Clinical impact of de-novo HLA antibodies in pancreas and islet transplantation

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1 Clinical impact of de-novo HLA antibodies in pancreas and islet transplantation David Turner, PhD, FRCPath Lead for H&I Services, Scottish National Blood Transfusion Service

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3 Treatment of Type I DM Insulin - Multiple Injections - Insulin pump Pancreas Transplantation Islet Transplantation

4 DE NOVO HLA-DSA IN WHOLE PANCREAS TRANSPLANTATION

5 167 pancreas Txs (152 SPK); all T cell CDC-XM neg (7 were HLAi) All received ATG induction 16% patient had HLA-DSA post Tx (ELISA/Luminex: A,B,DR,DQ) Mean onset for de novo HLA-DSA: 1.27 years

6 317 SPK, 116 pancreas. All T&B cell CDC-XM neg, no Txs with preformed DSA All received Campath induction 15% patients had HLA-DSA post Tx (Luminex: A,B,C,DR,DQ,DP)

7 256 SPK patients 33 lost graft <1 year Donor age and female gender associated with early pancreas graft loss no AMR suspicious for AMR acute AMR (7/7 cases pos for DSA) Pre-Tx no cases had DSA (ELISA/CDC/DynaChip) When grafts were lost to AMR, in 6/7 cases was > 1 month post Tx DSA were class II in 100% of cases

8 De novo HLA-DSA: clinical utility Presence of DSA post Tx associated with worse graft outcome in SPK and pancreas Tx Monitoring of HLA Abs may have clinical utility to identify patients who might benefit from changes in treatment

9 ISLET TRANSPLANTATION INTRODUCTION

10 Patient selection Insulin sensitive patients with Type I diabetes and normal renal function who experience recurrent severe hypoglycaemia despite optimised specialist management Insulin sensitive patients with a renal allograft who are unable to maintain HbA1c <7.0% despite optimised management

11 Aims of Islet Transplantation Reversal of hypo unawareness Reduced insulin requirement Insulin independence 2 sequential islet infusions

12 UK Pancreas Transplant Activity Pancreas/islet Tx SPK PAK/PTA islet 50 0 Pre NPAS

13 North America: 840 Tx in 340 Europe: 1,380 in 775 Japan: Iran: 2 Tx in 2 China: >16 Tx in 12?? Korea: >11 Tx in 6 34 Tx in 18 Brazil: 11 Tx in 5 Australia: 55 Tx in 20 Worldwide clinical islet transplant activity since 1999

14 Islet Isolation 5 X magnification

15 Measuring islet Tx outcome Various factors can be measured: HbA1c Blood glucose level Insulin dose requirement C-peptide Composite scores have been developed e.g. beta score (8=excellent function, 0 no residual function) and BETA-2 score

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17 Islet transplant outcomes in the UK (measured via C-peptide)

18 Islet transplant outcomes (Beta and Beta-2 scores) Edinburgh experience

19 Factors affecting outcome Immunosuppression Recurrence of disease; reappearance of autoabs Immunological rejection; cellular or DSA?

20 Diabetes recurrence

21 DE NOVO HLA-DSA IN ISLET TRANSPLANTATION

22 Can islet Tx lead to HLA Ab production? Yes! Especially following IS reduction / withdrawal after graft failure Can therefore lead to patients becoming highly sensitised But do de novo HLA Abs cause graft failure?

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25 Evidence that de novo HLA Abs are produced after islet transplant in immunosuppressed patients (>300 patients from 27 centres, measuring general HLA antibodies, not necessarily donor specific antibodies) Does this affect outcome?

26 59 islet recipients Baseline and de novo autoabs and HLA alloabs tested 39 pats showed increases in Abs post Tx Post Tx Ab increase associated with lower graft survival for both auto Abs and HLA-DSA

27 16 patients/26 islet Txs 5 pats developed DSA No patients were sensitised if received alemtuzumab and Etanercept Suggests that HLA-DSA can occur after islet Tx and are associated with graft loss

28 42 patients received graft(s) Sera tested for HLA Abs at time of Tx and once every year 13 had HLA-DSA post Tx (1 preformed) Mean time of appearance =1023d Mean MFI sum= % ci, 54% cii, 23% both HLA-DSA positive patients did not have worse outcome

29 Edinburgh HLA-DSA data BETA-2 score deterioration 40 patients / 72 islet Txs All received alemtuzumab induction BETA-2 score Tested 1,3,6,12 mo then annually 5/40 patients (12.5%) developed DSA to one or both grafts whilst on IS Month 3 Month 6 Month 12 Month 18 Month 24 Month 30 Month 36 Month 42 Month 48 Month 54 Month Function measured by BETA-2 score in DSA positive group deteriorated at similar rate HLA-DSA pos HLA-DSA neg

30 Explanation for variation between studies Immunosuppression Measurement of graft survival Timing of DSA sampling Looking at DSA to first/second etc graft? HLA-DSA titre Identification of true allo HLA-DSA Is there a plausible explanation as to why de novo HLA-DSA may not be deleterious in islet Tx?

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32 In vitro in RAG2 KO mice: when T cell immunity was reintroduced, islets were rejected, but when DSA were reintroduced, islets were NOT rejected No defect in Ab as killed islets in vitro resistance of allogeneic islets to DSA-mediated destruction in vivo may be due to graft-intrinsic properties

33 Does this only happen with islets? Yes, similar experiments using a cardiac Tx model showed signs of AMR when DSA were reintroduced

34 Angiogenesis in islet Tx Blood flow to grafted islets involves angiogenesis from recipient Experiments show that >66% of intra-islet ECs are of recipient origin 6 weeks post Tx But endocrine cells remain of donor origin; why are they not susceptible to DSA? Not due to lower Ag expression Experiments indicate that DSA may not be able to diffuse from the vasculature to the interstitial tissue

35 Allogeneic islets are protected from the effect of de novo DSA by... the fact that intra-islet vascularisation is derived from the recipient that large IgG and complement activators are retained in the vasculature, so have limited access to target donor Ags

36 Summary In whole pancreas Tx de novo HLA-DSA associated with graft survival In islet Tx role of HLA-DSA after Tx is less clear Patients exposed to high degree of HLA mismatches and these are immunogenic Recent data may indicate that islets are more protected from HLA-DSA due to recipient derived revascularisation of islet grafts Larger datasets are required Role of autoantibodies