Noninherited Maternal Antigens Research Articles

Pretransplant immune regulation predicts allograft outcome: bidirectional regulation correlates with excellent renal transplant function in living-related donor-recipient pairs.

Tolerance to noninherited maternal antigens has provided clinical advantage when kidney transplants are exchanged between siblings but not when mother herself is the donor. This paradox prompted us to revisit the "two-way" hypothesis of transplant tolerance--that the immune status of both the organ recipient and the organ donor critically influences allograft outcome. We obtained peripheral blood monocyte cells from 29 living donor-recipient pairs before transplant and used the trans-vivo-delayed type hypersensitivity assay to measure immune regulation in both the recipient antidonor and donor antirecipient directions. We found preexisting bidirectional regulation in all human leukocyte antigen (HLA)-identical sibling pairs tested (7/7), and one half (9/18) of the HLA haploidentical pairs. No significant regulation was found in four control living unrelated and two HLA haploidentical living-related donor recipient pairs, whereas unidirectional regulation was found in the remaining seven haploidentical pairs. Of the nine HLA haploidentical transplants with unidirectional or no pretransplant regulation, seven had an acute rejection episode and four of these experienced graft loss. In contrast, of the nine HLA haploidentical transplants with bidirectional regulation, only one had rejection. Renal function for the latter group was similar to HLA-identical kidney recipients at 3 years posttransplant. Significantly (P<0.05) lower mean serum creatinine values in bidirectional regulators were noted as early as 4 months and this difference became more pronounced at 12 (P<0.005) and 36 months (P<0.0001). Contrary to the belief that only the recipient's immune status matters, the data indicate that pretransplant immune status of both donor and recipient influence posttransplant outcome.

Decreased Risk of Graft Failure with Maternal Liver Transplantation in Patients with Biliary Atresia

The presence of maternal cells in offspring may promote tolerance to noninherited maternal antigens (NIMAs). Children with biliary atresia (BA) have increased maternal cells in their livers, which may impact tolerance. We hypothesized that patients with BA would have improved outcomes when receiving a maternal liver. We reviewed all pediatric liver transplants recorded in the SRTR database from 1996 to 2010 and compared BA and non-BA recipients of maternal livers with recipients of paternal livers for the incidences of graft failure and retransplantation. Rejection episodes after parental liver transplantation were examined for patients transplanted at our institution. BA patients receiving a maternal graft had lower rates of graft failure compared to those receiving a paternal graft (3.7% vs. 10.5%, p = 0.02) and, consequently, fewer episodes of retransplantation (2.7% vs. 7.5%, p = 0.04). These differences were not seen among non-BA patients or among BA patients who received female deceased donor grafts. In patients transplanted at our institution, paternal liver transplantation was associated with an increased incidence of refractory rejection compared to maternal liver transplantation only in BA. Our data support the concept that maternal cells in BA recipients promote tolerance to NIMAs and may be important in counseling BA patients who require liver transplantation.

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

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.

Early-Onset Chronic Inflammatory Disease Associated with Maternal Microchimerism

Maternal microchimerism (mMc) refers to the presence of a small population of cells originating from the mother. Whether mMc leads to autoimmune responses in children remains controversial. We describe here an 11-year-old boy with persistent fever and elevated levels of C-reactive protein from infancy onward. During infancy, the patient presented with high fever, skin rashes, and hepatic dysfunction. Careful examination including a liver biopsy failed to reveal the cause. At 4 years old, petechiae developed associated with thrombocytopenia and positive anti-dsDNA autoantibodies. Steroid pulse therapy was effective, but the effect of low-dose prednisone was insufficient. At age 9, an extensive differential diagnosis was considered especially for infantile onset autoinflammatory disorders but failed to make a definitive diagnosis. On admission, the patient exhibited short stature, hepatosplenomegaly, generalized superficial lymphadenopathy, and rashes. Laboratory findings revealed anemia, elevated levels of inflammation markers, and hypergammaglobulinemia. Serum complement levels were normal. Serum levels of IL-6 and B-cell activating factor were elevated. Viral infections were not identified. Although HLA typing revealed no noninherited maternal antigens in lymphocytes, female cells were demonstrated in the patient's skin and lymph nodes, suggesting that maternal microchimerism might be involved in the pathogenesis of fever without source in infants.

