BACKGROUND In Caucasians, fetal/neonatal alloimmune thrombocytopenia (FNAIT) is most frequently caused by maternal alloimmunization against the human platelet antigen HPA‐1a. The most serious complication of severe FNAIT is intracranial hemorrhage (ICH). ICH mainly occurs in utero; therefore, there is a need to identify noninvasive predictive factors of ICH to facilitate early identification of this condition and to determine response to maternal therapy. STUDY DESIGN AND METHODS We studied gynecologic and immunogenetic variables of severe cases of anti‐HPA‐1a FNAIT within three groups: Group I, FNAIT without ICH; Group II, FNAIT with ICH; and Group III, suspected FNAIT cases without detectable maternal anti‐HPA‐1a alloantibodies. RESULTS ICH was associated with a poor outcome because it led to death in 59% of cases. Multigravida (two or more pregnancies) was overrepresented in Group II, consistent with the high concentrations of maternal HPA‐1a alloantibody and the frequent detection of a strong newborn‐specific HLA class I antibody response at delivery. The proportion of HLA‐DRB4*01:01P (*01:01 or *01:03) women was similar in Groups I and II, but this allele was overrepresented in Group III, in which FNAIT was less severe than in the other two groups. Finally, antenatal intravenous immunoglobulin therapy tended to be more effective in HLA‐DRB3*01:01(+)/HLA‐DRB4*01:01P(+) women than for HLA‐DRB3*01:01(+)/HLA‐DRB4*01:01P(–) women. CONCLUSION The number of gestations is a predictive factor of ICH in anti‐HPA‐1a–alloimmunized women. Maternal immunogenetic variables should be investigated in the context of maternal immunization and may predict response to maternal therapy in subsequent pregnancies.

BackgroundIdentifying biomarkers to predict kidney transplant failure and to define new therapeutic targets requires more comprehensive understanding of the immune response to chronic allogeneic stimulation.MethodsWe investigated the frequency and function of CD8+ T cell subsets—including effector memory (EM) and terminally differentiated EM (TEMRA) CD8+ T cells—in blood samples from 284 kidney transplant recipients recruited 1 year post-transplant and followed for a median of 8.3 years. We also analyzed CD8+ T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants.ResultsIncreased frequency of circulating TEMRA CD8+ T cells at 1 year post-transplant associated with increased risk of graft failure during follow-up. This association remained after adjustment for a previously reported composite of eight clinical variables, the Kidney Transplant Failure Score. In contrast, increased frequency of EM CD8+ T cells associated with reduced risk of graft failure. A distinct TEMRA CD8+ T cell subpopulation was identified that was characterized by expression of FcγRIIIA (CD16) and by high levels of proinflammatory cytokine secretion and cytotoxic activity. Although donor-specific stimulation induced a similar rapid, early response in EM and TEMRA CD8+ T cells, CD16 engagement resulted in selective activation of TEMRA CD8+ T cells, which mediated antibody-dependent cytotoxicity.ConclusionsAt 1 year post-transplant, the composition of memory CD8+ T cell subsets in blood improved prediction of 8-year kidney transplant failure compared with a clinical-variables score alone. A subpopulation of TEMRA CD8+ T cells displays a novel dual mechanism of activation mediated by engagement of the T-cell receptor or of CD16. These findings suggest that TEMRA CD8+ T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8+ T cell monitoring for predicting risk of kidney transplant failure.

Graft failure remains a severe complication of hematopoietic stem cell transplantation (HSCT). Several risk factors have already been published. In this study, we re-evaluated them in a large cohort who had the benefit of the recent experience in HSCT (2006-2012). Data from 4684 unrelated donor HSCT from 2006 to 2012 were retrospectively collected from centers belonging to the French Society for Stem Cell Transplantation. Among the 2716 patients for whom HLA typing was available, 103 did not engraft leading to a low rate of no engraftment at 3.8%. In univariate analysis, only type of disease and status of disease at transplant for malignant diseases remained significant risk factors (P=0.04 and P<0.0001, respectively). In multivariate analysis, only status of disease was a significant risk factor (P<0.0001). Among the 61 patients who did not engraft and who were mismatched for 1 HLA class I and/or HLA-DP, 5 donor-specific antibodies (DSAs) were detected but only 1 was clearly involved in graft failure, for the others their role was more questionable. Second HSCT exhibited a protective although not statistically significant effect on OS (hazard ratio=0.57 [0.32-1.02]). In conclusion, only one parameter (disease status before graft) remains risk factor for graft failure in this recent cohort.

Donor-specific anti-HLA antibodies (DSAs) are a major risk factor associated with renal allograft outcomes. As a trigger of B cell antibody production, T follicular helper cells (Tfhs) promote DSA appearance. Herein, we evaluated whether circulating Tfhs (cTfhs) are associated with the genesis of antibody-mediated rejection. We measured cTfh levels on the day of transplantation and 1 year after transplantation in blood from a prospective cohort of 237 renal transplantation patients without DSA during the first year post-transplantation. Total cTfhs were characterized as CD4+CD45RA−CXCR5+, and the three following subsets of activated cTfh were analyzed: CXCR5+PD1+, CXCR5+PD1+ICOS+, an CXCR5+PD1+CXCR3−. Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5+PD1+, CXCR5+PD1+ICOS+, and CXCR5+PD1+CXCR3− cTfh subsets. In addition, ATG-depleting induction and calcineurin inhibitor treatments were associated with a relative increase of activated cTfh subsets frequencies at 1 year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5+PD1+ICOS+ at 1 year after transplantation in the blood of DSA-free patients was significantly associated with the risk of developing de novo DSA after the first year (p = 0.018, HR = 0.39), independently of HLA mismatches (p = 0.003, HR = 3.79). These results highlight the importance of monitoring activated Tfhs in patients early after transplantation and show that current treatments cannot provide early, efficient prevention of Tfh activation and migration. These findings indicate the need to develop innovative treatments to specifically target Tfhs to prevent DSA appearance in renal transplantation.

Background Informing kidney transplant recipients of their prognosis and disease progression is of primary importance in a patient-centred vision of care. By participating in decisions from the outset, transplant recipients may be more adherent to complex medical regimens due to their enhanced understanding. Methods We proposed to include repeated measurements of serum creatinine (SCr), in addition to baseline characteristics, in order to obtain dynamic predictions of the graft failure risk that could be updated continuously during patient follow-up. Adult recipients from the French Données Informatisées et VAlidées en Transplantation (DIVAT) cohort transplanted for the first or second time from a heart-beating or living donor and alive with a functioning graft at 1 year post-transplantation were included. Results The model was composed of six baseline parameters, in addition to the SCr evolution. We validated the dynamic predictions by evaluating both discrimination and calibration accuracy. The area under the receiver operating characteristic curve varied from 0.72 to 0.76 for prediction times at 1 and 6 years post-transplantation, respectively, while calibration plots showed correct accuracy. We also provided an online application tool (https://shiny.idbc.fr/DynPG). Conclusion We have created a tool that, for the first time in kidney transplantation, predicts graft failure risk both at an individual patient level and dynamically. We believe that this tool would encourage willing patients into participative medicine.