Egg donation (ED) makes it possible for subfertile women to conceive. Pregnancies achieved using ED with unrelated donors are unique, since the entire fetal genome is allogeneic to the mother. The... Show moreEgg donation (ED) makes it possible for subfertile women to conceive. Pregnancies achieved using ED with unrelated donors are unique, since the entire fetal genome is allogeneic to the mother. The aims of this review were to evaluate the consequences of ED pregnancies and to place them in the special context of their atypical immunologic relationships. This review comprised an online search of English language publications listed in Pubmed/Medline, up to 29 January 2010. Seventy-nine papers met inclusion criteria. Using the literature and the authors' own experience, the relevant data on pregnancy outcome and complications, placental pathology and immunology were evaluated. Multiple studies document that ED pregnancies are associated with a higher incidence of pregnancy-induced hypertension and placental pathology. The incidence of other perinatal complications, such as intrauterine growth restriction, prematurity and congenital malformations, is comparable to conventional IVF. During pregnancy, both local and systemic immunologic changes occur and in ED pregnancies these changes are more pronounced. There is almost no information in the literature on the long-term complications of ED pregnancies for the mother. ED pregnancies have a higher risk of maternal morbidity. Owing to the high degree of antigenic dissimilarity, ED pregnancies represent an interesting model to study complex immunologic interactions, as the fully allogeneic fetus is not rejected but tolerated by the pregnant woman. Knowledge of the immune system in ED pregnancies has broader significance, as it may also give insight into immunologic aspects of tolerance in solid organ transplantation. Show less
Purpose of review Highly sensitized patients on the kidney waitlist have the least chance to receive a cross-match negative offer and, once transplanted, have a lower patient and graft survival.... Show morePurpose of review Highly sensitized patients on the kidney waitlist have the least chance to receive a cross-match negative offer and, once transplanted, have a lower patient and graft survival. Until recently, complement-dependent cytotoxicity (CDC) was the standard method to define if a patient is sensitized or not. The introduction of more sensitive solid-phase assays (SPAs) to detect human leukocyte antigen (HLA) antibodies has led to a dramatic increase in the number of the patients on the waitlist. This review advocates the use of the 'old-fashioned' CDC to define the degree of sensitization and as the tool for allocation of kidneys to highly sensitized patients. Recent findings HLA-antibody screening using CDC is a cumbersome method that needs a high degree of expertise. SPA is easier, more reproducible and accessible to a large number of laboratories. The dogma that donor-specific antibodies (DSAs) are a contraindication for transplantation disappeared. The presence of SPA-DSA is rather a risk factor for complications than a contraindication. The opinion on the clinical relevance of SPA-DSA differs between the centers. Summary A proper designation of highly sensitized patients is crucial since it impacts the allocation. CDC-DSA is generally considered a contraindication for transplantation, whereas SPA-DSA remains controversial. The lack of consensus between centers is partly due to the heterogeneity of the HLA antibodies involved, the lack of standardization in antibody titer, the immunoglobulin (sub) class and the epitopes recognized. Until the issues are resolved, one should be careful to use the information generated in SPA for the allocation of kidneys and focus on the 'old CDC' that has shown to be effective in the past. Show less
Background. Blood transfusion (BT) may elicit both harmful and beneficial immune responses against a subsequent organ graft. Immune parameters of a single, nonleukocyte-depleted BT were... Show moreBackground. Blood transfusion (BT) may elicit both harmful and beneficial immune responses against a subsequent organ graft. Immune parameters of a single, nonleukocyte-depleted BT were investigated in two groups: non-human leukocyte antigen (HLA)-sensitized recipients with a one-HLA-DR matched donor (protocolled BT [PBT]) and females with previous exposure to HLA alloantigens through pregnancy (donor-specific transfusion [DST]). Methods. Thirty-five percent of DST recipients and 9.5% of PBT recipients developed HLA antibodies after BT. Phenotypic and functional analyses were performed in pre-BT, 2 weeks post-BT, and more than 10 weeks post-BT samples (PBT: n=10; DST: n=14). Result. The number of donor-reactive interferon-gamma-producing memory T cells increased 2 weeks post-BT, but only in the DST group, increased frequencies persisted beyond 10 weeks (P<0.004). In the DST recipients, the proportion of natural killer cells (CD3(-)CD56(+)) significantly increased after BT (P=0.01), whereas in PBT recipients, the proportion of regulatory T cells (CD4(+)CD25(+)Foxp3(+)CD127(low)) significantly increased at 2 weeks post-BT (P=0.039). Microarray analysis confirmed increased activity of genes involved in function of natural killer cells, T cells, and B cells in DST recipients and increased expression of immuneregulatory genes (galectin-1, Foxo3a, and follistatin-like 3) in PBT recipients. Galectin-1 expression by quantitative polymerase chain reaction was significantly enhanced in peripheral blood cells after PBT (P<0.05). Conclusion. Decreased immune effector mechanisms combined with an increased immune regulatory cell signature after HLA-DR-matched BT in nonsensitized patients is in line with clinical observations of improved outcome of a subsequent graft. Previous sensitization, however, may lead to HLA antibody formation and prolonged donor-specific memory T-cell reactivity after BT. Show less
