Semi-allogeneic Graft Research Articles

Beyond Immune Balance: The Pivotal Role of Decidual Regulatory T Cells in Unexplained Recurrent Spontaneous Abortion.

Recurrent spontaneous abortion (RSA) is defined as two or more consecutive pregnancy failures, which brings tremendous stress to women of childbearing age and seriously affects family well-being. However, the reason in about 50% of cases remains unknown and is defined as unexplained recurrent spontaneous abortion (URSA). The immunological perspective in URSA has attracted widespread attention in recent years. The embryo is regarded as a semi-allogeneic graft to the mother. A successful pregnancy requires transition to an immune environment conducive to embryo survival at the maternal-fetal interface. As an important member of regulatory immunity, regulatory T (Treg) cells play a key role in regulating immune tolerance at the maternal-fetal interface. This review will focus on the phenotypic plasticity and lineage stability of Treg cells to illustrate its relationship with URSA.

Medawar and the immunological paradox of pregnancy: in context.

In 1953, Peter Medawar defined 'the immunological paradox of pregnancy', whereby the semi-allogeneic foetus can survive for 9 months in its mother, while a semi-allogeneic graft would be rejected. Here, I revisit the immunological paradox of pregnancy, setting it in the context of the time in which it was proposed. I go on to examine the extent to which Medawar's ideas on the subject have stood the test of time and how they have shaped reproductive immunology.

Medawar's Paradox and Immune Mechanisms of Fetomaternal Tolerance.

Brazilian-born British biologist Dr. Peter Medawar played an integral role in developing the concepts of immunologic rejection and tolerance, which led to him receiving the Nobel Prize “for the discovery of acquired immunologic tolerance” and eventually made organ transplantation a reality. However, at the time of his early work in tolerance, a paradox to his theories was brought to his attention; how was pregnancy possible? Pregnancy resembles organ transplantation in that the fetus, possessing paternal antigens, is a semi-allogeneic graft that can survive without immunosuppression for 9 months. To answer this question, Medawar proposed three hypotheses of how a mother supports her fetus in utero, now known as “Medawar’s Paradox.” The mechanisms that govern fetomaternal tolerance are still incompletely understood but may provide critical insight into how to achieve immune tolerance in organ transplantation. Here, we review current understanding of the immune factors responsible for fetomaternal tolerance during pregnancy and discuss the potential implications for advances in transplantation science.

In the absence of natural killer cell activation donor-specific antibody mediates chronic, but not acute, kidney allograft rejection

Antibody mediated rejection (ABMR) is a major barrier to long-term kidney graft survival. Dysregulated donor-specific antibody (DSA) responses are induced in CCR5-deficient mice transplanted with complete major histocompatibility complex (MHC)-mismatched kidney allografts, and natural killer (NK) cells play a critical role in graft injury and rejection. We investigated the consequence of high DSA titers on kidney graft outcomes in the presence or absence of NK cell activation within the graft. Equivalent serum DSA titers were induced in CCR5-deficient B6 recipients of complete MHC mismatched A/J allografts and semi-allogeneic (A/J x B6) F1 kidney grafts, peaking by day 14 post-transplant. A/J allografts were rejected between days 16-28, whereas B6 isografts and semi-allogeneic grafts survived past day 65. On day 7 post-transplant, NK cell infiltration into A/J allografts was composed of distinct populations expressing high and low levels of the surface antigen NK1.1, with NK1.1low cells reflecting the highest level of activation. These NK cell populations increased with time post-transplant. In contrast, NK cell infiltration into semi-allogeneic grafts on day 7 was composed entirely of NK1.1high cells that decreased thereafter. On day 65 post-transplant the semi-allogeneic grafts had severe interstitial fibrosis, glomerulopathy, and arteriopathy, accompanied by expression of pro-fibrogenic genes. These results suggest that NK cells synergize with DSA to cause acute kidney allograft rejection, whereas high DSA titers in the absence of NKcell activation cannot provoke acute ABMR but instead induce the indolent development of interstitial fibrosis and glomerular injury that leads to late graft failure.

