Alloreactivity of umbilical cord blood mononuclear cells: specific hyporesponse to noninherited maternal antigens (original) (raw)
Related papers
American Journal of Reproductive Immunology, 1998
Munksgaard, Copenhagen PROBLEM: Human leukocyte antigen (HLA)-G is a major histocompatibility complex class I antigen, which is referred to as nonclassical because it displays a tissue-restricted distribution in the placenta, a reduced cytoplasmic domain, a limited polymorphism, and several isoforms. The HLA-G antigen is thought to play an essential role during pregnancy by protecting the semi-allogeneic fetus from recognition and destruction by maternal immune cells. METHOD OF STUDY: Alternative splicing of HLA-G mRNA was analyzed by Southern blot of reverse transcriptase-polymerase chain reaction products from trophoblasts of the first trimester of gestation and term placenta. The regulation of HLA-G gene expression was investigated by electrophoretic mobility shift assays using nuclear extracts from cells expressing different levels of HLA-G gene activity. Using polymerase chain reaction-single strand conformational polymorphism and sequencing, we studied HLA-G gene polymorphism in families from the Centre d'Etude du Polymorphisme Humain in Paris. To understand the function of the HLA-G molecule, cytotoxicity assays were carried out with peripheral blood mononuclear cells or polyclonal natural killer effectors cells from 30 different donors against HLA-GI and HLA-G2 transfectants. RESULTS: Four main aspects have been elucidated: 1) The primary transcript of the HLA-G gene is alternatively spliced into five main mRNA forms: HLA-GI (full length), HLA-G2 (minus exon 3), which encodes a membrane-bound isoform associated with beta-2 microglobulin, HLA-G3 (minus exons 3 and 4), HLA-G4 (minus exon 4), and HLA-G5 (plus intron 4), which encodes a soluble form of the HLA-G antigen; 2) specific nuclear factors bind to an important regulatory element located more than 1.2 kb from the HLA-G gene. Three specific complexes are observed in cells that show HLA-G transcriptional activity and an additional factor that could correlate with the repression of HLA-G gene expression that is detected in natural killer cells; 3) we observed an important genomic polymorphism in exon 3 but a very low polymorphism at the protein level; 4) HLA-GI and HLA-G2 transfectants clearly demonstrated that both HLA-G isoforms are capable of inhibiting natural killer lytic activity. CONCLUSION: These results suggest that HLA-G acts as the public ligand for natural killer inhibitory receptors, thus protecting the fetus against maternal rejection.
Biology of Blood and Marrow Transplantation
Cord blood (CB) is an alternative stem cell source for allogeneic hematopoietic stem cell transplantation (HSCT). The unique advantages of using CB as a stem cell source are a degree of permissibility for HLA mismatch, rapid availability, and relatively risk-free cell collection. Because HLA is highly polymorphic and population-specific, optimal HLA-matched unrelated donors or cord blood units (CBUs) might not be available. In view of the possibility that matched CBUs that include noninherited maternal antigens (NIMAs) might contain acceptable HLA mismatches, we attempted to determine the degree of alloreactivity of CB mononuclear cells (MNCs) on stimulation by the maternal, paternal, and unrelated stimulator cells. Suppression of T cell proliferation, cytotoxicity, and a cytokine profile indicating suppressed Th1 and elevated IL-10 and TGF-b1 responses were observed in the mixed lymphocyte reaction in response to NIMAs. The increases in IL-10 and TGF-b1 production may be due to the Th2 response and/or regulatory T cells (Tregs). The reduced IL-10 and TGF-b1 production after CD25 depletion could have been due to removal of Tregs from the CB cells. Thus, Tregs appear to play an important role in the CB MNC response to NIMAs, possibly due to the induction of IL-10 and TGF-b1. We hope that our work can provide some evidence of the beneficial effect of NIMAs.
