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Pestana N, Malheiro J, Silva F, Silva A, Ribeiro C, Pedroso S, Almeida M, Dias L, Henriques AC, Martins LS. Impact of Pancreatic Autoantibodies in Pancreas Graft Survival After Pancreas-Kidney Transplantation. Transplant Proc 2020; 52:1370-1375. [PMID: 32245621 DOI: 10.1016/j.transproceed.2020.02.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 02/07/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND In simultaneous pancreas-kidney transplantation (SPKT), persistence or recurrence of pancreatic autoantibodies (PAs) has been associated with pancreas graft (PG) autoimmune-driven injury. Our aim was to analyze the impact of PAs on PG survival. METHODS Between January 1, 2000, and December 31, 2017, we studied 139 patients with post-SPKT anti-glutamic acid decarboxylase (GAD) autoantibody. Alloimmune (ALI) events were defined as PG rejection and/or de novo donor-specific antibodies (DSA). Hence, 3 groups were defined: patients without ALI events or anti-GAD (n = 42), those with ALI events (n = 14), or those only with autoimmune events (positive for anti-GAD and no ALI events; n = 83). RESULTS Male sex was predominant (n = 72, 52%). Median age was 35 years (interquartile range: 31-39) and median follow-up was 6-7 years (interquartile range: 4.1-9.2). Regarding anti-GAD positivity post-SPKT (n = 90, 65%), no differences were observed concerning age, sex, anti-HLA antibodies, HLA mismatch number and de novo DSA. ALI events were present in 10% (n = 14). PG survival 15 years post-SPKT was better in patients without immune events (96%) followed by those with ALI (69%) and autoimmune events (63%) (P = .025). Anti-GAD was associated to higher annualized mean Hb1AC (P = .006) and lower mean C-peptide (P = .013). According to pre- and post-SPKT anti-GAD status, conversion from negative to positive was associated to worse (63%) 10-year PG survival (P = .044), compared to persistence of negative (100%) or positive anti-GAD (88%). Anti-islet cell and anti-insulin autoantibodies had no impact. CONCLUSION Anti-GAD presence post-SPKT was associated to higher pancreas disfunction and lower PG survival. De novo anti-GAD seems to offer a particular risk of PG failure.
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Affiliation(s)
- Nicole Pestana
- Nephrology Department, Hospital Central do Funchal, Funchal, Portugal.
| | - Jorge Malheiro
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - Filipa Silva
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - Andreia Silva
- Nephrology Department, Centro Hospitalar Tondela-Viseu, Viseu, Portugal
| | - Catarina Ribeiro
- Nephrology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Porto, Portugal
| | - Sofia Pedroso
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - Manuela Almeida
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - Leonídio Dias
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - António Castro Henriques
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
| | - La Salete Martins
- Nephrology Department, Renal and Pancreatic Transplant Units, Centro Hospitalar Universitário do Porto, Lg Prof Abel Salazar, Portugal
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Argente-Pla M, Martínez-Millana A, Del Olmo-García MI, Espí-Reig J, Pérez-Rojas J, Traver-Salcedo V, Merino-Torres JF. Autoimmune Diabetes Recurrence After Pancreas Transplantation: Diagnosis, Management, and Literature Review. Ann Transplant 2019; 24:608-616. [PMID: 31767825 PMCID: PMC6896746 DOI: 10.12659/aot.920106] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background Pancreas transplantation can be a viable treatment option for patients with type 1 diabetes mellitus (T1DM), especially for those who are candidates for kidney transplantation. T1DM may rarely recur after pancreas transplantation, causing the loss of pancreatic graft. The aim of this study was to describe the prevalence of T1DM recurrence after pancreas transplantation in our series. Material/Methods Eighty-one patients transplanted from 2002 to 2015 were included. Autoantibody testing (GADA and IA-2) was performed before pancreas transplantation and during the follow-up. Results The series includes 48 males and 33 females, mean age 37.4±5.7 years and mean duration of diabetes 25.5±6.5 years. Patients received simultaneous pancreas kidney (SPK) transplantation. After SPK transplantation, 56 patients retained pancreatic graft, 8 patients died, and 17 patients lost their pancreatic graft. T1DM recurrence occurred in 2 of the 81 transplanted patients, yielding a prevalence of 2.5%, with an average time of appearance of 3.3 years after transplant. Pancreatic enzymes were normal in the 2 patients, ruling out pancreatic rejection. T1DM recurrence was confirmed histologically, showing selective lymphoid infiltration of the pancreatic islets. Conclusions T1DM recurrence after pancreas transplantation is infrequent; however, it is one of the causes of pancreatic graft loss that should always be ruled out. Negative autoimmunity prior to transplantation does not ensure that T1DM does not recur.