Donor-specific antibody mediates chronic, but not acute, kidney allograft rejection in the absence of natural killer cells

Abstract Dysregulated donor-specific antibody (DSA) responses are induced in B6.CCR5−/− mice transplanted with complete MHC mismatched kidney allografts and NK cells play a critical role in acute graft injury and failure. The current study investigated the consequence of high DSA titers on graft outcomes in the presence vs. absence of NK cell activation within the kidney graft. B6.CCR5−/− recipients of complete MHC mismatched A/J allografts or semi allogeneic (A/J x B6)F1 kidney grafts responded with equivalent serum DSA titers that reached peak by day 14 post-transplant. B6.CCR5−/− recipients rejected A/J allografts between days 15–30, whereas B6 isografts and (A/J x B6)F1 semi allogeneic grafts survived past day 65. On day 7 post-transplant NK cell infiltration into A/J allografts was composed of distinct Ly49b+ cell populations expressing low and high levels of NK1.1 and both NK1.1high and NK1.1low cells increased in A/J allografts with time to rejection. In contrast, NK cell infiltration into (A/J x B6)F1 grafts on day 7 post-transplant was composed entirely of NK1.1high cells that decreased to background/isograft numbers thereafter. (A/J x B6)F1 grafts at day 65 post-transplant had severe chronic injury with prominent interstitial fibrosis, glomerulopathy and arteriopathy that was accompanied by gene expression of profibrogenic factors. These results indicate that NK cells synergize with DSA to cause acute kidney allograft failure whereas high titers of DSA in the absence of NK cell activation cannot cause acute antibody-mediated rejection but induce the indolent development of interstitial fibrosis and glomerular injury that leads to graft dysfunction and failure at later times after transplantation.

Evaluation of HLA-G 14-bp ins/del and +3142G>C polymorphisms with susceptibility to recurrent spontaneous abortion

ObjectiveHLA-G is critically important for successful implantation during pregnancy. Increasing evidence supposed that HLA-G plays a key role in tolerance of the semi-allogeneic graft in pregnancy by inhibiting the cytotoxic functions of T and NK cells. The present study aimed to evaluate the impact of HLA-G rs1063320 (+3142G>C) and 14-bp insertion (ins)/deletion (del) polymorphisms on recurrent spontaneous abortion (RSA). Materials and MethodsGenomic DNA from 93 RSA patients and 93 normal fertile women was isolated using the salting out method. Genotyping of HLA-G +3142G>C and 14-bp ins/del variants was done by polymerase chain reaction restriction fragment length polymorphism (PCR-RFP) and PCR method, respectively. ResultsThe HLA-G +3142G>C polymorphism increased the risk of RSA in codominant (OR = 2.39, 95%CI = 1.27–4.49, p = 0.010, GC vs GG; OR = 3.28, 95%CI = 1.16–9.72, p = 0.040, CC vs GG) and dominant (OR = 2.52, 95%CI = 1.37–4.64, p = 0.004, GC + CC vs GG) tested inheritance models. HLA-G rs1063320 C allele was associated with increased risk of RSA (OR = 1.84, 95%CI = 1.20–2.83, p = 0.007). The del/del genotype as well as del allele of 14-bp ins/del variant increased that risk of RSA (OR = 3.02, 95%CI = 1.23–7.41, p = 0.025 and OR = 1.65, 95%CI = 1.09–2.50, p = 0.022, respectively). ConclusionIn summary, our results showed that HLA-G gene polymorphisms significantly increased the risk of RSA in a sample of the Iranian population.

Association of 14-bp insertion/deletion polymorphism of HLA-G gene with idiopathic recurrent miscarriages in infertility center patients in Yazd, Iran