Differential immunogenicity of paternal HLA Class I antigens in pregnant women
Human Immunology, 2003
More insight into the differential immunogenicity of human leukocyte antigen (HLA) mismatches will be beneficial for donor selection in clinical transplantation. In this study the immunogenicity of HLA antigens was analyzed by examining the antibody profiles in women who have been pregnant. In total 888 women, who had pregnancy induced HLA alloantibodies, were included in this study, while 413 women who had not been immunized by their pregnancy, served as controls. First it was analyzed whether women expressing particular HLA antigens are more likely to produce HLA alloantibodies. Next we determined whether certain HLA mismatches of their children are more immunogenic than other ones. Finally we studied whether the immunogenicity of specific HLA mismatches is dependent on the HLA phenotype of the women. Women expressing HLA-A3, HLA-A32, and HLA-B21 are more likely to produce alloantibodies whereas women expressing HLA-B13 and HLA-B17 have a significantly lower incidence of alloan-tibodies compared with women expressing other HLA antigens. Children with HLA-A2 or HLA-B5 mismatches induced alloantibodies significantly more often whereas children with HLA-A30,-A31 or-A33 and HLA-A28 induced alloantibodies significantly less often than children with other HLA class I mismatches. Finally we could demonstrate that the immunogenicity of a particular HLA mismatch is dependent on the HLA phenotype of the women. Information on the differential immunogenicity of HLA mismatches may be of benefit for the determination of acceptable and taboo mismatches in the case of donor selection for (highly sensitized) patients. Human Immunology 64, 600-606 (2003).
Cytokine-enhanced mixed lymphocyte reaction (MLR) in cord blood
Clinical and Experimental Immunology, 1998
SUMMARY Although in cord blood (CB) transplantation graft-versus-host disease (GVHD) is reported to be less severe, GVHD may occur even in patients with HLA-identical sibling donors. This result shows that HLA typing can not entirely predict GVHD. The standard MLR with CB cells was either normal or slightly reduced compared with adult peripheral blood (PB) cells. We used two manipulations to increase the responses of CB cells to allo-antigens. The first was to treat the stimulator cells with cytokines, and the second to amplify weak proliferative responses by adding exogenous cytokines to MLR cultures (modified MLR). The stimulator cells were treated with both interferon-gamma (IFN-γ) and IL-4. The responder cells were treated with both IL-2 and tumour necrosis factor-alpha (TNF-α). It is still to be determined whether or not this cytokine-enhanced MLR could be a possible predictor of GVHD. However, using these cytokines, 90% of CB could recognize allo-antigens, even if the standard...
HLA class I noninherited maternal antigens in cord blood and breast milk
Human Immunology, 2004
Maternally induced allotolerance both in clinical and experimental organ transplantation appears to require both in utero and oral exposure to noninherited maternal antigens (NIMA). Soluble major histocompatibility complex (MHC) class I antigens were studied in 18 mother-baby pairs in order to determine the extent of neonatal exposure to NIMA. Enzyme-linked immunoabsorbent assay (ELISA) analysis of cord blood from three genetically HLA-A2 negative babies born to HLA-A2ϩ mothers and from two HLA-A3 negative babies born to HLA-A3ϩ mothers revealed significant NIMA HLA-A levels in cord plasma. The level of NIMA-A2 or-A3 in cord blood were approximately 10% of the predicted value for a baby genetically positive for that allele. HLA-A2 or-A3 was undetectable (Ͻ1.0 ng/ml) in cord blood from HLA-A2 or-A3 negative babies whose mothers were also HLA-A2 or-A3 negative. Breast milk from HLA-A2ϩ mothers contained soluble HLA-A2 (sHLA-A2) at levels averaging 36.2 ng/ml, resulting in milligram quantities of ingested antigen over 3 months of nursing. Western blot analysis of cord plasma confirmed that bands corresponding to NIMA HLA-A protein were present. This study demonstrates that oral and intravenous exposure to NIMA sHLA in the fetus and newborn is much higher than previously thought, and emphasizes the importance of nursing in the overall antigen dose achieved. Human Immunology 65, 231Ϫ239
The immunological privilege of the fetus: Decreased expression of paternal HLA
Immunogenetics, 1977
Abstraet. The amounts of a maternally and paternally inherited histocompatibility antigen (HLA) on cord (or fetal) lymphocytes was measured by a microabsorption cytotoxicity procedure and compared with the amounts of antigen on parental peripheral blood lymphocytes. There were equal amounts of maternally inherited HLA on cord (or fetal) and maternal lymphocytes. The amount of paternally inherited antigen on cord (or fetal) lymphocytes was in all cases 30-90% less than that on paternal lymphocytes. This decreased expression of paternally inherited antigen is due to masking of antigen by placentally transmitted maternal blocking factor. Suppression of 'foreign' paternally-inherited antigens during gestation would explain the survival of the fetus as a tolerated allograft.