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Affiliation(s)
- María Argente-Pla
- Department of Endocrinology and Nutrition, La Fe University and Polytechnic Hospital, Valencia, Spain.,Mixed Research Unit of Endocrinology, Nutrition and Dietetics, La Fe Health Research Institute, Valencia, Spain
| | | | - María Isabel Del Olmo-García
- Department of Endocrinology and Nutrition, La Fe University and Polytechnic Hospital, Valencia, Spain.,Mixed Research Unit of Endocrinology, Nutrition and Dietetics, La Fe Health Research Institute, Valencia, Spain
| | - Jordi Espí-Reig
- Department of Nephrology, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Judith Pérez-Rojas
- Department of Pathological Anatomy, La Fe University and Polytechnic Hospital, Valencia, Spain
| | | | - Juan Francisco Merino-Torres
- Department of Endocrinology and Nutrition, La Fe University and Polytechnic Hospital, Valencia, Spain.,Mixed Research Unit of Endocrinology, Nutrition and Dietetics, La Fe Health Research Institute, Valencia, Spain.,Department of Medicine, University of Valencia, Valencia, Spain
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Gunasekaran M, Vachharajani N, Gaut JP, Maw TT, Delos Santos R, Shenoy S, Chapman WC, Wellen J, Mohanakumar T. Development of immune response to tissue-restricted self-antigens in simultaneous kidney-pancreas transplant recipients with acute rejection. Clin Transplant 2017. [PMID: 28639386 DOI: 10.1111/ctr.13009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Simultaneous kidney-pancreas transplantation (SKP Tx) is a treatment for end-stage kidney disease secondary to diabetes mellitus. We investigated the role of immune responses to donor human leukocyte antigens (HLA) and tissue-restricted kidney and pancreas self-antigens (KSAgs and PSAgs, respectively) in SKP Tx recipients (SKP TxRs). Sera collected from 39 SKP TxRs were used to determine de novo Abs specific for KSAgs (collagen-IV, Col-IV; fibronectin, FN) and PSAgs (insulin, islet cells, glutamic acid decarboxylase, and pancreas-associated protein-1) by ELISA. KSAg-specific IFN-γ, IL-17, and IL-10 cytokines were enumerated by ELISpot. Abs to donor HLA classes I and II were determined by Luminex assay. Abs to KSAgs and PSAgs were detectable in recipients with rejection compared with stable recipients (P<.05). Kidney-only rejection recipients had increased Abs against KSAgs compared with stable (P<.05), with no increase in Abs against PSAgs. Pancreas-only rejection recipients showed increased Abs against PSAgs compared to stable (P<.05), with no Abs against KSAgs. SKP TxRs with rejection showed increased frequencies of KSAg-specific IFN-γ and IL-17 with reduction in IL-10-secreting cells. SKP TxRs with rejection developed Abs to KSAgs and PSAgs demonstrated increased frequencies of kidney or pancreas SAg-specific IFN-γ and IL-17-secreting cells with reduced IL-10, suggesting loss of peripheral tolerance to SAgs.
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Affiliation(s)
| | - Neeta Vachharajani
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Joseph P Gaut
- Department of Anatomic and Molecular Pathology, Washington University School of Medicine, St. Louis, MO, USA
| | - Thin Thin Maw
- Department of Medicine, Nephrology, University of Southern California, Los Angeles, CA, USA
| | - Rowena Delos Santos
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Surendra Shenoy
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - William C Chapman
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Jason Wellen
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
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Abstract
Treatments for autoimmune diseases including type 1 diabetes (T1D) are aimed at resetting the immune system, especially its adaptive arm. The innate immune system is often ignored in the design of novel immune-based therapies. There is increasing evidence for multiple natural killer (NK) subpopulations, but their role is poorly understood in autoimmunity and likely is contributing to the controversial role reported for NKs. In this review, we will summarize NK subsets and their roles in tolerance, autoimmune diabetes, and immunotherapy.
