Islet transplantation outcomes in type 1 diabetes and transplantation of HLA-DQ8/DR4: results of a single-centre retrospective cohort in Canada.

Background

In solid organ transplantation, HLA matching between donor and recipient is associated with superior outcomes. In islet transplantation, an intervention for Type 1 diabetes, HLA matching between donor and recipient is not performed as part of allocation. Susceptibility to Type 1 diabetes is associated with the presence of certain HLA types. This study was conducted to determine the impact of these susceptibility antigens on islet allograft survival.

Methods

This is a single-centre retrospective cohort study. This cohort of transplant recipients (n = 268) received islets from 661 donor pancreases between March 11th, 1999 and August 29th, 2018 at the University of Alberta Hospital (Edmonton, AB, Canada). The frequency of the Type 1 diabetes susceptibility HLA antigens (HLA-A24, -B39, -DQ8, -DQ2 and-DQ2-DQA1∗05) in recipients and donors were determined. Recipient and donor HLA antigens were examined in relation to time to first C-peptide negative status/graft failure or last observation point. Taking into account multiple transplants per patient, we fitted a Gaussian frailty survival analysis model with baseline hazard function stratified by transplant number, adjusted for cumulative islet dose and other confounders.

Findings

Across all transplants recipients of donors positive for HLA-DQ8 had significantly better graft survival (adjusted HRs 0.33 95% CI 0.17-0.66; p = 0.002). At first transplant only, donors positive for HLA-DQ2-DQA1∗05 had inferior graft survival (adjusted HR 1.96 95% CI 1.10-3.46); p = 0.02), although this was not significant in the frailty analysis taking multiple transplants into account (adjusted HR 1.46 95% CI 0.77-2.78; p = 0.25). Other HLA antigens were not associated with graft survival after adjustment for confounders.

Interpretation

Our findings suggest islet transplantation from HLA-DQ8 donors is associated with superior graft outcomes. A donor positive for HLA-DQ2-DQA1∗05 at first transplant was associated with inferior graft survival but not when taking into account multiple transplants per recipient. The relevance of HLA-antigens on organ allocation needs further evaluation and inclusion in islet transplant registries and additional observational and interventional studies to evaluate the role of HLA-DQ8 in islet graft survival are required.

Funding

None.

Informations de copyright

© 2023 The Author(s).

Déclaration de conflit d'intérêts

SF collaborates with and receives grant funding from Novo Nordisk Cell Therapy Programme and has received funding from charities including Medical Research Council, Diabetes UK, Chief Scientist Office, British Heart Foundation, Medical Research Scotland, EASTBIO Foundation and the Helmsley Foundation, is a member of the JDRF UK Scientific Committee, Novo Nordisk UK Research Foundation Board of Trustees and has previously served on a Diabetes UK Research Steering Committee and on a Society for Endocrinology Research Network and has previously served as a consultant to Novo Nordisk. AH has received grant funding from Canadian Institutes of Health Research, Canadian Foundation for Innovation, Canadian Society of Transplantation and has received honoraria from the Canadian Society of Transplantation and support from International Society for Transplantation. AL has received funding from the JDRF. LH is president of American Society for Histocompatibility and Immunogenetics, serves as a board member of United Network for Organ Sharing/Organ Procurement and Transplantation Network, a member of the Transplant Diagnostics Community of Practice Executive Committee and has received consultancy fees from AdaptImmune LLC and support from Thermo Fisher Scientific to attend scientific meetings. PAS has received grants from Canadian Institutes of Health Research, JDRF and Novo Nordisk, has received consultancy fees or honoraria from Abbott, Bayer, Eli Lilly, GSK, Insulet, Novo Nordisk, Sanofi, Vertex and previously served in an independent data monitoring committee overseeing safety of stem cell-derived β-cells for type 1 diabetes (Vertex Pharmaceuticals), as a board chair for Diabetes Canada, and as a co-lead for Diabetes Action Canada's innovations in a type 1 diabetes goal group. PC was previously President Of The American Society Of Histocompatibility And Immunogenetics And Previously Chair Of The Canadian Blood Services HLA Advisory Committee. AMJS has received grants or contracts from the Juvenile Diabetes Research Foundation, Canadian Stem Cell Network, Diabetes Research Foundation in Canada, ViaCyte, and the US National Institute of Diabetes and Digestive and Kidney Diseases; serves or has served as a consultant to Protokinetix, ViaCyte, Hemostemix, Pelican Therapeutics, Diagon, Aspect Biosystems and Betalin Therapeutics inc; and is a co-inventor for a patent on TNFRSF25-mediated treatments of immune diseases and disorders (PCT/US2020/053,085) and for a Cellular Transplant Site- Device-less technology (US 14/863541, CA.286512). All other authors declare no competing interests.