Correlation between post transplant maternal microchimerism and tolerance across MHC barriers in mice

Dutta, Partha; Burlingham, William J.

doi:10.4161/chim.18083

Cited by 14 publications

(19 citation statements)

References 27 publications

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“…DCs are known to generate EVs capable of inducing transplant tolerance (26), but other MHC-II + cellular subsets cannot be ruled out as EV sources. However, one can distinguish tolerant from graft-rejecter NIMA d mice by MMc presence in CD11c and CD11b lineages (27), implicating a myeloid cell. Because EVs derived from rare maternal cells (H2-K d+ ) had CD86, but lacked PD-L1 (Fig.…”

Section: Proposed Model For Rare Cell Amplification and Split Toleranmentioning

confidence: 99%

Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance

Bracamonte‐Baran

Florentin

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Maternal microchimerism (MMc) has been associated with development of allospecific transplant tolerance, antitumor immunity, and cross-generational reproductive fitness, but its mode of action is unknown. We found in a murine model that MMc caused exposure to the noninherited maternal antigens in all offspring, but in some, MMc magnitude was enough to cause membrane alloantigen acquisition (mAAQ; "cross-dressing") of host dendritic cells (DCs). Extracellular vesicle (EV)-enriched serum fractions from mAAQ + , but not from non-mAAQ, mice reproduced the DC crossdressing phenomenon in vitro. In vivo, mAAQ was associated with increased expression of immune modulators PD-L1 (programmed death-ligand 1) and CD86 by myeloid DCs (mDCs) and decreased presentation of allopeptide+self-MHC complexes, along with increased PD-L1, on plasmacytoid DCs (pDCs). Remarkably, both serum EV-enriched fractions and membrane microdomains containing the acquired MHC alloantigens included CD86, but completely excluded PD-L1. In contrast, EV-enriched fractions and microdomains containing allopeptide+self-MHC did not exclude PD-L1. Adoptive transfer of allospecific transgenic CD4 T cells revealed a "split tolerance" status in mAAQ + mice: T cells recognizing intact acquired MHC alloantigens proliferated, whereas those responding to allopeptide+self-MHC did not. Using isolated pDCs and mDCs for in vitro culture with allopeptide+self-MHC-specific CD4 T cells, we could replicate their normal activation in non-mAAQ mice, and PD-L1-dependent anergy in mAAQ + hosts. We propose that EVs provide a physiologic link between microchimerism and split tolerance, with implications for tumor immunity, transplantation, autoimmunity, and reproductive success.

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Section: Proposed Model For Rare Cell Amplification and Split Toleranmentioning

confidence: 99%

Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance

Bracamonte‐Baran

Florentin

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…On the other hand, the tolerance rate using NIPA d offspring as recipients was 0%. [9,58] They also found existence of MMc in different tissues (heart, liver, blood) belonging mainly to CD11c and CD11b subsets (monocyte/macrophages and DCs). [9] In the same studies, they found the existence of a MHC-II subset of cells dimly expressing H2-K d in NIMA recipients.…”

Section: Transplacental Cell Trafficmentioning

confidence: 95%

“…[9,58] They also found existence of MMc in different tissues (heart, liver, blood) belonging mainly to CD11c and CD11b subsets (monocyte/macrophages and DCs). [9] In the same studies, they found the existence of a MHC-II subset of cells dimly expressing H2-K d in NIMA recipients. [9,58] Interestingly, such expression was transient in NIMA rejecters, but persisted lifelong in tolerant ones.…”

Section: Transplacental Cell Trafficmentioning

confidence: 95%

“…[28] Notwithstanding, this traffic phenomenon is not enough to explain the development of persistent MMc and FMc, because it implies the seeding of allogeneic cells in specific organs and the development of tolerance to NIMA and IPA, respectively, in order to create an immunologic niche where such allogeneic cells can survive. [8,9] It is proposed that induction of peripheral tolerance allowing Mc to take hold is the first step in the development of global allospecific tolerance with an impact on pregnancy physiology, as well as transplantation outcomes. [37] It is important to note that breast feeding seems to play a significant role in the establishment of long-term MMc.…”

Section: Transplacental Cell Trafficmentioning

confidence: 99%

“…[7,8] This can be defined as the presence of less than 1% of allogeneic cells in a living organism, while it is possible to detect levels of Mc as low as 0.001% due to the improvements in quantitative polymerase chain reaction (qPCR) techniques. [9] During pregnancy, the trophoblast plays a permissive role allowing bidirectional trafficking of stem cells and leukocytes, giving rise to maternal microchimerism (MMc) in the fetal tissues and fetal microchimerism (FMc) in the maternal tissues. [10,11] Both kinds of Mc persist for a long time after the end of pregnancy.…”

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confidence: 99%

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Non-inherited maternal antigens, pregnancy, and allotolerance

Bracamonte‐Baran¹,

Burlingham²

2015

Biomed J

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

Kruchen,

Fehse,

Müller

2024

Semin Immunopathol

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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.

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Correlation between post transplant maternal microchimerism and tolerance across MHC barriers in mice

Cited by 14 publications

References 27 publications

Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance

Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance

Non-inherited maternal antigens, pregnancy, and allotolerance

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

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