Klerk, M. de; Deijl, W.M. van der; Witvliet, M.D.; Haase-Kromwijk, B.J.J.M.; Claas, F.H.J.; Weimar, W. 2010
P>Living donor kidney exchange programs offer incompatible donor-recipient pairs the opportunity to be transplanted. To increase the number of these transplants, we examined in our actual donor... Show moreP>Living donor kidney exchange programs offer incompatible donor-recipient pairs the opportunity to be transplanted. To increase the number of these transplants, we examined in our actual donor-recipient couples how to reach the maximum number of matches by using different chain lengths. We performed 20 match procedures in which we constructed four different chain lengths: two, up to three, up to four and unlimited. The actual inflow and outflow of donor-recipient couples for each run were taken into consideration in this analysis. The total number of matched pairs increased from 148 pairs for only two-way exchanges to 168 for three-way exchanges. When a chain length of 4 was allowed five extra couples could be matched over a period of 5 years. Unlimited chain length did not significantly affect the results. The optimal chain length for living donor kidney exchange programs is 3. Longer chains with their inherent logistic burden do not lead to significantly more transplants. Show less
PURPOSE OF REVIEW: Highly sensitized patients on the kidney waitlist have the least chance to receive a cross-match negative offer and, once transplanted, have a lower patient and graft survival.... Show morePURPOSE OF REVIEW: Highly sensitized patients on the kidney waitlist have the least chance to receive a cross-match negative offer and, once transplanted, have a lower patient and graft survival. Until recently, complement-dependent cytotoxicity (CDC) was the standard method to define if a patient is sensitized or not. The introduction of more sensitive solid-phase assays (SPAs) to detect human leukocyte antigen (HLA) antibodies has led to a dramatic increase in the number of the patients on the waitlist. This review advocates the use of the 'old-fashioned' CDC to define the degree of sensitization and as the tool for allocation of kidneys to highly sensitized patients. RECENT FINDINGS: HLA-antibody screening using CDC is a cumbersome method that needs a high degree of expertise. SPA is easier, more reproducible and accessible to a large number of laboratories. The dogma that donor-specific antibodies (DSAs) are a contraindication for transplantation disappeared. The presence of SPA-DSA is rather a risk factor for complications than a contraindication. The opinion on the clinical relevance of SPA-DSA differs between the centers. SUMMARY: A proper designation of highly sensitized patients is crucial since it impacts the allocation. CDC-DSA is generally considered a contraindication for transplantation, whereas SPA-DSA remains controversial. The lack of consensus between centers is partly due to the heterogeneity of the HLA antibodies involved, the lack of standardization in antibody titer, the immunoglobulin (sub)class and the epitopes recognized. Until the issues are resolved, one should be careful to use the information generated in SPA for the allocation of kidneys and focus on the 'old CDC' that has shown to be effective in the past. Show less
Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general... Show moreNarcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility. Show less
The mechanisms by which alloreactive memory T-cells are generated in non-sensitized individuals have begun to be elucidated. It is generally accepted that a very high level of crossreactivity is an... Show moreThe mechanisms by which alloreactive memory T-cells are generated in non-sensitized individuals have begun to be elucidated. It is generally accepted that a very high level of crossreactivity is an essential feature of the T-cell receptor. Indeed it has recently been shown that alloreactivity from viral specific memory T-cells is far more common than predicted, 45% of viral specific T-cell clones were found to be allo-HLA crossreactive. In this overview the evidence for crossreactive alloresponses from human viral specific memory T-cells is discussed with special emphasis on the unexpected high frequency of these crossreactive responses, the peptide and tissue specificity of the responses, and the mechanistic insights gleaned from the elucidation of the crystal structure of an allo-HLA crossreactive viral specific TCR. The possible implications for clinical solid organ and bone marrow transplantation and tolerance induction will be discussed. Show less