HLA-G is supposed to play a pivotal role in tolerance of the semi-allogeneic graft in pregnancy by inhibiting the cytotoxic functions of T and NK cells. A 14-bp insertion and/or deletion polymorphism in exon-8 has a possible role in HLA-G expression. The present study analyzed the 14-bp insertion/deletion polymorphism in normal pregnancy and recurrent miscarriage patients in order to discover a possible correlation between the 14-bp polymorphism and recurrent miscarriage (RM). In this study, genomic DNA from 200 RM patients and 200 normal fertile control individuals using the routine salting out method were isolated. Exon-8 of HLA-G gene of the two groups were amplified using polymerase chain reaction and analyzed by electrophoresis on 10% non-denaturing polyacrylamide gel electrophoresis containing ethidium bromide and visualized under ultraviolet light. HLA-G allele frequencies and genotypes in RM women and the fertile control group were compared using a Chi-square test. The results showed that there was a difference in allelic frequencies of 14-bp insertion polymorphism between fertile controls and RM patients; the frequency of +14 bp/−14 bp heterozygotes was significantly higher in RM patients as compared with fertile controls. Furthermore, the frequency of +14-bp insertion allele was significantly higher in those with RM as compared with normal fertile controls. From the findings here, it was concluded that a 14-bp insertion/deletion polymorphism in exon 8 could play a possible role in recurrent miscarriages. These results might ultimately be of significance for clinicians and those involved in understanding infertility and RM.

T regulatory cells: regulating both term and preterm labor?

T regulatory cells: regulating both term and preterm labor?

Cytokines in Placental Physiology and Disease

Cytokines in Placental Physiology and Disease

Immunologic hurdles of therapeutic stem cell transplantation

Detailed knowledge of the immunologic properties of embryonic stem (ES) cells is a prerequisite for safe applications of ES cell-based regenerative medicine. Recently, the long-standing assumption that ES cells are ignored by immunocompetent hosts was disproved. Instead, it is becoming increasingly clear that ES cells actively protect themselves via several immunomodulatory and immunoevasive mechanisms against cytotoxic T-lymphocytes and natural killer cells. Here we review current knowledge about the immunologic properties of ES cells and discuss the implications for ES cell-based regenerative medicine, for the immunobiology of the embryo as a semi-allogeneic graft, and for the regenerative capacity of adult stem cells.

Increased semi-allogeneic skin graft survival after FTY720 treatment

FTY720 is a new compound which increases allograft survival in animal models through not fully elucidated mechanisms. Purpose: We investigated the effects of the FTY720 administration in semi-allogeneic skin graft survival in an animal model and its associated mechanisms. Methods: Both transplanted, Non-treated (Tx) and Treated (Tx+FTY720) groups were daily observed to determine the semi- allogeneic skin graft survival. In another set of experiments both groups were assessed in different time points for lymphocyte numbers and activation markers in blood and spleen. In a third experiment, mice recipients that accepted skin semi-allogeneic graft had spleen, blood, or axillary lymph node cells harvested and adoptively transferred to naïve C57BL/6 mice followed after 24 hours by a F1 skin semi- allogeneic graft transplantation. Results: Skin semi-allogeneic graft survival increased significantly in Treated Group (21.3±10.1 days) when compared to the Non-treated Group (12.9±0.4 days) (p=0.002). Five days after transplantation, Treated Group presented significantly lower amount of lymphocyte in spleen and blood (44.7±11.6x106 and 38.2±14.8%) than Non-treated mice (77.5±19.5x106 and 70.0±12.3%), respectively (p<0.005). MHC II expression in splenocytes was 26.3±5.6% in Treated, and 28.0±11.0% in Non-treated Group (p=0.3) whereas such marker presented a significant lower expression in blood: 5.6±4.1% versus 28.9±8.0% (p<0.005), respectively. Graft infiltrating cells were significantly higher in Non-treated than in Treated mice (p<0.005). Adoptive transfer caused no improvement in skin semi-allogeneic graft survival. Conclusion: The FTY720 treatment successfully improved mice skin semi-allogeneic graft survival, impairing antigen presentation and reducing graft cell infiltration. Functional tolerance after FTY720 administration was not observed.

