Geert W. Haasnoot

Fetal–maternal HLA-C mismatch is associated with decidual T cell activation and induction of functional T regulatory cells

Human leukocyte antigen-C (HLA-C) is the only polymorphic classical histocompatibility antigen expressed by fetal trophoblasts at the fetal-maternal interface. Interactions between HLA-C and decidual natural killer (NK) cells may facilitate trophoblast invasion into maternal tissue. Thus far no evidence has been provided that decidual T cells specifically recognize and respond to fetal alloantigens at the fetal-maternal interface. In this study, we show that pregnancies containing a HLA-C mismatched child induce an increased percentage of CD4(+)CD25(dim) activated T cells in decidual tissue. In addition, HLA-C mismatched pregnancies exhibit a decidual lymphocyte response to fetal cells and contain functional CD4(+)CD25(bright) regulatory T cells in decidual tissue, whereas HLA-C matched pregnancies do not. This suggests that decidual T cells specifically recognize fetal HLA-C at the fetal-maternal interface but are prevented from inducing a destructive immune response in uncomplicated pregnancies.

Subsequent squamous- and basal-cell carcinomas in kidney-transplant recipients after the first skin cancer: cumulative incidence and risk factors.

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 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%, 1 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.

HLA-B62 and HLA-DQ8 are associated with Complex Regional Pain Syndrome with fixed dystonia

ABSTRACT Complex Regional Pain Syndrome (CRPS) is clinically characterized by pain in combination with sensory, autonomic, and motor symptoms that may include weakness, tremor, myoclonus and dystonia of the affected limb(s). The syndrome is multifactorial in origin and mostly attributed to tissue injury. There is some evidence that the human leukocyte antigen (HLA) system plays a role in the pathophysiology of CRPS, but previous studies lacked power. Here we performed the most extensive study investigating the contribution of HLA alleles (i.e. HLA‐A, HLA‐B, HLA‐DRB1, and HLA‐DQB1) in 150 CRPS patients who also had fixed dystonia. HLA‐B62 (OR = 2.05 [95% CI 1.41–2.99], P = 0.0005) and HLA‐DQ8 (OR = 1.75 [95% CI 1.20–2.57], P = 0.005) were found significantly associated with CRPS and dystonia. The association remained significant after correction (HLA‐B62 Pcorrected [Pc] = 0.02 and HLA‐DQ8 Pc = 0.04). The involvement of HLA‐B62 and HLA‐DQ8 in CRPS with dystonia may indicate that these HLA loci are implicated in the susceptibility or expression of the disease.

Human monoclonal HLA antibodies reveal interspecies crossreactive swine MHC class I epitopes relevant for xenotransplantation.

Crossreactivity of anti-HLA antibodies with SLA alleles may limit the use of pig xenografts in some highly sensitized patients. An understanding of the molecular basis for this crossreactivity may allow better selection of xenograft donors. We have tested 68 human monoclonal HLA class I antibodies (mAbs) for reactivity with pig lymphocytes from SLA defined pigs and found nine to be crossreactive. Eight of nine were broadly HLA reactive IgM-mAbs. The putative HLA epitopes for seven mAbs. were conserved in the aminoacid sequence of the SLA alleles studied. The lack of reactivity of a large number of mAbs largely correlated with the absence of the putative epitopes in the SLA alleles studied. We conclude that most patients with anti-HLA class I antibodies should be able to find pig donors lacking SLA antigens that cross react with their antibodies and that many of the crossreacting epitopes can be defined by analysis of shared epitopes in the aminoacid sequence of human and pig MHC antigens.

Incidence of cancer in kidney-transplant recipients: a long-term cohort study in a single center.

