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Cited by 215Diabetes and associated disordersPancreatic function and diabetesT-cell and B-cell Immunology

Recurrence of Type 1 Diabetes After Simultaneous Pancreas-Kidney Transplantation, Despite Immunosuppression, Is Associated With Autoantibodies and Pathogenic Autoreactive CD4 T-Cells

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Vendrame, Francesco, Pileggi, Antonello, Laughlin, Elsa, Allende, Gloria, Martin-Pagola, Ainhoa, Molano, R. Damaris, Diamantopoulos, Stavros, Standifer, Nathan +16 more·2010·Diabetes
DOI 10.2337/db09-0498PMC PMC2844842
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Abstract

OBJECTIVE: To investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients. RESEARCH DESIGN AND METHODS: We monitored autoantibodies and autoreactive T-cells (using tetramers) and performed biopsy. The function of autoreactive T-cells was studied with in vitro and in vivo assays. RESULTS: Autoantibodies were present pretransplant and persisted on follow-up in one patient. They appeared years after transplantation but before the development of hyperglycemia in the remaining patients. Pancreas transplant biopsies were taken within ∼1 year from hyperglycemia recurrence and revealed β-cell loss and insulitis. We studied autoreactive T-cells from the time of biopsy and repeatedly demonstrated their presence on further follow-up, together with autoantibodies. Treatment with T-cell–directed therapies (thymoglobulin and daclizumab, all patients), alone or with the addition of B-cell–directed therapy (rituximab, two patients), nonspecifically depleted T-cells and was associated with C-peptide secretion for >1 year. Autoreactive T-cells with the same autoantigen specificity and conserved T-cell receptor later reappeared with further C-peptide loss over the next 2 years. Purified autoreactive CD4 T-cells from two patients were cotransplanted with HLA-mismatched human islets into immunodeficient mice. Grafts showed β-cell loss in mice receiving autoreactive T-cells but not control T-cells. CONCLUSIONS: We demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating β-cell destruction. Markers of autoimmunity can help diagnose this underappreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents used.

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  • Islet-cell transplantation depends on overcoming recurrent autoimmunity and averting alloimmunity.

    “Similarly, islet-cell transplantation depends on overcoming recurrent autoimmunity and averting alloimmunity.153”

    From Type 1 diabetes (2014) · cites this paper as [153]

    The Conclusions and Discussion describe recurrent autoimmunity as a cause of graft loss despite immunosuppression. The Results also document rejection of a second pancreas graft, supporting the need to avert alloimmune rejection. However, the patients received pancreas-kidney transplants, not islet-cell transplants, so the claim extends the clinical finding to a different transplant setting. (LLM, conf=0.84)

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Authors
Vendrame, F., Pileggi, A., Laughlin, E., Allende, G., Martin-Pagola, A., Molano, R. D., Diamantopoulos, S., Standifer, N., Geubtner, K., Falk, B. A., Ichii, H., Takahashi, H., Snowhite, I., Chen, Z., Mendez, A., Chen, L., Sageshima, J., Ruiz, P., Ciancio, G., Ricordi, C., Reijonen, H., Nepom, G. T., Burke, G. W., & Pugliese, A.
Affiliations
  • University of Miami (US)
  • Benaroya Research Institute (US)
  • Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida;
  • Amgen (United States) (US)
Corresponding author
Pugliese, Alberto
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2010-01-19
Volume
59
Issue
4
Pages
947-957
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db09-0498
PMC
PMC2844842
OpenAlex
W2122204548
Cited by
215
References
50
Citations by year
2026: 5 · 2025: 3 · 2024: 4 · 2023: 12 · 2022: 4 · 2021: 11 · 2020: 9 · 2019: 10 · 2018: 10 · 2017: 12 · 2016: 20 · 2015: 19 · 2014: 17 · 2013: 18 · 2012: 29
FWCI
14.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institute of Allergy and Infectious Diseases (U19AI050864, AI 50864)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DP3DK085696, R01DK070011, 5R01-DK-070011)
  • National Center for Research Resources (M01RR016587, M01‐RR16587, U42RR016603)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
type 1 diabetes, simultaneous pancreas-kidney transplantation, diabetes recurrence, autoantibodies, autoreactive CD4+ T cells, beta cell destruction, insulitis, hyperglycemia, thymoglobulin, daclizumab, rituximab, T cell receptor, islet transplantation, graft loss, immune monitoring
MeSH terms
Adult, Animals, Autoantibodies, Biopsy, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Female, Humans, Male, Recurrence, T-Lymphocytes, Transplantation, Homologous, CD4-Positive T-Lymphocytes, Autoimmunity, Kidney Transplantation, Pancreas Transplantation, Mice

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