Anne Cesbron

The influence of HLA A-B-DR matching on cytomegalovirus disease after renal transplantation : evidence that HLA-DR7-matched recipients are more susceptible to cytomegalovirus disease

We examined the prevalence of cytomegalovirus infectious episodes, as defined by clinical, virological, and serological criteria (i.e., CMV disease), in 660 kidney graft recipients; 109 patients (16.5%) developed the disease, and 551 did not. No significant statistical link between CMV disease prevalence and a given HLA-A, -B, or -DR allele was observed. However, patients with HLA-DR7 matched grafts were statistically more frequently found (P<0.01) in the group of recipients who developed CMV disease as compared with the group who did not develop CMV disease. Furthermore, among pa

Characterization of antigen-specific B cells using nominal antigen-coated flow-beads.

In order to characterize the reactivity of B cells against nominal antigens, a method based on the coupling of antigens onto the surface of fluorescent core polystyrene beads was developed. We first demonstrate that murine B cells with a human MOG-specific BCR are able to interact with MOG-coated beads and do not recognize beads coated with human albumin or pp65. B cells purified from human healthy volunteer blood or immunized individuals were tested for their ability to interact with various nominal antigens, including viral, vaccine, self and alloantigens, chosen for their usefulness in studying a variety of pathological processes. A substantial amount of B cells binding self-antigen MOG-coated beads can be detected in normal blood. Furthermore, greater frequencies of B cell against anti-Tetanic Toxin or anti-EBNA1 were observed in primed individuals. This method can reveal increased frequencies of anti-HLA committed B cells in patients with circulating anti-HLA antibodies compared to unsensitized patients and normal individuals. Of interest, those specific CD19 cells were preferentially identified within CD27−IgD+ (i-e naïve) subset. These observations suggest that a broad range of medical situations could benefit from a tool that allows the detection, the quantification and the characterization of antigen-specific blood B cells.

Differential Modulation of Donor-Specific Antibodies After B-Cell Depleting Therapies to Cure Chronic Antibody Mediated Rejection

Background Donor-specific antibodies (DSA) are considered as reliable biomarkers for antibody-mediated rejection (ABMR) diagnosis. However, it is unclear whether DSA monitoring is necessary and could predict graft outcome after antirejection treatment. Methods We analyzed 28 non-sensitized kidney transplant patients with ABMR associated with de novo anti–human leukocyte antigen (HLA) DSA. Donor-specific antibody levels were measured by single antigen bead assays 12 months after antirejection therapy onset. Patients were placed in three groups according to their antirejection treatment: group I (n = 10), plasma exchange-Rituximab; group II (n = 8), Bortezomib; and group III (n = 10), optimization of maintenance immunosuppression. Half of the patients in group I demonstrated concomitant acute cellular rejection (ACR+). Results De novo DSA were mainly anti-DQ (60%). Anti–class I and anti–DR DSA disappeared after treatment in group I and remained negative during follow-up, whereas anti–DQ DSA persisted without any modulation. In contrast, class I-II HLA-DSA mean fluorescence intensity remained unchanged in groups II and III. Graft loss was observed in 80% and 20% of patients from group I (ACR+) and group III, respectively. One year after the ABMR treatment, a 16-mL/min decline in estimated glomerular filtration rate was observed in patients from group I (ACR−) and group III. Group II showed better outcomes with a mean estimated glomerular filtration rate decline of 6.4 mL/min. Conclusion Modulation of DSA at and after treatment of ABMR did not correlate with graft outcome over a 12-month period.

Impact of Graft-Versus-Graft Natural Killer Cell Alloreactivity on Single Unit Dominance After Double Umbilical Cord Blood Transplantation

Background Natural killer (NK) cell alloreactivity is favored after double umbilical cord blood transplantation (dUCBT) in which cord blood (UCB) units and patients are often HLA class I mismatched. Generally, only 1 UCB unit persists after dUCBT. We hypothesize, that NK cell alloreactivity mediated by killer cell immunoglobulin-like receptor (KIR)-HLA interactions may explain the dominance of 1UCB unit over the other after dUCBT. Methods We investigated the impact of KIR+ NK cell alloreactivities on the dominance of 1 full UCB unit in 50 dUCBT. We analyzed the effects of the KIR/HLA genetic incompatibilities and studied cord blood cells at both the phenotypic and functional levels. Results The genetic combination of KIR3DL1+ loser UCB unit/Bw4− winner UCB unit determined both the dominance of 1 UCB unit (hazards ratio, 2.88 [1.32-6.27], P = 0.0077) and correlated with an increased incidence of relapse (hazards ratio, 4.91 [1.39-17.3], P = 0.0134). It is interesting to note that cord blood cells exhibited extremely low HLA class I expression. Moreover, resting cord blood KIR3DL1+ NK cells exhibited a basal alloreactivity against Bw4− target cells that increased upon activation, thus triggering death by apoptosis. Conclusions Our unicentric study suggests, for the first time, the significant impact of KIR+ NK cell alloreactivity in the determination of which UCB unit will dominate in dUCBT.

