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International audience; Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts.

A 56 year-old, multiparous woman suffering from a myeloproliferative syndrome, who had received multiple red blood cell and platelet transfusions, was the recipient of an allograft of peripheral blood stem cells derived from her HLA-A, B, DR, DQ and DP and ABO identical sister, following myeloablative conditioning. The persistence of severe, isolated thrombopenia resistant to platelet transfusions led to the discovery of anti-HLA class I allo-immunisation. As HLA compatible platelet transfusions did not result in satisfactory platelet increments, we then discovered the simultaneous presence of anti-HPA-1a allo-immunisation. Genotyping of the HPA-1 systems of the patient (HPA-1B/B) and her sister (HPA-1A/B) enabled us to elucidate the mechanism underlying the persistent thrombopenia and the inefficacy of transfusion. In fact, only transfusion of HPA-1B/B platelets (HLA compatible or incompatible) proved to be efficacious. To reduce the level of anti-HPA-1a antibodies, we performed plasmapheresis sessions and used an anti-CD20 monoclonal antibody. It was only on achieving total haematopoietic chimerism, through rapid interruption of the immunosuppression, that we obtained spontaneous normalisation of the platelet count. The present case emphasises the necessity, before undertaking any allograft of haematopoietic stem cells - even if the latter come from a strictly HLA identical member of the family - of performing a search for eventual anti-HPA allo-immunisation.

Huit laboratoires pilotes de l’EFS ont deploye en 2016 une technique de sequencage HLA nouvelle generation HOLOTYPE (OMIXON). Depuis, des typages ont ete menes sur les locus A et B (13704), C, DRB1, DRB3, DQB1 (13516), DPB1 et DQA1 (4735). Deuxx cent dix-sept nouveaux polymorphismes ont ete identifies, representant en moyenne 2.3 nouveaux alleles/1000 typages/locus. Ces mutations ont ete differenciees selon qu’elles s’accompagnent d’une modification de la resolution 6 digits seulement (n = 65, sequence proteique inchangee), d’une modification de la resolution 4 digits, mais pas de la haute resolution (n = 117) ou d’une modification de la haute resolution ou de la creation d’un allele nul (n = 35, modification de l’expression des domaines presentant les peptides antigeniques). Les frequences observees pour chacun de ces types de mutations/1000 typages/locus sont : A* : 0.6, 0.1, 0.1 ; B* : 0.6, 1.1, 0.4 ; C* : 1, 2.4, 0.4 ; DRB1* : 1.2, 1.6, 0.3 et DRB3* 0.0, 0.1, 0.0 ; DQB1* : 0.6, 1, 0.1 ; DPB1* : 0.6, 1.7, 0 ; DQA1* : 1.7, 1.7, 0.6. Ces donnees confirment le faible polymorphisme des genes de la classe II en dehors de l’exon 2. Neanmoins, le plus grand nombre des mutants modifiant la sequence proteique concernent les domaines non impliques dans la presentation de l’antigene, particulierement pour les locus C, DRB1, DPB1 et DQA1 car non explores systematiquement avant le NGS. Deux nouveaux alleles nuls HLA-B* et C* (indetectables par les autres methodes de typage : codon stop dans l’exon 1) ont ete identifies qui auraient pu constituer un mismatch pour une allogreffe non apparentee. Le NGS permet donc de detecter des mutants ayant un impact clinique reel (alleles nuls) ou qui reste a estimer (alleles exprimes)