Accelerated Kidney Transplant Rejection and Hypertensive Encephalopathy in a Pediatric Patient Associated With Antibodies Against Angiotensin Type 1 Receptor and HLA Class II

Accelerated Kidney Transplant Rejection and Hypertensive Encephalopathy in a Pediatric Patient Associated With Antibodies Against Angiotensin Type 1 Receptor and HLA Class II

Microchimerism

The bidirectional exchange of cells, both mature and progenitor types, at the maternal-fetal interface is a common feature of mammalian reproduction. The presence of semiallogeneic cells in a host can have significant immunological effects on transplantation tolerance and rejection. Here, we review recent advances in this area. Maternal microchimerism (MMc) in blood and various organs was found to be directly correlated with noninherited maternal antigen (NIMA)-specific CD4(+) regulatory T cells (Tregs), in F(1) backcross mice. In humans, MMc induced NIMA-specific FoxP3(+) CD4 Tregs in lymph nodes and spleen of fetuses. Tolerance to NIMA(+) allografts could be predicted in mice by measuring levels of the NIMA-specific Tregs in offspring before transplantation. On the contrary, fetal microchimerism (FMc) in multiparous female mice was largely confined to CD34(+) hematopoietic stem cells (HSCs) and was associated with sensitization rather than Treg induction. The recent discovery of a 'layered' T-cell development in humans whereby fetal HSCs are more likely to produce Tregs than adult HSCs, which may explain why MMc often induces tolerance, whereas FMc tends to induce sensitization. Microchimerism may cause tolerance resulting in acceptance of an allograft bearing antigens shared by the microchimeric cells. However, microchimerism may also cause sensitization resulting in rejection. Distinguishing these effects prior to the transplant may revolutionize the field of living-related renal transplantation wherein MMc and FMc can exert a powerful influence on graft outcome.

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

Exposure to non-inherited maternal antigens (NIMA) during fetal and neonatal life can result in lifelong maternal microchimerism (MMc) and tolerance to NIMA(+) allografts. We have previously shown that 40-50% of BDF1 female x B6 male offspring have multi-organ and multi-lineage MMc, while 70% have evidence of acquired maternal class I antigen in circulating PBMC and splenocytes. These features correlated with the presence of NIMA(d)-specific CD4(+) Treg cells, while offspring lacking MMc also lacked NIMA-specific Tregs. Furthermore, after a DBA/2 heart transplant, NIMA(d)-specific CD4(+) Treg cells rapidly mobilize to the allograft where they produce IL10 and TGFβ, suppressing early acute rejection, while mice deficient in MMc and NIMA(d)-specific Treg reject, allowing IFNγ-producing T effector cells to predominate in the grafts. We hypothesized that maternal cells occupy key sites of alloantigen presentation after transplant, sustaining pre-existing host Treg amidst a rising tide of donor alloantigen released from the graft. Using quantitative PCR to detect GFP transgeneic maternal cells, we found that transplant tolerance was associated with elevated MMc levels in blood, heart & lung, but surprisingly, not in liver. Rejection was associated with significantly lower levels of MMc in CD11b(+) (p = 0.0001) and CD11c(+) (p = 0.045) splenocytes, but not with differences in T cell MMc. Furthermore, compared with low pre-transplant baseline rate of maternal antigen acquisition, long-term graft survival was associated with an increased mean % of cells in blood [0.5% pre vs. 5.0% post] and spleen that were dimly positive for H-2K(d), indicative of de novo cell-surface alloantigen acquisition from the DBA/2 donor heart allograft. In contrast, NIMA-exposed mice that rejected their DBA/2 graft showed a transient increase in H-2K(d-dim) cells in blood during rejection (day 9-12) but a complete absence of donor MHC acquisition 100 days after transplant. As was the case prior to transplant, antigen acquisition was largely confined to MHC class II+ professional APC. When a NIMA-expressing organ allograft is accepted, MMc persists, mainly distributed into the antigen-presenting cell compartment, where the bulk of graft-derived alloantigen for "semi-direct" presentation is also present.