Graft-versus-host disease and immunologic rejection: implications for diagnosis and treatments of pregnancy complications

This paper summarizes recent evidence from transplantation, autoimmune and obstetrical literatures, suggesting that exposure to (allogeneic) donor cell traffic may be prerequisite for successful tolerance of allogeneic grafts in organ transplantation and pregnancy, where the fetus represents a semiallogeneic graft. It is based on a review of the literature utilizing PubMed and Medline searches. Donor cells can induce adverse effects, including graft-versushost disease, acute and/or chronic graft rejection and/or related autoimmune phenomena. Observations in the pre-eclampsia/eclampsia syndrome suggest that some still largely unexplained conditions of pregnancy, possibly including labor, may represent acute graftversus-host disease states. Abnormal clinical and laboratory responses may be the consequence of excessive histocompatibility (HLA) antigen dosaging, due to excessive fetal–maternal cell traffic. On other occasions, antigen dosaging may be appropriate, but maternal/paternal HLA may be too similar. ...

CD4 +CD25 + regulatory/suppressor T cells prevent allogeneic fetus rejection in mice

Recent evidences indicate that naturally occurring CD4 +CD25 + regulatory/suppressor T cells (T reg) regulate not only autoimmunity, but also alloreactivity. In mice, they notably control tolerance to allogeneic transplants and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Here, we studied the role of T reg in maternal tolerance to fetuses, i.e. natural semi-allogeneic grafts. We show that semi-allogeneic pregnancies in mice induce an expansion of T reg, but not of activated CD4 + and CD8 + T cells, in para-aortic lymph nodes draining fetal antigens. The treatment of female mice with an anti-CD25 antibody before mating results in depletion of T reg and expansion of activated CD4 + and CD8 + T cells solely in the draining lymph nodes, ultimately leading to fetus rejection. These observations were not made in the context of syngeneic pregnancies. Thus, T reg play a major role in maternal–fetal tolerance.

Less HLA-G Expression in Plasmodium falciparum-Infected Third Trimester Placentas is Associated with More Natural Killer Cells

During pregnancy, maternal immune tolerance of the fetal semi-allogeneic graft is partly the consequence of extravillous trophoblast HLA-G expression and its interaction with natural killer (NK) cells. Plasmodium falciparum malaria is frequently associated with maternal and fetal complications. Local HLA-G expression and the number of NK cells were evaluated immunohistochemically in P. falciparum-infected and uninfected placentas (15 each) collected in a seasonal malaria-hypoendemic area. In control placentas, HLA-G was almost always expressed in extravillous trophoblast whereas, in infected placentas, it was significantly more weakly expressed in extravillous trophoblast but was also detected in intervillous space macrophages. NK cells were evaluated in intervillous and intravillous spaces and in basal plate. NK cells were always more abundant in basal plate than in intervillous and intravillous spaces in infected or control placentas. For each area, more NK cells were seen in infected than control placentas. These data suggest that HLA-G down-regulation and more NK cells in placentas may be among the mechanisms involved in poor birth outcome associated with P. falciparum infection.

Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone

Women mount more vigorous antibody- and cell-mediated immune responses following either infection or vaccination than men. The incidence of most autoimmune diseases is also higher in women than in men; however, during pregnancy many autoimmune diseases go into remission, only to flare again in the early post-partum period. Successful pregnancy requires that the female immune system tolerate the presence of a semi-allogeneic graft for 9 months. Oral contraceptive use can increase susceptibility to certain genital tract infections and sexually transmitted diseases in women. Moreover, treatment of mice and rats with female sex hormones is required to establish animal models of genital tract Chlamydia, Neisseria and Mycoplasma infection. This review describes what is currently known about the effects of the female sex hormones oestradiol and progesterone on innate and adaptive immune responses in order to provide a framework for understanding these sex differences. Data from both human and animal studies will be reviewed.

Pregnancy and the immune system: between tolerance and rejection

Interactions between the conceptus and the mother are bi-directional: the feto-placental tissues need nutrition and a suitable environment in homeostatic condition whereas the mother influenced by the placental factors adapts her metabolism and immune system. Many different mechanisms acting locally or at distance ensure tolerance of the semi-allogeneic graft by the maternal natural and adaptive immune defences. In front of this tolerance, mechanisms exist ensuring rejection of the conceptus by the mother (spontaneous abortion) through rupture of one or more tolerance mechanisms, notably in stress situations endangering the mother. Thus outcome of a pregnancy is dependent on efficiently working tolerance mechanisms, and rupture of such mechanisms can lead to rejection. The balance of influence leading either to tolerance or rejection is under control of internal (maternal and fetal) and external (environmental) factors. Rejection, if triggered, mainly occurs through immune-induced inflammation, tissue degradation and coagulation.