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Affiliation(s)
- Chris Fraker
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Allison L Bayer
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
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Ribeiro RS, Cristelli M, Amor AJ, Guerrero V, Ferrer J, Ricart MJ, Esmatjes E. The Effect of Corticosteroid Withdrawal on Glucose Metabolism and Anti-GAD Antibodies in Simultaneous Pancreas-Kidney Transplant Patients. Prog Transplant 2016; 26:249-54. [PMID: 27317270 DOI: 10.1177/1526924816654371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
CONTEXT Corticosteroid withdrawal may reduce insulin resistance; however, it could also influence pancreatic autoantibody profile in simultaneous pancreas-kidney (SPK) transplant patients. OBJECTIVE To evaluate the effect of corticosteroid withdrawal on glucose metabolism and anti-glutamic acid decarboxylase (GAD) antibody titers in SPK patients with type 1 diabetes after 12 months of follow-up. DESIGN In this retrospective study, fasting glucose and glycated hemoglobin (A1c) were compared before and after 3, 6, and 12 months of corticosteroid withdrawal in 80 SPK patients. In addition, weight, anti-GAD, and C-peptide levels were compared before and after withdrawal. Finally, fasting and postglucose, insulin, and C-peptide levels were compared before and after withdrawal in 25 patients undergoing oral glucose tolerance test (OGTT). RESULTS Fasting glucose levels did not change during corticosteroid discontinuation. After 12 months, A1c slightly increased from 4.6% (0.4%) to 4.8% (0.6%) (P < .01) and C-peptide decreased from 2.8 (1.1) ng/mL to 2.4 (1.3) ng/mL (P <. 01). In patients submitted to OGTT, glucose, insulin, and C-peptide levels did not change. There was no alteration in the proportion of anti-GAD positive tests (41% vs 45%). Anti-GAD titers remained stable or decreased in 70% of positive patients. CONCLUSION Corticosteroid withdrawal has no significant effect on glucose metabolism and on anti-GAD profile among SPK patients.
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Affiliation(s)
- Rogério Silicani Ribeiro
- Diabetes Unit, Hospital Clínic de Barcelona, Barcelona, Spain Diabetes Program, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Marina Cristelli
- Renal Transplant Unit, Hospital Clínic de Barcelona, Barcelona, Spain Hospital do Rim, Universidade Federal de São Paulo, Sao Paulo, Brazil
| | - Antonio J Amor
- Diabetes Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Vanessa Guerrero
- Renal Transplant Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Joana Ferrer
- Surgery Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - María José Ricart
- Renal Transplant Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Enric Esmatjes
- Diabetes Unit, Hospital Clínic de Barcelona, Barcelona, Spain
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Abstract
There is a clear need to develop strategies to induce tolerance without the need of chronic immunosuppression in transplant recipient and in patients with autoimmunity. Adoptive T regulatory cell (Treg) therapy offers the potential of long-lasting protection. However, based on results of clinical trials so far with ex vivo expanded autologous Tregs in type 1 diabetic (T1D) patients, it seems unlikely that single immunotherapy with Treg infusion without immunomodulation regimens that promote stable donor Treg engraftment and persistence would afford truly significant clinical benefit. Combination therapies could provide improved outcomes with consideration of the fundamental factors required for Treg generation, homeostasis, and function to promote long-term donor Treg persistence to provoke beneficial therapeutic outcomes.
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Martins LS. Autoimmune diabetes recurrence should be routinely monitored after pancreas transplantation. World J Transplant 2014; 4:183-187. [PMID: 25346891 PMCID: PMC4208081 DOI: 10.5500/wjt.v4.i3.183] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 05/21/2014] [Accepted: 07/17/2014] [Indexed: 02/05/2023] Open
Abstract
Autoimmune type 1 diabetes recurrence in pancreas grafts was first described 30 years ago, but it is not yet completely understood. In fact, the number of transplants affected and possibly lost due to this disease may be falsely low. There may be insufficient awareness to this entity by clinicians, leading to underdiagnosis. Some authors estimate that half of the immunological losses in pancreas transplantation are due to autoimmunity. Pancreas biopsy is the gold standard for the definitive diagnosis. However, as an invasive procedure, it is not the ideal approach to screen the disease. Pancreatic autoantibodies which may be detected early before graft dysfunction, when searched for, are probably the best initial tool to establish the diagnosis. The purpose of this review is to revisit the autoimmune aspects of type 1 diabetes and to analyse data about the identified autoantibodies, as serological markers of the disease. Therapeutic strategies used to control the disease, though with unsatisfactory results, are also addressed. In addition, the author’s own experience with the prospective monitoring of pancreatic autoantibodies after transplantation and its correlation with graft outcome will be discussed.