Pretransplant Immune-Regulation Predicts Allograft Tolerance

CD4⁺ Tregs specific for noninherited maternal antigens (NIMA(d) ) are detectable in some but not all B6 × BDF₁ backcross, H-2(b) homozygous offspring, and their presence is strongly correlated with extent of maternal (BDF₁) microchimerism. We hypothesized that the level of pretransplant donor antigen-specific Tregs could predict allograft tolerance. To test this idea, mice were screened for bystander suppression in a DTH assay, followed 1 week later by DBA/2 heterotopic heart transplantation. NIMA(d) -exposed, H-2(b) offspring that failed to suppress DTH uniformly rejected heart allografts (12/12) by d15. In contrast, 5/6 NIMA(d) -exposed DTH 'regulators' accepted their allografts >100 days. The defect in 'nonregulator" offspring could be corrected by transfer of CD4⁺CD25⁺, but not CD4⁺ CD25(neg) or CD8⁺ T cells from transplant acceptor mice. In conclusion, donor-specific T reg screening of F1 backcross offspring correctly predicted which recipients would accept a heart allograft. If translated to the clinic, similar pretransplant Treg screening could greatly enhance the effectiveness of tolerance as a clinical strategy in transplantation between family members.

Could microchimerism be a source of disease-associated HLA alleles in patients with scleroderma?

Background and objectivesSystemic sclerosis (SSc) is an autoimmune disease divided in two subsets, diffuse cutaneous and limited cutaneous SSc (dcSSc and lcSSc), affecting mostly women. We, and others showed that...

Genetics of ACPA-positive rheumatoid arthritis: the beginning of the end?

Heritability is a measure for the contribution of genetic variation to the variation in liability to disease and for rheumatoid arthritis (RA) had previously been estimated to be about 60%....

Cord Blood Vα24-Vβ11+ Natural Killer T Cells Display a Th2-Chemokine Receptor Profile and Cytokine Responses

BackgroundThe fetal immune system is characterized by a Th2 bias but it is unclear how the Th2 predominance is established. Natural killer T (NKT) cells are a rare subset of T cells with immune regulatory functions and are already activated in utero. To test the hypothesis that NKT cells are part of the regulatory network that sets the fetal Th2 predominance, percentages of Vα24+Vβ11+ NKT cells expressing Th1/Th2-related chemokine receptors (CKR) were assessed in cord blood. Furthermore, IL-4 and IFN-γ secreting NKT cells were quantified within the single CKR+ subsets.ResultsCord blood NKT cells expressed the Th2-related CCR4 and CCR8 at significantly higher frequencies compared to peripheral blood NKT cells from adults, while CXCR3+ and CCR5+ cord blood NKT cells (Th1-related) were present at lower percentages. Within CD4negCD8neg (DN) NKT cells, the frequency of IL-4 producing NKT cells was significantly higher in cord blood, while frequencies of IFN-γ secreting DN NKT cells tended to be lower. A further subanalysis showed that the higher percentage of IL-4 secreting DN NKT cells was restricted to CCR3+, CCR4+, CCR5+, CCR6+, CCR7+, CCR8+ and CXCR4+ DN subsets in cord blood. This resulted in significantly decreased IFN-γ /IL-4 ratios of CCR3+, CCR6+ and CCR8+ cord blood DN NKT cells. Sequencing of VA24AJ18 T cell receptor (TCR) transcripts in sorted cord blood Vα24Vβ11 cells confirmed the invariant TCR alpha-chain ruling out the possibility that these cells represent an unusual subset of conventional T cells.ConclusionsDespite the heterogeneity of cord blood NKT cells, we observed a clear Th2-bias at the phenotypic and functional level which was mainly found in the DN subset. Therefore, we speculate that NKT cells are important for the initiation and control of the fetal Th2 environment which is needed to maintain tolerance towards self-antigens as well as non-inherited maternal antigens.

