Daratumumab treatment in six highly sensitised solid organ transplant recipients: A case series and literature review.

We report data on six kidney or heart recipients who were administered daratumumab to treat or prevent antibody-mediated rejection (ABMR). To date, data are scarce concerning the use of daratumumab in solid organ transplantation and most reports show a decrease in donor-specific antigen (DSA) levels and an improvement in ABMR using a multiple myeloma daratumumab administration scheme, that is, with sequential systematic administration. Here, we report on the efficacy of daratumumab 1/ in reducing the histological signs of ABMR, 2/ in reducing the ability of DSA to bind to donor cells in vitro through negativation of flow cytometry crossmatching, 3/ in preferentially being directed towards antibodies sharing epitopes, suggesting that daratumumab may specifically target activated plasma cells, 4/ and when administered as a single dose. This last point suggests, for the first time, that, as for rituximab in auto-immune diseases, the scheme for daratumumab administration could be different for targeting DSA-producing plasma cells than for tumour cells.

Characterization of the novel HLA-DQB1*02:01:01:21Q allele by sequencing-based typing.

HLA-DQB1*02:01:01:21Q differs from HLA-DQB1*02:01:01:01 by one nucleotide substitution in the splice site in the beginning of intron 3.

Histological characterization of liver involvement in systemic mastocytosis.

BACKGROUND AND AIMS: Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools. METHODS: Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist. RESULTS: A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002). CONCLUSIONS: MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.

Characterization of the novel HLA-A*32:177 allele by sequencing-based typing.

HLA-A*32:177 differs from HLA-A*32:01:01:01 by one nucleotide substitution in codon -16 in exon 1.

Characterization of the novel HLA-DPB1*1516:01 allele by sequencing-based typing.

HLA-DPB1*1516:01 differs from HLA-DPB1*1229:01 by seven nucleotide substitutions in exon 3.

[Obstetrical outcome of renal transplant patients followed in a type III maternity hospital. Retrospective study from 2000 to 2020]. / Devenir obstétrical des patientes transplantées rénales suivies dans une maternité de type III. Étude rétrospective de 2000 à 2020.

AIM: To describe pregnancy outcome of kidney transplant patients till 1 year postpartum. METHODS: This retrospective, monocentric study included 15 kidney transplant patients who presented 18 pregnancies, between January 2000 and January 2020. For each of them, we searched for possible obstetrical, fetal and renal complications and we evaluated renal function before, during and after pregnancy. RESULTS: The live birth rate was 84% (16/19) with an average gestational age at delivery of 37 weeks of gestation. The rate of prematurity was 50% (8/16), gestational diabetes was 16.6% (3/18) and preeclampsia was 27.7% (5/18). Cesarean section was performed in 61.1% (11/18) of cases including, 81.8% (9/11) unplanned surgery. The average birth weight was 2635 grams and 37.5% (6/16) of the newborn were small for gestational age. All patients had stable renal function before conception of pregnancy. We noticed two acute graft rejection during pregnancy with only one resulting in graft loss. Four patients had a reduced graft function in 12months of the postpartum. CONCLUSION: Risk of maternal, fetal and renal complications remained high in kidney transplant recipients. Pregnancy should be carefully planned in transplanted women associated with adequate follow-up according to clinical guidelines (normal renal function and blood pressure without proteinuria before pregnancy, no recent graft rejection, period of one year after transplant respected and no teratogenic treatment in the month before pregnancy).

Characterization of the novel HLA-DPA1*02:122 allele by sequencing-based typing.

HLA-DPA1*02:122 differs from HLA-DPA1*02:01:01:02 by one nucleotide substitution in codon 78 in exon 2.

Characterization of the novel HLA-DRB3*02:194 allele by sequencing-based typing.

HLA-DRB3*02:194 differs from HLA-DRB3*02:02:01:02 by one nucleotide substitution in codon 78 in exon 2.

Characterization of the novel HLA-B*14:122 allele by sequencing-based typing.

HLA-B*14:122 differs from HLA-B*14:02:01:01 by one nucleotide substitution in codon 102 in exon 3.

Adoptive T Cell Therapy in Solid Tumors: State-of-the Art, Current Challenges, and Upcoming Improvements.