Purpose of review For a long period of time complement-dependent cytotoxicity was the standard assay to demonstrate clinically relevant HLA antibodies in the serum of patients before... Show morePurpose of review For a long period of time complement-dependent cytotoxicity was the standard assay to demonstrate clinically relevant HLA antibodies in the serum of patients before transplantation. The introduction of more sensitive solid-phase assays to detect HLA antibodies had led to a lot of discussion on the clinical relevance of the presence of these antibodies before transplantation and the appearance of these antibodies after transplantation. This review discusses the current controversies. Recent findings The old dogma that the presence of donor-specific HLA antibodies before transplantation is a contra-indication for transplantation does not exists anymore. The correlation between the presence of HLA antibodies and clinical outcome is less strict although the presence of circulating donor-specific antibodies, both before and after transplantation, should be considered a risk factor. It is clear, however, that the opinion on the clinical relevance of donor-specific HLA antibodies is very different amongst the transplant centers. Summary The clinical relevance of the presence of donor-specific HLA antibodies before transplantation and the appearance of these antibodies after transplantation is a controversial issue. The lack of consensus between different centers is partly due to the heterogeneity of the HLA antibodies involved. Standardization is essential and future studies must focus on the further characterization of the antibody titers, the immunoglobulin (sub) classes of the antibodies and the epitopes recognized. It remains to be established in which cases the HLA antibodies are the direct cause of or just associated with (chronic) graft failure. Show less
The mechanisms by which alloreactive memory T-cells are generated in non-sensitized individuals have begun to be elucidated. It is generally accepted that a very high level of crossreactivity is an... Show moreThe mechanisms by which alloreactive memory T-cells are generated in non-sensitized individuals have begun to be elucidated. It is generally accepted that a very high level of crossreactivity is an essential feature of the T-cell receptor. Indeed it has recently been shown that alloreactivity from viral specific memory T-cells is far more common than predicted, 45% of viral specific T-cell clones were found to be allo-HLA crossreactive. In this overview the evidence for crossreactive alloresponses from human viral specific memory T-cells is discussed with special emphasis on the unexpected high frequency of these crossreactive responses, the peptide and tissue specificity of the responses, and the mechanistic insights gleaned from the elucidation of the crystal structure of an allo-HLA crossreactive viral specific TCR. The possible implications for clinical solid organ and bone marrow transplantation and tolerance induction will be discussed. (C) 2010 Elsevier B.V. All rights reserved. Show less
Inhibition of natural killer (NK) cells is mediated by MHC class I receptors including the killer cell Ig-like receptor (KIR). We demonstrate that HLA-C binding peptides can function as altered... Show moreInhibition of natural killer (NK) cells is mediated by MHC class I receptors including the killer cell Ig-like receptor (KIR). We demonstrate that HLA-C binding peptides can function as altered peptide ligands for KIR and antagonize the inhibition mediated by KIR2DL2/KIR2DL3. Antagonistic peptides promote clustering of KIR at the interface of effector and target cells, but do not result in inhibition of NK cells. Our data show that, as for T cells, small changes in the peptide content of MHC class I can regulate NK cell activity. Show less
Rekers, N.V.; Bajema, I.M.; Mallat, M.; Zuidwijk, K.; Anholts, J.D.H.; Goemaere, N.; ... ; Eikmans, M. 2010
Self and non-self recognition is the key mechanism by which the immune system determines whether or not to mount an immune response. During pregnancy the maternal immune system must tolerate the... Show moreSelf and non-self recognition is the key mechanism by which the immune system determines whether or not to mount an immune response. During pregnancy the maternal immune system must tolerate the persistence of non-self semi-allogeneic fetal cells in the maternal tissue. Although many mechanisms have been shown to contribute to the prevention of a destructive maternal immune response to fetal cells, the immune acceptance of the allogeneic fetus in pregnancy largely remains an immunological paradox (Billingham et al., 1953). The aim of this review is to describe the expression of the polymorphic histocompatibility antigens at the fetal-maternal interface, their interaction with maternal leukocytes and their possible roles in immune regulation at the fetal-maternal interface during human pregnancy. (C) 2010 Elsevier Ireland Ltd. All rights reserved. Show less
Brand-Schaaf, S.H.; Roelen, D.L.; Linden, M. van der; Doxiadis, I.I.N.; Stein, S.; Witvliet, M.; Claas, F.H.J. 2010