Major and minor histocompatibility antigens to NIMA

The immunologic effects of developmental exposure to non-inherited maternal antigens (NIMA) are heterogeneous, either tolerogenic or immunogenic. The role of minor histocompatibility antigens (MiHA) in NIMA effects is unknown. We have recently reported that the NIMA effect can be classified into two distinct reactivities, low and high responder, to NIMA in utero and during nursing depending on the degree of maternal microchimerism (MMc) and Foxp3 expression of peripheral blood CD4+CD25+ cells after graft-versus-host disease (GVHD) induction. These reactivities were predictable before transplantation, using an MLR-ELISPOT (mixed lymphocyte reaction; enzyme-linked immunospot) assay by comparing the number of IFN-γ-producing cells stimulated with NIMA. Moreover, This assay was also applicable in both major and minor NIMA-mismatched setting. These observations are clinically relevant and suggest that it is possible to predict the immunological tolerance to NIMA.

Histocompatibility and immunogenetics in cord blood transplantation.

This review of the immunogenetics of cord blood transplantation attempts to highlight the connections between classical studies and conclusions of the tissue transplantation field as a scholarly endeavor, exemplified by the work of Professor Hoecker, with the motivations and some recent and key results of clinical cord blood transplantation. The authors review the evolution of understanding of transplantation biology and find that the results of the application of cord blood stem cells to Transplantation Medicine are consistent with the careful experiments of the pioneers in the field, from the results of tumor and normal tissue transplants, histocompatibility immunogenetics, to cell and molecular biology. Recent results of the National Cord Blood Program of the New York Blood Center describe the functioning in cord blood transplantation of factors, well known in transplantation immunogenetics, like the Fl anti-parent effect and the tolerance-like status of donors produced by non-inherited maternal HLA antigens. Consideration of these factors in donor selection strategies can improve the prognosis of transplantation by characterizing "permissibility" in HLA-incompatible transplantation thereby increasing the probability of survival and reducing the likelihood of leukemic relapse.

Effect of parity on fetal and maternal microchimerism: interaction of grafts within a host?

AbstractSmall amounts of genetically foreign cells (microchimerism, Mc) traffic between a mother and fetus during pregnancy. Commonly, these grafts durably persist. For women, multiple naturally acquired Mc grafts can accrue, as they harbor Mc from their own mothers (maternal Mc, MMc) and subsequently acquire fetal Mc (FMc) through pregnancy. The nature of interactions between these naturally acquired grafts may inform, and be informed by, observations in transplantation, including the effect of noninherited maternal HLA antigens (NIMA) and double-unit cord blood transplantation (CBT). We asked whether FMc and MMc are impacted by the addition of new grafts as evaluated by increasing parity. Mc was identified by quantitative PCR for a nonshared polymorphism unique to the Mc source. Despite increasing sources of Mc, FMc did not increase with increasing parity. MMc concentration was significantly lower with increasing parity. The odds ratio for detection of MMc for 2 or more births compared with 1 birth was .11 (95% CI 0.03-0.42, P = .001). These observations suggest that interactions occur among naturally acquired grafts and are of interest in light of recent observations of graft-graft interaction resulting in predominance of 1 unit in double-unit CBT and the correlation of MMc with the NIMA effect.

