited maternal antigens (NIMA), which are expressed on maternal microchimeric cells, demonstrated a strong association with decreased risk for the development of acute GvHD in the context of various transplantation strategies. Despite the fact that advances in graft manipulation and immunosuppression ameliorated the safety and outcome after HSCT, NIMA-matching retained a beneficial role in selection of sibling, child, or maternal donors, as well as for cord blood units. Recent findings indicate the existence of a microchimeric stem cell niche, in which only one dominant microchimeric cell population of only one semi-allogeneic origin persists at a time. This implies that studies regarding the impact of (maternal and fetal) microchimerism (MC) on clinical outcome of HSCT should combine analysis of NIMA and direct detection of microchimeric cells from donor and recipient on the verge of HSCT to be efficiently conclusive.

Keywords: Feto-maternal immune tolerance; Hematopoietic stem cell transplantation; Microchimerism; Non-inherited maternal antigen.

Fig. 1

Dynamics of microchimeric cells in female hosts. The first microchimeric cells in a female individual are maternal and possibly of older sibling’s or a twin’s origin. With each pregnancy later on in life, these microchimeric cells will (in part) be exchanged with filial microchimeric cells. This balance might be perturbed by certain transient conditions like preeclampsia or surgical or chemical pregnancy terminations

Fig. 2

Biology and persistence of microchimeric cells and their immunological implications for hematopoietic stem cell transplantation (HSCT). The upper panel depicts maternal and fetal microchimeric cell populations and factors that positively influence their persistence. While maternal microchimeric cells are mostly reported to be hematopoietic stem cells (HSC) and mature immune cells, fetal microchimeric cells are more often detected in stem cell or progenitor populations (HPC: hematopoietic progenitor cell, MSC: mesenchymal stromal cell). Histocompatibility and the development of regulatory T cells (T_regs) play a role in persistence of both, maternal microchimerism (mMC) and fetal microchimerism (fMC). The lower panel summarizes major implications for HSCT. An mMC (e.g., in cord blood transplantations) may confer strong graft-versus-leukemia effects (GvL) with a decreased incidence of graft-versus-host disease (GvHD). In mother-to-child transplantations, similar effects could be ascribed to fMC, and in non inherited maternal antigen (NIMA)-mismatched (sibling) transplantations low incidences of GvHD were abundantly described. Overall, an interplay between NIMA- and/or IPA-specific T_regs, CTLs and B cells gives rise to a pregnancy- derived immunologic memory in the mother, which can be beneficial for HSCT. IPA: inherited paternal antigen, CTL: cytotoxic T lymphocyte, B: B cell