المؤلفون: Vendrame, Francesco, Pileggi, Antonello, Laughlin, Elsa, Allende, Gloria, Martin-Pagola, Ainhoa, Molano, R Damaris, Diamantopoulos, Stavros, Standifer, Nathan, Geubtner, Kelly, Falk, Ben A, Ichii, Hirohito, Takahashi, Hidenori, Snowhite, Isaac, Chen, Zhibin, Mendez, Armando, Chen, Linda, Sageshima, Junichiro, Ruiz, Phillip, Ciancio, Gaetano, Ricordi, Camillo, Reijonen, Helena, Nepom, Gerald T, Burke, George W, Pugliese, Alberto

المصدر: Diabetes. 59(4)

مصطلحات موضوعية: Clinical Research, Autoimmune Disease, Diabetes, Kidney Disease, Organ Transplantation, Transplantation, 2.1 Biological and endogenous factors, Aetiology, Renal and urogenital, Metabolic and endocrine, Adult, Animals, Autoantibodies, Autoimmunity, Biopsy, CD4-Positive T-Lymphocytes, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Female, Humans, Kidney Transplantation, Male, Mice, Pancreas Transplantation, Recurrence, T-Lymphocytes, Transplantation, Homologous, Medical and Health Sciences, Endocrinology & Metabolism

الوصف: ObjectiveTo investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients.Research design and methodsWe 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.ResultsAutoantibodies 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 approximately 1 year from hyperglycemia recurrence and revealed beta-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 beta-cell loss in mice receiving autoreactive T-cells but not control T-cells.ConclusionsWe demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating beta-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.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6m79n86sTest

المؤلفون: Hänninen, Arno, Soilu‐Hänninen, Merja, Hampe, Christiane S., Deptula, Angie, Geubtner, Kelly, Ilonen, Jorma, Knip, Mikael, Reijonen, Helena

المصدر: Diabetes/Metabolism Research and Reviews ; volume 26, issue 4, page 271-279 ; ISSN 1520-7552 1520-7560

الوصف: Background Glutamic acid decarboxylase (GAD) is a rate‐limiting enzyme in the synthesis of gamma‐amino butyric acid (GABA) and an important autoantigen both in patients with type 1 diabetes (T1D) and stiff‐person syndrome (SPS). Autoantibodies (GADA) to the 65‐kDa isoform of GAD are a characteristic feature in both diseases. Approximately 30% of patients with SPS develop diabetes, yet, it is unclear to which extent co‐existing autoimmunity to GAD65 and other islet autoantigens determines the risk of developing T1D. Methods In this study, we monitored CD4+ T‐cell responses to GAD65 and proinsulin in a patient with SPS who remained normoglycaemic during the 46‐month follow‐up. Results Fluctuating but persistent T‐cell reactivity to GAD65 was identified, as well as T‐cell reactivity to proinsulin at one time point. The majority of the T‐cell clones isolated from the patient with SPS produced high levels of Th2 cytokines (IL‐13, IL‐5 and IL‐4). We also examined levels of GADA, insulin and IA‐2 autoantibodies, and epitope specificity of GADA. In both serum and cerebrospinal fluid (CSF), GADA levels were high, and GADA persisted throughout the follow‐up. Despite T‐cell reactivity to both GAD65 and proinsulin, autoantibodies to other islet autoantigens did not develop. Conclusions Further follow‐up will determine whether the beta‐cell autoimmunity observed in this patient will eventually lead to T1D. Copyright © 2010 John Wiley & Sons, Ltd.

الإتاحة: https://doi.org/10.1002/dmrr.1083Test

المؤلفون: Öling, Viveka, Geubtner, Kelly, Ilonen, Jorma, Reijonen, Helena

المصدر: Autoimmunity ; volume 43, issue 8, page 573-582 ; ISSN 0891-6934 1607-842X

الإتاحة: https://doi.org/10.3109/08916930903540424Test

المؤلفون: Reichstetter, Sandra, Standifer, Nathan E., Geubtner, Kelly A., Liu, Andrew W., Agar, Stacy L., Kwok, William W.

المصدر: Immunology ; volume 117, issue 3, page 350-357 ; ISSN 0019-2805 1365-2567

الوصف: Summary Alloreactivity is one of the most serious problems in organ transplantation. It has been hypothesized that pre‐existing alloreactive T cells are actually cross‐reacting cells that have been primed by the autologous major histocompatibility complex (MHC) and a specific peptide. CD8 + cytotoxic T lymphocytes that are alloreactive and recognize a virus‐peptide that is presented by the autologous MHC have been reported. Here we demonstrate a cross‐reactivity that exists between DQ0602 restricted, herpes simplex type 2 VP16 40–50 specific CD4 + T‐cell clones, which can be alloreactive to DQ0601. Though most of the DQ0602 restricted T‐cell clones we isolated from two different donors were not alloreactive, weakly cross‐reacting T‐cell clones could be isolated from both donors. Two strongly cross‐reacting T‐cell clones with high affinity interaction of their T‐cell receptor (TCR) with both DQ0602/VP16 40–50 and DQ0601 could be isolated from one donor. DNA sequencing of the a fragment of the Vβ gene used in their TCR confirmed that these two T cells indeed are two independent clones. These clones are cytotoxic and produce cytokines of a T helper 2‐like pattern. Possible implications in a DR‐matched transplantation setting are discussed.

الإتاحة: https://doi.org/10.1111/j.1365-2567.2005.02308.xTest

المؤلفون: Reichstetter, Sandra, Standifer, Nathan E., Geubtner, Kelly A., Liu, Andrew W., Agar, Stacy L., Kwok, William W.

المصدر: Immunology; Mar2006, Vol. 117 Issue 3, p350-357, 8p, 2 Charts, 8 Graphs

مصطلحات موضوعية: HERPES simplex, MAJOR histocompatibility complex, TRANSPLANTATION of organs, tissues, etc., IMMUNOREGULATION, NUCLEOTIDE sequence, T-cell receptor genes, CYTOKINES, T cells

مستخلص: Alloreactivity is one of the most serious problems in organ transplantation. It has been hypothesized that pre-existing alloreactive T cells are actually cross-reacting cells that have been primed by the autologous major histocompatibility complex (MHC) and a specific peptide. CD8⁺ cytotoxic T lymphocytes that are alloreactive and recognize a virus-peptide that is presented by the autologous MHC have been reported. Here we demonstrate a cross-reactivity that exists between DQ0602 restricted, herpes simplex type 2 VP16 40–50 specific CD4⁺ T-cell clones, which can be alloreactive to DQ0601. Though most of the DQ0602 restricted T-cell clones we isolated from two different donors were not alloreactive, weakly cross-reacting T-cell clones could be isolated from both donors. Two strongly cross-reacting T-cell clones with high affinity interaction of their T-cell receptor (TCR) with both DQ0602/VP16 40–50 and DQ0601 could be isolated from one donor. DNA sequencing of the a fragment of the Vβ gene used in their TCR confirmed that these two T cells indeed are two independent clones. These clones are cytotoxic and produce cytokines of a T helper 2-like pattern. Possible implications in a DR-matched transplantation setting are discussed. [ABSTRACT FROM AUTHOR]

: Copyright of Immunology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)