Fetal microchimerism persists at high levels in c-kit+ stem cells in sensitized mothers

We previously showed that fetal and maternal exposure to non-inherited maternal antigens (NIMA) during gestation and nursing resulted in lifelong tolerance to NIMA in some offspring. This NIMA-specific tolerance was mediated by regulatory T cells (Tregs) and was correlated with the level of multi-lineage maternal microchimerism (Mc) indicating a causative link between Mc and Treg development. To determine if transfer of fetal cells into mothers resulted in a similar tolerance to fetal cells, we used qPCR to detect rare fetal derived cells and a delayed type hypersensitivity (DTH) assay to detect fetal alloantigen-specific effector and regulatory T cells in mothers. We found that 5/8 B6 mothers of H2(b/d) offspring were sensitized to the alloantigens H2(d) and HY, indicating a dominance of alloantigen-specific effector T cells. Though these sensitized mothers did not have detectable fetal Mc (FMc) in any of the organs tested, they had very high levels of fetus-derived c-kit(+) stem cells in their bone marrow. The remaining 3/8 B6 mothers that were not sensitized to the fetal antigens had detectable FMc found mostly in heart, lungs and liver, and in 2/3, we could detect alloantigen-specific regulatory T cells. This data indicates that, as in NIMA-specific tolerance, tolerance in multiparous females to inherited paternal antigens (IPA) expressed by the fetus is associated with the presence of fetal Mc in differentiated cell subsets. Surprisingly, robust lin(-)c-kit(+) bone marrow cell fetal Mc can occur in sensitized mothers. This suggests a continuous source of allospecific priming, coupled with active elimination of mature IPA-expressing lin(+) cells by effector T cells of the maternal host.

The pendulum swings

Fetal and/or perinatal exposure to noninherited maternal antigens (NIMA) has been reported to induce NIMA-specific tolerance. This tolerant state is highly beneficial in transplantation settings; enhanced graft acceptance has been observed when transplanted tissues express NIMA. Reduction in severe graft-vs-host disease has also been noted when bone marrow grafts originate from donors exposed to NIMA in early life. However, there is emerging evidence that exposure to NIMA can alternatively lead to specific priming. The processes regulating tolerance versus priming to NIMA are poorly understood and probably multifactorial. Based on studies in both humans and mice, we propose that both the quality and the quantity of NIMA exposure will be found to be key determinants of these opposing outcomes.

Breast milk and transplantation tolerance

Recent experimental and clinical studies suggest that exposure of the fetus to noninherited maternal antigens (NIMAs) during pregnancy has an impact on allogeneic transplantations performed later in life. We have reported that NIMA exposure by breastfeeding further potentiates the tolerogenic NIMA effect mediated by in utero NIMA exposure during pregnancy in mice of allogeneic hematopoietic stem cell transplantation (HSCT). Breastfeeding generates Foxp3(+) regulatory T cells that suppress anti-maternal immunity and persist until adulthood. These results reveal a previously unknown impact of breastfeeding on the outcome of allogeneic HSCT.