In solid tumors, three main complementary approaches of adoptive T-cell therapies were successively developed: tumor-infiltrating lymphocytes, chimeric antigen receptor engineered T cells, and high-affinity T-cell receptor engineered T cells. In this review, we summarized rational and main results of these three adoptive T-cell therapies in solid tumors field and gave an overview of encouraging data and their limits. Then, we listed the major remaining challenges (including tumor antigen loss, on-target/off-tumor effect, tumor access difficulties and general/local immunosubversion) and their lines of research. Finally, we gave insight into the ongoing trials in solid tumor.

Characterization of the novel HLA-C*16:98:02 allele by sequencing-based typing.

HLA-C*16:98:02 differs from HLA-C*16:98:01 by one nucleotide substitution in codon 132 in exon 3.

Characterization of the novel HLA-DRB1*13:03:13 allele by sequencing-based typing.

HLA-DRB1*13:03:13 differs from HLA-DRB1*13:03:01:01 by one nucleotide substitution in codon 180 in exon 3.

Characterization of the novel HLA-B*39:06:09 allele by sequencing-based typing.

HLA-B*39:06:09 differs from HLA-B*39:06:02:01 by one nucleotide substitution in codon 135 in exon 3.

Characterization of the novel HLA-DPA1*01:03:51 allele by sequencing-based typing.

HLA-DPA1*01:03:51 differs from HLA-DPA1*01:03:01:01 by one nucleotide substitution in codon 146 in exon 3.

Characterization of the novel HLA-B*08:312 allele by sequencing-based typing.

HLA-B*08:312 differs from HLA-B*08:01:01:01 by one nucleotide substitution in codon 324 in exon 6.

Temporal regulation of transgene expression controlled by amino acid availability in human T cells.

T cell therapy strategies, from allogeneic stem cell transplantation toward genetically-modified T cells infusion, develop powerful anti-tumor effects but are often accompanied by side effects and their efficacy remains sometimes to be improved. It therefore appears important to provide a flexible and easily reversible gene expression regulation system to control T cells activity. We developed a gene expression regulation technology that exploits the physiological GCN2-ATF4 pathway's ability to induce gene expression in T cells in response to one essential amino acid deficiency. We first demonstrated the functionality of NUTRIREG in human T cells by transient expression of reporter genes. We then validated that NUTRIREG can be used in human T cells to transiently express a therapeutic gene such as IL-10. Overall, our results represent a solid basis for the promising use of NUTRIREG to regulate transgene expression in human T cells in a reversible way, and more generally for numerous preventive or curative therapeutic possibilities in cellular immunotherapy strategies.

Characterization of the novel HLA-DRB1*11:324 allele by sequencing-based typing.

HLA-DRB1*11:324 differs from HLA-DRB1*11:62:02 by one nucleotide substitution in codon 38 in exon 2.

Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes.

BACKGROUND: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. OBJECTIVE: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT. METHODS: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. RESULTS: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT- patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). CONCLUSION: Here we confirm the increase incidence of anaphylaxis in HαT+ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.

Impact of Calcineurin Inhibitor-Based Immunosuppression Maintenance During the Dialysis Period After Kidney Transplant Failure on the Next Kidney Graft Outcome: A Retrospective Multicenter Study With Propensity Score Analysis.

The impact of immunosuppressive therapy (IS) strategies after kidney transplant failure (KTF) on potential future new grafts is poorly established. We assessed the potential benefit of calcineurin inhibitor (CNI)-based IS maintenance throughout the dialysis period on the outcome of the second kidney transplant (KT). We identified 407 patients who underwent a second KT between January 2008 and December 2018 at four French KT centers. Inverse probability of treatment weighting was used to control for potential confounding. We included 205 patients with similar baseline characteristics at KTF: a total of 53 received at least CNIs on the retransplant day (G-CNI), and 152 did not receive any IS (G-STOP). On the retransplant date, G-STOP patients experienced a longer pretransplant dialysis time, were more often hyperimmunized, and underwent more expanded-criteria donor KTs than G-CNI patients. During the second KT follow-up period, rejection episodes were similar in both groups. The 10-year survival rates without death and dialysis were 98.7% and 59.5% in G-CNI and G-STOP patients, respectively. In the multivariable analysis, CNI-based IS maintenance was associated with better survival (hazard ratio: 0.08; 95% confidence interval: 0.01-0.58, p = 0.01). CNI-based IS maintenance throughout the dialysis period after KTF may improve retransplantation outcomes.

Characterization of the novel HLA-DRB3*02:193 allele by sequencing-based typing.

HLA-DRB3*02:193 differs from DRB3*02:02:01:11 by one nucleotide substitution in exon 1, and intronic changes.