Self and non-self recognition is the key mechanism by which the immune system determines whether or not to mount an immune response. During pregnancy the maternal immune system must tolerate the... Show moreSelf and non-self recognition is the key mechanism by which the immune system determines whether or not to mount an immune response. During pregnancy the maternal immune system must tolerate the persistence of non-self semi-allogeneic fetal cells in the maternal tissue. Although many mechanisms have been shown to contribute to the prevention of a destructive maternal immune response to fetal cells, the immune acceptance of the allogeneic fetus in pregnancy largely remains an immunological paradox (Billingham et al., 1953). The aim of this review is to describe the expression of the polymorphic histocompatibility antigens at the fetal-maternal interface, their interaction with maternal leukocytes and their possible roles in immune regulation at the fetal-maternal interface during human pregnancy. Show less
Background. The risk of skin cancer is highly increased in kidney-transplant recipients (KTR), but the risk of subsequent skin cancers is less well studied. The aim of this study was to estimate... Show moreBackground. The risk of skin cancer is highly increased in kidney-transplant recipients (KTR), but the risk of subsequent skin cancers is less well studied. The aim of this study was to estimate the cumulative incidence of subsequent squamous- and basal-cell carcinomas (BCCs) and to analyze potential risk factors. Methods. All histologically confirmed skin cancers between 1966 and 2006 were included in the study and counted. Cumulative incidences of subsequent squamous- and BCCs were calculated using Kaplan-Meier survival analyses. For the analyses of risk factors, we used Cox proportional hazard analyses. Results. A total of 239 (13%) of 1906 KTR developed skin cancer of whom 222 were diagnosed in our hospital. Altogether 167 (75%) of these 222 patients developed multiple skin cancers. The cumulative incidence of a second skin cancer increased from 32%, I year, to 59%, 3 years, and 72%, 5 years after the first skin cancer. KTR who started with squamous-cell carcinoma (SCC) mainly developed SCC and recipients who started with BCC mainly developed BCC as second skin cancer. Immunosuppression with azathioprine in combination with prednisone was associated with a significantly increased risk of subsequent SCCs but not with subsequent BCCs. Conclusion. Skin cancer multiplicity is common in KTR. Patients with a first skin cancer are at increased risk for more skin cancers and need to be carefully checked for subsequent skin cancers. Show less
Graft-versus-host disease and graft rejection are major complications of allogeneic HLA-mismatched stem cell transplantation or organ transplantation that are caused by alloreactive T cells.... Show moreGraft-versus-host disease and graft rejection are major complications of allogeneic HLA-mismatched stem cell transplantation or organ transplantation that are caused by alloreactive T cells. Because a range of acute viral infections have been linked to initiating these complications, we hypothesized that the cross-reactive potential of virus-specific memory T cells to allogeneic (allo) HLA molecules may be able to mediate these complications. To analyze the allo-HLA reactivity, T cells specific for Epstein-Barr virus, cytomegalovirus, varicella zoster virus, and influenza virus were tested against a panel of HLA-typed target cells, and target cells transduced with single HLA molecules. Eighty percent of T-cell lines and 45% of virus-specific T-cell clones were shown to cross-react against allo-HLA molecules. The cross-reactivity of the CD8 and CD4 T-cell clones was directed primarily against HLA class I and II, respectively. However, a restricted number of CD8 T cells exhibited cross-reactivity to HLA class II. T-cell receptor (TCR) gene transfer confirmed that allo-HLA reactivity and virus specificity were mediated via the same TCR. These results demonstrate that a substantial proportion of virus-specific T cells exert allo-HLA reactivity, which may have important clinical implications in transplantation settings as well as adoptive transfer of third-party virus-specific T cells. (Blood. 2010;115(15):3146-3157) Show less
Maternal lymphocytes at the fetal-maternal interface play a key role in the immune acceptance of the allogeneic fetus. Most studies focus on decidual NK cells and their interaction with fetal... Show moreMaternal lymphocytes at the fetal-maternal interface play a key role in the immune acceptance of the allogeneic fetus. Most studies focus on decidual NK cells and their interaction with fetal trophoblasts, whereas limited data are available on the mechanisms of fetus specific immune recognition and immune regulation by decidual T cells at the fetal-maternal interface. The aim of this review is to describe the phenotypic characteristics of decidual T cell subsets present at the fetal-maternal interface, their interaction with HLA-C expressed by fetal trophoblasts and their role in immune recognition and regulation at the fetal-maternal interface during human pregnancy. (C) 2010 Published by IFPA and Elsevier Ltd. Show less