In a long-term cohort study, we calculated cancer incidences and survival rates after the development of these cancers in kidney-transplant recipients. The cancer incidences were compared with those in the general population. The occurrence of cancer was recorded in all patients who received kidney transplantation between 1966 and 2006. The median follow-up time was more than 9 years with a maximum of almost 40 years. Altogether 327 (17%) of 1906 patients developed cancer after transplantation: 142 (7%) had non-cutaneous malignancies; 178 (9%) cutaneous squamous-cell carcinomas and 138 (7%) basal-cell carcinomas. The cumulative incidence of any cancer was 13%, 33% and 47% after 10, 20 and 30 years, respectively. The incidences of cancers of the oral cavity, stomach, female genital organs, kidney, thyroid gland, leukemias and lymphomas, and cutaneous squamous-cell carcinoma were significantly increased with a highest standardized morbidity ratio of 40 for cutaneous squamous-cell carcinomas. Survival rates after non-cutaneous malignancies were 57%, 43% and 36% and after non-melanocytic skin cancer 99%, 90% and 77% after 1, 3 and 5 years, respectively. The increased incidence of non-cutaneous malignancies after kidney transplantation is associated with a high mortality. Prevention of cancer after kidney transplantation should be a major focus of future research.

The presence of HLA-antibodies in recurrent miscarriage patients is associated with a reduced chance of a live birth

Anti-paternal HLA-antibodies are considered a harmless phenomenon during most pregnancies, whereas their role in recurrent miscarriage (RM) patients is disputed. In contrast to primary RM, patients with secondary RM have carried a fetus to term pregnancy prior to a series of miscarriages, which increases the chance that allogeneic fetal cells appear in the maternal circulation. This study investigates the frequency of HLA-antibodies in secondary RM, primary RM patients and parous controls and analyzes whether the presence of HLA-antibodies in early pregnancy is associated with pregnancy outcome. Sera from women with secondary RM (n=56), primary RM (n=13) and parous controls (n=24) were tested for HLA-antibodies using an ELISA assay and complement dependent cytotoxicity. Samples were taken at gestational week 4-5 in 62 (90%) of the patients. HLA-antibodies were significantly more frequent in secondary RM patients with a boy prior to the miscarriages (62%) compared to secondary RM patients with a firstborn girl (29%, p=0.03), primary RM patients (23%, p=0.02) and parous controls (25%, p=0.005). Forty-one percent of HLA-antibody positive pregnant RM patients had a live birth compared to 76% of HLA-antibody negative RM patients, p=0.006 (adjusted OR: 0.22 (0.07-0.68), p=0.008). In conclusion, HLA-antibodies are significantly more frequent in secondary RM patients with a firstborn boy than in other RM patients and controls. The presence of these antibodies in early pregnancy is associated with a reduced chance of a live birth. Further exploring this association may increase our understanding of maternal acceptance of the fetal allograft.

Simpler and equitable allocation of kidneys from postmortem donors primarily based on full HLA-DR compatibility.

Background. The introduction of human leukocyte antigen (HLA)-matching in nonliving kidney transplantation has resulted into a better graft outcome, but also in an increase of waiting time, especially for patients with rare HLA phenotypes. We addressed the question of the differential influence of HLA-DR-matching versus HLA-A,B in clinical kidney transplantation. Methods. We used Kaplan-Meier product limit method to estimate survival rates, and Cox proportional hazard regression for the estimation of relative risks (Hazard-ratios) for different variables. Results. A single center study (n=456 transplants, performed between 1985 and 1999) showed that full HLA-DR compatibility leads to a lower incidence of biopsy confirmed acute rejections in the first 180 posttransplantation days. These results were substantiated using the Eurotransplant database (n=39,205 transplants performed between 1985 and 2005) where graft survival in the full HLA-DR compatible group was significantly better than in the incompatible. An additional positive effect of HLA-A,B matching was only found in the full HLA-DR compatible group. In both studies, the introduction of a single HLA-DR incompatibility eliminates the HLA-A,B matching effect. Conclusions. We propose to allocate postmortem kidneys only to patients with full HLA-DR compatibility, and use HLA-A,B compatibility as an additional selection criterion. All patients, irrespective of their ethnic origin, will profit since the polymorphism of HLA-DR is by far lower than that of HLA-A,B. Excessive kidney travel and cold ischemia time will be significantly reduced.