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Martins LS, Henriques AC, Fonseca IM, Rodrigues AS, Oliverira JC, Dores JM, Dias LS, Cabrita AM, Silva JD, Noronha IL. Pancreatic autoantibodies after pancreas-kidney transplantation - do they matter? Clin Transplant 2014; 28:462-9. [PMID: 24655222 DOI: 10.1111/ctr.12337] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2014] [Indexed: 02/05/2023]
Abstract
Type 1 diabetes recurrence has been documented in simultaneous pancreas-kidney transplants (SPKT), but this diagnosis may be underestimated. Antibody monitoring is the most simple, noninvasive, screening test for pancreas autoimmune activity. However, the impact of the positive autoimmune markers on pancreas graft function remains controversial. In our cohort of 105 SPKT, we studied the cases with positive pancreatic autoantibodies. They were immunosuppressed with antithymocyte globulin, tacrolimus, mycophenolate, and steroids. The persistence or reappearance of these autoantibodies after SPKT and factors associated with their evolution and with graft outcome were analyzed. Pancreatic autoantibodies were prospectively monitored. Serum samples were collected before transplantation and at least once per year thereafter. At the end of the follow-up (maximum 138 months), 43.8% of patients were positive (from pre-transplant or after recurrence) for at least one autoantibody - the positive group. Antiglutamic acid decarboxylase was the most prevalent (31.4%), followed by anti-insulin (8.6%) and anti-islet cell autoantibodies (3.8%). Bivariate analysis showed that the positive group had higher fasting glucose, higher glycated hemoglobin (HbA1c), lower C-peptide levels, and a higher number of HLA-matches. Analyzing the sample divided into four groups according to pre-/post-transplant autoantibodies profile, the negative/positive group tended to present the higher HbA1c values. Multivariate analysis confirmed the significant association between pancreas autoimmunity and HbA1c and C-peptide levels. Positivity for these autoantibodies pre-transplantation did not influence pancreas survival. The unfavorable glycemic profile observed in the autoantibody-positive SPKT is a matter of concern, which deserves further attention.
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Affiliation(s)
- La Salete Martins
- Nephrology Department, Hospital Santo António, Centro Hospitalar do Porto, Porto, Portugal; Transplantation Department, Hospital Santo António, Centro Hospitalar do Porto, Porto, Portugal
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Zanone MM, Favaro E, Quadri R, Miceli I, Giaretta F, Romagnoli R, David E, Perin PC, Salizzoni M, Camussi G. Association of cytomegalovirus infections with recurrence of humoral and cellular autoimmunity to islet autoantigens and of type 1 diabetes in a pancreas transplanted patient. Transpl Int 2009; 23:333-7. [PMID: 19906032 DOI: 10.1111/j.1432-2277.2009.00994.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Association of type 1 diabetes and cytomegalovirus (CMV) is suspected and CMV infections have also been linked to increased risk of new onset post-transplantation diabetes. We monitored response to islet autoantigens, pancreatic endocrine function, and CMV infections in one type 1 diabetic patient receiving pancreas allograft. Time course analyses of levels of islet autoantibodies (Abs), IFN-gamma ELISPOT response, analysis of T cell function, levels of C peptide together with CMV pp65 antigenaemia and viraemia and graft biopsy histopathology were performed in comparison with a cohort of diabetic recipients. Evidence of autoimmune activation to GAD and IA2, modification of CD4(+) CD25hi T cells, loss of pancreatic function, concomitantly with multiple CMV infections and allograft rejection with peri-insulitis is provided. The parallel between metabolic outcome, initiation and progression of autoreactivity to islet autoantigens and early CMV infections after transplantation, suggests that persistent CMV infections may be relevant to the pathogenesis of type 1 diabetes.
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Affiliation(s)
- Maria M Zanone
- Department of Internal Medicine, University of Turin, Turin, Italy.
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