Rituximab for second desensitization in patients with rebound of donor-specific anti-HLA antibodies before T-replete haplo-transplant using high-dose post-transplant cyclophosphamide

Letter to the editor T-replete haplo-transplant using high-dose post transplant cyclophosphamide (PTCY) is increasingly used in patients without match related or unrelated donors [1]. However, the presence of donor-specific anti-HLA antibodies (DSA) in the recipient, which may be identified between 10 and 21% of patients, especially in multiparous females, may compromise the success of the procedure [2, 3]. Indeed, DSA have been associated with a high rate of primary graft failure (between 20 and 75%) or poor graft function after the haplo-transplant, despite the use of PTCY [2, 3] In fact, the search for recipient’s DSA is the first step to choose the best donor in a haploidentical-setting [4]. Various tests are available to detect anti-HLA class I and II DSA, including solid-phase bead based immunoassays performed on a Luminex platform. Results are expressed as mean fluorescence intensity (MFI). No clear cutoff has been determined, indicating that DSA are likely to cause graft failure [2, 3]. Recently, C1q activation was developed to detect the complement-binding DSA (C1q-positive), which may predict that activation of the complement cascade will be responsible for donor cells destruction and graft rejection. C1q-positive test is generally correlated with high DSA levels and may be more appropriate to predict graft failure. However, only one study reported this result yet without any clear definition of C1q-positivity [5]. Pre allograft desensitization protocols combine various strategies to avoid graft cell destruction by DSA. They include: direct reduction of the DSA load by plasma exchange (PE), decrease of DSA production by B cells depletion using anti-CD20 monoclonal antibody therapy or plasma cells depletion using bortezomib/dexamethasone, blocking of macrophages Fc receptors by high-dose intravenous (I.V.) immunoglobulin (Ig) therapy, and inhibition of complement activation by C1q clearance through transfusion of donor-derived platelets/leucocytes bearing HLA antigens corresponding to the DSA (buffy coat) or by using the anti-C5a antibody eculizumab. These strategies are mostly partially effective and unfortunately DSA rebound may occur at the time of transplant with no clear established medical care [6]. Here we report two such rebound cases for whom the use of repeated doses of rituximab as second desensitization may have contributed to the successful engraftment.

HLA-DRB3/4/5 mismatches are associated with increased risk of acute GVHD in 10/10 matched unrelated donor hematopoietic cell transplantation

Matching for HLA‐A, ‐B, ‐C, and ‐DRB1 loci (8/8 match) is currently the gold standard for unrelated donor hematopoietic cell transplantation (HCT). In Europe, patients are also matched at the HLA‐DQB1 loci (10/10 match). However, there is increasing evidence that matching at HLA‐DRB3/4/5 loci may help to lower transplant‐related morbidity and mortality. We therefore investigated the impact of HLA‐DRB3/4/5 mismatches on outcomes in 1975 patients who received a first 10/10 matched unrelated donor (MUD) HCT in France from 2000 to 2012 for a hematological malignancy. High‐resolution typing was performed at HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, ‐DPB1, and ‐DRB3/4/5 loci for all donor/recipient pairs. Compared with DRB3/4/5‐matched pairs, patients who received a MUD HCT from a DRB3/4/5 mismatched donor had a significantly increased risk of grade II‐IV acute graft‐versus‐host disease (aGVHD) (Adjusted Hazard Ratio (HR) 1.43 (1.07 to 1.90)) associated with lower graft‐versus‐host disease‐free and relapse‐free survival (GRFS) (Adjusted HR 1.20 (1.02 to 1.42)). Conversely, we observed no differences in terms of chronic GVHD, nonrelapse mortality, relapse and overall survival. However, we believe that patients stand to benefit from DRB3/4/5 loci being considered for unrelated donor selection to improve GRFS and then quality of life after unrelated HCT.