The 25th anniversary of the Eurotransplant Acceptable Mismatch program for highly sensitized patients

In 2014, the Eurotransplant Acceptable Mismatch (AM) program celebrated its 25th anniversary. The AM program was initiated to enhance transplantation of highly sensitized patients awaiting a renal transplant within the Eurotransplant region. Unlike the regular renal transplant allocation, in which the histocompatibility parameters consist of the degree of compatibility with the patients human leucocyte antigen (HLA) type and the absence of unacceptable antigens, the AM program is based on compatibility of the possible donor with the combination of the patients HLA type and the acceptable antigens. These acceptable antigens are defined as HLA antigens to which the patient has never made antibodies. This strategy aims at the prediction of a negative cross match. Since the start of the program almost 2000 patients participated and more than 1000 patients were transplanted with excellent transplant outcome, comparable to that of non-immunized transplant recipients within Eurotransplant. Progressive insights have led to fine-tuning of the AM program through the years, as well as to novel initiatives, including a recent consortium study to determine the feasibility of a Europe-wide AM program. The current review will tell the story of the AM program in a historical perspective, but will also provide an open-minded look into the future of transplanting highly sensitized patients.

Exclusive characteristics of graft survival and risk factors in recipients with immunoglobulin A nephropathy : A retrospective analysis of registry data

Background. Some studies have claimed that patients with immunoglobulin A (IgA) nephropathy have better graft survival than other renal graft recipients, whereas others have rejected this statement. We have addressed this paradox in the present study. Methods. In all, 1,207 patients with IgA nephropathy who received a primary cadaveric renal graft from 1990 to 2002 were identified in the Eurotransplant database. For comparison, we analyzed 7,935 patients with nonglomerular diseases. Death-censored graft survival was calculated using Kaplan Meier estimates and a multivariable Cox regression analysis was used for risk calculations. Results. Death-censored graft survival was superior in patients with IgA nephropathy in the first period after transplantation. After 3 years posttransplant, however, there was an accelerated decline in graft survival in recipients with IgA nephropathy. The fully adjusted risk of graft loss in the first year was increased by 40% in the control group compared to IgA nephropathy (hazard ratio [HR] 1.40, 95% CI 1.12–1.75), whereas the risk was significantly lower in the control group after the first year posttransplant (HR 0.75, 95% CI 0.63–0.88). Cold ischemia time, immunization and HLA-DR mismatch were risk factors for graft loss in the control group but not for IgA nephropathy, whereas HLA-AB mismatch was an independent risk factor, exclusively for the IgA nephropathy group. Conclusions. Recipients with IgA nephropathy have better 1-year graft survival, presumably due to favorable immunological behavior. This benefit was however abolished in the long-term by increased graft loss with time. Studies are needed to explain the difference in graft survival and the reason why different risk factors are involved in graft failure.

Increased Risk of Squamous-Cell Carcinoma in Simultaneous Pancreas Kidney Transplant Recipients Compared with Kidney Transplant Recipients

The purpose of this study was to ascertain the risk of non-melanocytic skin cancer (NMSC) in simultaneous pancreas kidney transplant recipients (SPKTRs) compared with kidney transplant recipients (KTRs) in relation to other potential risk factors of skin cancer. In a cohort study, 208 SPKTRs were compared with 1,111 KTRs who were transplanted during the same time period. The effects of age, sex, country of origin, time period after transplantation, HLA matching, immunosuppressive regimen, and rejection treatments on the risk of NMSC were investigated in multivariable Coxs proportional hazard models. In SPKTRs, the incidence of NMSC increased from 19 to 36%, respectively, 10 and 15 years after transplantation, which was significantly higher compared with that in KTRs (6 and 10%, respectively). After adjustment for age and sex, SPKTRs had a 6.2 (3.0-12.8) increased risk of squamous-cell carcinoma (SCC) compared with KTRs. An additional adjustment for maintenance immunosuppression decreased the hazard ratio to 3.1 (1.3, 7.2), which indicates partial confounding by the immunosuppressive regimen. Adjustment for induction and rejection therapy or HLA mismatching did not change the hazard ratio significantly. SPKTRs have an increased risk of SCC compared with KTRs, despite partial confounding by the immunosuppressive regimen.