Tolerogenic effect of non-inherited maternal antigens in hematopoietic stem cell transplantation

Abstract

Major histocompatibility complex antigens that provoke severe transplant reactions are referred to as the human leukocyte antigen (HLA) in human and as the H-2 in mice. Even if the donor and recipient are HLA-identical siblings, graft-versus-host reactions have been linked to differences in the minor histocompatibility antigen. As the chance of finding an HLA-identical sibling donor is only 25%, attention has been focused on using alternative donors. An HLA-mismatched donor with non-inherited maternal antigens (NIMA) is less immunogenic than that with non-inherited paternal antigens, because the contact between the immune systems of the mother and child during pregnancy affects the immune response of the child against NIMA. However, the immunologic effects of developmental exposure to NIMA are heterogeneous, and can be either tolerogenic or immunogenic. We recently have devised a novel method for predicting the tolerogenic effect of NIMA. In this review, we overview the evidence for the existence of the NIMA tolerogenic effect, the possible cellular and molecular basis of the phenomenon, and its utilization in hematopoietic stem cell transplantation. We suggest a future direction for the safe clinical use of this phenomenon, fetomaternal tolerance, in the transplantation field.

Keywords: NIMA; acute GVHD; hematopoietic stem cell transplantation; tolerance.

FIGURE 1

Significance of non-inherited maternal antigen in transplantation. The nomenclature of the HLA haplotype is patient-oriented in the transplantation field. Children inherit one haplotype from each of parent. Siblings of the patient share one haplotype with the donor, and the other haplotype is the non-inherited haplotype. The HLA haplotypes in parentheses are shown as representative examples. When the patient is transplanted with donor from one of the parents or from a haploidentical sibling, the non-inherited maternal HLA antigens (NIMA) or non-inherited paternal HLA antigens (NIPA) are the mismatched haplotype. The NIMA and NIPA-mismatched siblings can be potential donors.

FIGURE 2

Murine models for non-inherited maternal antigens. (A) Left, C57BL/6 (B6) males (H-2^b/b) were mated with (B6 × DBA/2) F1 females (H-2^b/d), thus exposing the H-2^b/b offspring in utero and via breastfeeding to NIMA^d antigens. Right, (B6 × DBA/2) F1 males were mated with B6 females, creating H-2^b/b backcross offspring that had not been exposed to “d,” as reported by Andrassy et al. (2003). (B) Left, B10.BR males (H-2^k) were mated with (B10.D2 × B10) F1 females (H-2^d/b), thus exposing the H-2^d/k type offspring to NIMA^b, and H-2^b/k type offspring to NIMA^d. Right, (B10.D2 × B10) F1 males (H-2^d/b) were mated with B10.BR females (H-2^k), creating the controls; both H-2^d/k and H-2^b/k type offspring that had not been exposed to “b” and “d,” respectively. These mice have a B10 background, in other words, their MiHA are matched, and the H-2 antigens are mismatched for both class I and II.

FIGURE 3

Prediction of the reactivity to NIMA by the MLR-ELISPOT assay. (A) The ELISPOT assay combined with MLR (MLR-ELISPOT) is a sensitive functional assay to detect alloreactivity for both major and minor histocompatibility antigens in mice. (B) The mice were classified into two groups based on their reactivity to NIMA; the high responders (HR ≥ mean ± 1 SD in NIMA-non-exposed) or the low responders (LR < mean ± 1 SD) group by using MLR (Araki et al., 2010). The IFN-γ-producing ability before the induction of GVHD was presented by the MLR-ELISPOT assay. Peripheral blood mononuclear cells from NIMA-exposed LR mice (n = 8), NIMA-exposed HR mice (n = 7), and non-exposed mice (n = 6) were stimulated with B10 mouse peripheral blood mononuclear cells. The data are expressed as the means ± SD of individual animals. *p < 0.05.