Stem cell microchimerism and tolerance to non-inherited maternal antigens

Exposure to non-inherited maternal antigens (NIMA) in fetal and neonatal life of an F(1) backcross (BDF(1) female × B6 male) mouse can result in lifelong tolerance to allografts expressing the NIMA (H2(d)). We have recently shown that the NIMA-specific regulatory T cells were directly correlated with level of maternal microchimerism (MMc) in adult mice, indicating a causative link between the two, and that both Tregs and multi-lineage MMc were dependent on ingestion of milk from a NIMA(+) mother during nursing. Yet how maternal cells obtained in fetal and neonatal life are maintained in adult life remains unclear. Since stem cells are deficient in MHC class I & II expression, we hypothesized that maternally derived stem cells that replenish MMc remain throughout life without eliciting immunity, but differentiated maternal cells can either be deleted by alloreactive T and B effector cells or persist, inducing NIMA-specific tolerance. Consistent with this hypothesis, we found maternally-derived lineage(neg) c-kit(+) cells in the bone marrow of most of adult offspring by quantitative PCR; however, only 50% had detectable MMc in lineage(+) bone marrow cells. Mesenchymal stem cells (lineage(neg) and plate-adherent cells) propagated from the bone marrow also contained maternally-derived cells, albeit in 10-fold lower frequency compared with MMc in myeloid lineage (CD11b(+) and CD11c(+)) cells. Maternally-derived cardiac stem cells were also detected in lineage(neg) c-kit(+) cells purified from heart tissue of NIMA-exposed mice, indicating a local pool of stem cells sustaining MMc in a non-lymphoid tissue. Cardiac stem cell MMc correlated with the presence of maternally derived cardiomyocytes. Lastly, liver MMc increased after nursing suggesting a seeding of maternal cells into the liver via breast milk. Whether orally-derived liver MMc also included maternal stem cells, was not determined. Maternal stem cells in bone marrow and tissues of NIMA-exposed mice are likely responsible for sustaining MMc in adult mice, but their presence alone does not guarantee multi-lineage MMc and tolerance.

Analysis of maternal–offspring HLA compatibility, parent‐of‐origin effects, and noninherited maternal antigen effects for HLA–DRB1 in systemic lupus erythematosus

Genetic susceptibility to systemic lupus erythematosus (SLE) is well established, with the HLA class II DRB1 and DQB1 loci demonstrating the strongest association. However, HLA may also influence SLE through novel biologic mechanisms in addition to genetic transmission of risk alleles. Evidence for increased maternal-offspring HLA class II compatibility in SLE and differences in maternal versus paternal transmission rates (parent-of-origin effects) and nontransmission rates (noninherited maternal antigen [NIMA] effects) in other autoimmune diseases have been reported. Thus, we investigated maternal-offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 in SLE. The cohort comprised 707 SLE families and 188 independent healthy maternal-offspring pairs (total of 2,497 individuals). Family-based association tests were conducted to compare transmitted versus nontransmitted alleles (transmission disequilibrium test) and both maternally versus paternally transmitted (parent-of-origin) and nontransmitted alleles (using the chi-square test of heterogeneity). Analyses were stratified according to the sex of the offspring. Maternally affected offspring DRB1 compatibility in SLE families was compared with paternally affected offspring compatibility and with independent control maternal-offspring pairs (using Fisher's test) and was restricted to male and nulligravid female offspring with SLE. As expected, DRB1 was associated with SLE (P < 1 x 10(-4)). However, mothers of children with SLE had similar transmission and nontransmission frequencies for DRB1 alleles when compared with fathers, including those for the known SLE risk alleles HLA-DRB1*0301, *1501, and *0801. No association between maternal-offspring compatibility and SLE was observed. Maternal-offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 are unlikely to play a role in SLE.

Histocompatibility and Immunogenetics in Cord Blood Transplantation

This review of the immunogenetics of cord blood transplantation attempts to highlight the connections between classical studies and conclusions of the tissue transplantation field as a scholarly endeavor, exemplified by the work of Professor Hoecker, with the motivations and some recent and key results of clinical cord blood transplantation. The authors review the evolution of understanding of transplantation biology and find that the results of the application of cord blood stem cells to Transplantation Medicine are consistent with the careful experiments of the pioneers in the field, from the results of tumor and normal tissue transplants, histocompatibility immunogenetics, to cell and molecular biology. Recent results of the National Cord Blood Program of the New York Blood Center describe the functioning in cord blood transplantation of factors, well known in transplantation immunogenetics, like the Fl anti-parent effect and the tolerance-like status of donors produced by non-inherited maternal HLA antigens. Consideration of these factors in donor selection strategies can improve the prognosis of transplantation by characterizing "permissibility" in HLA-incompatible transplantation thereby increasing the probability of survival and reducing the likelihood of leukemic relapse.