Intestinal crypt cell apoptosis in murine acute graft versus host disease is mediated by tumour necrosis factor α and not by the FasL-Fas interaction: effect of pentoxifylline on the development of mucosal atrophy

BACKGROUNDMurine T cell mediated acute semiallogeneic graft versus host disease (GVHD) is characterised by lymphocytic infiltrates, crypt hyperplasia, and villous atrophy. It has been shown that programmed cell death (apoptosis)...

Serum levels of pro- and anti-inflammatory cytokines in non-pregnant women, during pregnancy, labour and abortion.

Disturbance of the cytokine equilibrium has been accused for many pathological disorders. Microbial infections, autoimmune diseases, graft rejection have been correlated to over- or under-production of specific cytokines which are produced as responder molecules to the various immune stimuli. The sole naturally occurring immune reaction in the organism is developed during the gestational period where, despite the presence of a semi-allogeneic graft, maternal immunoreactivity is driven to support fetal growth. The successful embryo development has been attributed to the important intervention of cytokines where some have been characterized as indispensable and others deleterious to fetal growth. However, the physiological levels of many factors during the gestational process have not been determined. Thus, in the present study we have measured and established the values of IL-1alpha, IL-2, IL-3, IL-4, IL-6, IL-10, IL-12, GM-CSF, TNF-alpha and IFN-gamma during all phases of human pregnancy (first, second and third trimester of pregnancy, labour, abortions of the first trimester) as well as in the non-pregnant control state. This is an attempt to assess serum protein concentrations and present the physiological levels of these cytokines at certain time intervals providing thus a diagnostic advantage in pregnancy cases where the mother cannot immunologically support the fetus. Exploitation of this knowledge and further research may be useful for therapeutic interventions in the future.

Unique CD8+ T cell-rich lymphoid aggregates in human uterine endometrium

Using confocal scanning laser microscopy of viable tissue sections, we have demonstrated organized lymphoid aggregates (LA), that have a unique structure, in the stratum basalis of uterine endometrium. These LA consist of a core of B cells surrounded by more numerous T cells and an outer halo of monocytes/ macrophages. The T cells in the LA were almost exclusively CD8+CD4-. These CD8+ LA, in terms of both their T cell and B cell components, were either small or absent during the early proliferative stage of the menstrual cycle, significantly larger in size at mid-cycle and during the secretory phase, and absent in post-menopausal women, suggesting that their development is hormonally influenced. This new finding of a menstrual cycle-dependent, phenotypically unique, organized immune cell structure may lead to new insights into the mechanisms by which the endometrium accepts a semiallogeneic graft while providing resistance to infectious organisms.

Osteogenic Growth Peptide Increases Blood and Bone Marrow Cellularity and Enhances Engraftment of Bone Marrow Transplants in Mice

The osteogenic growth peptide (OGP) was characterized recently in regenerating bone marrow (BM) and normal serum. In vitro, the OGP regulates stromal-cell proliferation and differentiated functions. In vivo, an increase in serum OGP accompanies the osteogenic phase of postablation BM regeneration. The present results in normal mice show that OGP induces a balanced increase in WBC counts and overall BM cellularity. In mice receiving myeloablative irradiation and syngeneic or semiallogeneic BM transplants, OGP stimulates hematopoietic reconstruction and doubles the survival rate; these effects are dependent on initiating the OGP administration before irradiation. Chimerism measurements in semiallogeneic graft recipients suggest no preferential effect of OGP on residual host cells. The data implicate OGP in the acceleration of hematopoiesis secondary to expansion of the stromal microenvironment and/or enhancement of stroma-derived signals to stem cells. The low-dose effectiveness of OGP is explained by the demonstration of an autocrine positive feedback loop that together with the OGP-binding protein sustains high serum levels of the peptide. A potential OGP-based treatment in combination with chemoradiotherapy is attractive because of the OGP-induced balanced multi-lineage enhancement of hematopoiesis and possible replacement of expensive recombinant cytokines by a readily synthesized peptide.