Transfusion, 2007
BACKGROUND: Human platelet antigen (HPA)-1a fetomaternal alloimmune thrombocytopenia, responsible in the most severe cases for fetal or neonatal intracranial hemorrhages leading to death or survival with neurologic sequelae, was shown to be restricted to the human leukocyte antigen (HLA) Class II DRB3*0101encoded molecule. Whereas more than 90 percent of alloimmunized mothers display the DRB3*0101 allele, the positive predictive value of the presence of DRB3*0101 is only 35 percent. Additional genetic risk factors may exist of which elucidation could improve the undertaking of incompatible pregnancies in at-risk families, encouraging an antenatal screening. Interactions of killer immunoglobulinlike receptors (KIRs) on maternal decidual NK cells with HLA-Cw molecules on fetal trophoblasts were reported as one of the mechanisms involved in the fetomaternal tolerance during pregnancy. STUDY DESIGN AND METHODS: Genotyping was performed of 16 KIR genes in HPA-1a-negative/ DRB3*0101-positive alloimmunized mothers and in HPA-1a-negative/DRB3*0101-positive nonimmunized mothers as well as HLA-Cw genotyping in thrombocytopenic children and their nonaffected siblings. RESULTS: No particular KIR genes or KIR genotypes were observed in the alloimmunized or nonimmunized mothers. Distribution of HLA-Cw genes in affected infants and nonaffected siblings did not reveal any HLA-Cw specificity associated with triggering or modulation of the HPA-1a alloimmunization. No maternal KIR/fetal HLA-Cw combinations were demonstrated in association with a detrimental or a protective effect on the HPA-1a alloimmunization. CONCLUSION: Maternal KIR/fetal HLA-Cw gene combinations that are involved in the fetomaternal tolerance do not appear to play a role in the HPA-1a alloimmunization.
Anti-HLA Antibodies in Double Umbilical Cord Blood Transplantation
Biology of Blood and Marrow Transplantation, 2011
Recent registry data suggest that host-versus-graft alloreactions mediated by anti-donor HLA antibodies in recipients of adult allogeneic hematopoietic stem cells or single-unit umbilical cord blood (UCB) contribute to the risk of graft failure. The present study evaluated the impact of anti-HLA antibodies on engraftment and unit predominance in 126 double-UCB (dUCB) recipients. Eighteen dUCB recipients were identified with at least 1 of 2 UCB units recognized by anti-HLA antibodies directed against donor-directed HLA-specific antibodies (DSAs). Overall, 9 of 12 patients who had DSAs against 1 of the 2 UCB units composing the graft and 5 of 6 patients who had DSAs against both units engrafted. The cumulative incidence of engraftment was similar in patients with and without DSAs (83% vs 78%). Thus, our data do not support a negative effect of anti-HLA antibodies on engraftment, at least in the setting of cyclosporine and mycophenolate mofetil and the conditioning regimens used at the University of Minnesota, and argue against routine screening for use in graft selection before dUCB transplantation. Further studies are needed to fully understand the value of anti-HLA antibody testing in dUCB graft selection and its impact on transplantation outcomes.