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Editorials
antigens were studied so as to develop a more balanced model of what the Grandmother Effect might encompass. Out of the 549 rbc antigens not expressed by the mothers (after exclusion for antigens with no exposure from grand- mother, or where antigen exposure was unknown), there were 330 known rbc antigen exposures in these women. The differences became meaningful in that, after at least two months of oral NIMA exposure via breast-feeding (i.e., per the maternal grandmother), the odds ratio of the moth- er (now an adult) forming an antibody to her baby’s rbc was very low (0.12). Although continuation of breast-feeding of the grandmother beyond two months did not add addition- al protections, it was clear that breast-feeding was associat- ed with the protections gained by the NIMA-exposed mother who had been re-exposed to the same antigen as an IPA during her pregnancy.
Discussion
The observations of Schonewille et al.1 add to literature on the NIMA effect in important ways. The original observation of Ray Owen was challenged by a variety of individuals in the Ob/Gyn and blood transfusion fields. However, there was no adequate breast-feeding history of the mothers involved in Ray’s study nor of the mothers whose results were claimed to have refuted Owen et al.2 However, it was clear from a study by Frans Claas and col- leagues in 1988, published in Science,3 that in patients awaiting kidney transplant who were highly sensitized to HLA (>90% reactivity to a random panel), the existence of a NIMA among the different HLA types of cells tested by cytotoxicity assay tended to identify the rare cells to which the highly sensitized patient was unable to make an antibody. Similarly, in 1998 our lab published a paper4 showing that the presence of a NIMA HLA haplotype on a sibling kidney allograft donor greatly increased long- term graft survival in the recipient. This was despite the fact that there was an increased rate of early transplant rejection episodes when the NIMA haplotype was present on the haplo-mismatched kidney.4 This emphasized the split tolerance nature of the NIMA effect, where certain aspects of cellular immunity, particularly the so-called direct pathway of cellular immunity, were increased by re- exposure to the NIMA, whereas the indirect pathway, which controls antibody responses in long-term kidney allograft recipients, was impaired. Some 10 years later, Jeff Mold, Mike McCune and colleagues published a cou- ple of papers, one in 20085 and one in 2010,6 outlining in human studies strong support for the NIMA effect in utero, based on the development of NIMA-specific fetal T reg populations, and developing a new category for the “nor- mal” CD4 T cell during in utero life—i.e., as one that has “T reg-like” qualities. Finally, Kinder et al.,7 working in Sing Sing Way’s lab, published a mouse study in 2015 showing exactly how such cross-generational tolerance occurs, and identifying a mechanism whereby NIMA exposure from the grandmother protects the daughter’s later pregnancy from fetal loss due to a Listeria infection.
The elegant study by Schonewille and colleagues raises
certain questions for the new era of “surrogate” mother- hood. First, the surrogate mother is in a completely separate generational lineage, having been exposed by her own mother to certain non-inherited antigens that may or may not match with the antigens of the fetus which she carries. One wonders about the records of successful term pregnan- cies vs. premature delivery or fetal loss in these “two HLA haplotype mismatched” (fully allogeneic) intrauterine trans- plants. A second question arising from the study by Schonewille et al.1 would be, “Does the surrogate mom breast-feed the baby or not, and if indeed she is breastfed by the surrogate mom, is a baby girl born to the surrogate mom now going to have outcomes of pregnancy that are related to the surrogate mom exposure?” This question can only be answered by further research on these individuals as they become adults. Another question regarding the implications of “milk-kinship” in certain Islamic and Native American societies (en.wikipedia.org/wiki/Milk_kinship), wherein a child is nursed by a woman who is not his/her biologic mother, might now be re-examined in light of the tolerogenic effects of breast-feeding described by Schonewille et al.,1 particularly in those cases where the period of breast-feeding by the “wet nurse” is ≥2 months duration.
Summary
Overall, the paper by Schonewille et al.1 is an important contribution to the literature on the NIMA effect. It is fitting that one of the co-authors of this paper is Jon van Rood, who passed away in 2017. Jon would have been very happy to see this paper published. He was an early cham- pion of the NIMA hypothesis, who shared in the discovery of HLA as a key element in human transplantation, even though the Nobel prize for this was awarded to Jean Dausset. Whether or not the paper promotes a recommen- dation from Ob/Gyn specialists for two or more months of breast-feeding, it certainly supports such a strategy for female babies, in order to insure long-term protection of babies in the next generation from HDFN.
References
1. SchonewilleH,vanRoodJJ,VerduinEP,etal.Exposuretonon-inherit- ed maternal antigens by breastfeeding affects antibody responsiveness. Haematologica 2018;104(2):259-264.
2. OwenRD,WoodHR,FoordAG,SturgeonP,BaldwinLG.Evidencefor actively acquired tolerance to Rh antigens. Proc Natl Acad Sci U S A. 1954;40(6):420-424.
3. ClaasFH,GijbelsY,vanDerVelden-deMunckJ,vanRoodJJ.Induction of B cell unresponsiveness to noninherited maternal HLA antigens dur- ing fetal life. Science. 1988;241(4874):1815-1817.
4. BurlinghamWJ,GrailerAP,HeiseyDM,etal.Theeffectoftoleranceto noninherited maternal HLA antigens on the survival of renal trans- plants from sibling donors. N Engl J Med. 1998;339(23):1657-1664.
5. MoldJE,MichaelssonJ,BurtTD,etal.Maternalalloantigenspromote the development of tolerogenic fetal regulatory T cells in utero. Science. 2008;322(5907):1562-1565.
6. Mold JE, Venkatasubrahmanyam S, Burt TD, et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science. 2010;330(6011):1695-1699.
7. Kinder JM, Jiang TT, Ertelt JM, et al. Cross-generational reproductive fitness enforced by maternal cells. Cell. 2015;162(3):1-11.
haematologica | 2019; 104(2)