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3. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

Author

Cossarizza, A, Chang, H, Radbruch, A, Abrignani, S, Addo, R, Akdis, M, Andra, I, Andreata, F, Annunziato, F, Arranz, E, Bacher, P, Bari, S, Barnaba, V, Barros-Martins, J, Baumjohann, D, Beccaria, C, Bernardo, D, Boardman, D, Borger, J, Bottcher, C, Brockmann, L, Burns, M, Busch, D, Cameron, G, Cammarata, I, Cassotta, A, Chang, Y, Chirdo, F, Christakou, E, Cicin-Sain, L, Cook, L, Corbett, A, Cornelis, R, Cosmi, L, Davey, M, De Biasi, S, De Simone, G, del Zotto, G, Delacher, M, Di Rosa, F, Santo, J, Diefenbach, A, Dong, J, Dorner, T, Dress, R, Dutertre, C, Eckle, S, Eede, P, Evrard, M, Falk, C, Feuerer, M, Fillatreau, S, Fiz-Lopez, A, Follo, M, Foulds, G, Frobel, J, Gagliani, N, Galletti, G, Gangaev, A, Garbi, N, Garrote, J, Geginat, J, Gherardin, N, Gibellini, L, Ginhoux, F, Godfrey, D, Gruarin, P, Haftmann, C, Hansmann, L, Harpur, C, Hayday, A, Heine, G, Hernandez, D, Herrmann, M, Hoelsken, O, Huang, Q, Huber, S, Huber, J, Huehn, J, Hundemer, M, Hwang, W, Iannacone, M, Ivison, S, Jack, H, Jani, P, Keller, B, Kessler, N, Ketelaars, S, Knop, L, Knopf, J, Koay, H, Kobow, K, Kriegsmann, K, Kristyanto, H, Krueger, A, Kuehne, J, Kunze-Schumacher, H, Kvistborg, P, Kwok, I, Latorre, D, Lenz, D, Levings, M, Lino, A, Liotta, F, Long, H, Lugli, E, Macdonald, K, Maggi, L, Maini, M, Mair, F, Manta, C, Manz, R, Mashreghi, M, Mazzoni, A, Mccluskey, J, Mei, H, Melchers, F, Melzer, S, Mielenz, D, Monin, L, Moretta, L, Multhoff, G, Munoz, L, Munoz-Ruiz, M, Muscate, F, Natalini, A, Neumann, K, Ng, L, Niedobitek, A, Niemz, J, Almeida, L, Notarbartolo, S, Ostendorf, L, Pallett, L, Patel, A, Percin, G, Peruzzi, G, Pinti, M, Pockley, A, Pracht, K, Prinz, I, Pujol-Autonell, I, Pulvirenti, N, Quatrini, L, Quinn, K, Radbruch, H, Rhys, H, Rodrigo, M, Romagnani, C, Saggau, C, Sakaguchi, S, Sallusto, F, Sanderink, L, Sandrock, I, Schauer, C, Scheffold, A, Scherer, H, Schiemann, M, Schildberg, F, Schober, K, Schoen, J, Schuh, W, Schuler, T, Schulz, A, Schulz, S, Schulze, J, Simonetti, S, Singh, J, Sitnik, K, Stark, R, Starossom, S, Stehle, C, Szelinski, F, Tan, L, Tarnok, A, Tornack, J, Tree, T, van Beek, J, van de Veen, W, van Gisbergen, K, Vasco, C, Verheyden, N, von Borstel, A, Ward-Hartstonge, K, Warnatz, K, Waskow, C, Wiedemann, A, Wilharm, A, Wing, J, Wirz, O, Wittner, J, Yang, J, Cossarizza A., Chang H. -D., Radbruch A., Abrignani S., Addo R., Akdis M., Andra I., Andreata F., Annunziato F., Arranz E., Bacher P., Bari S., Barnaba V., Barros-Martins J., Baumjohann D., Beccaria C. G., Bernardo D., Boardman D. A., Borger J., Bottcher C., Brockmann L., Burns M., Busch D. H., Cameron G., Cammarata I., Cassotta A., Chang Y., Chirdo F. G., Christakou E., Cicin-Sain L., Cook L., Corbett A. J., Cornelis R., Cosmi L., Davey M. S., De Biasi S., De Simone G., del Zotto G., Delacher M., Di Rosa F., Santo J. D., Diefenbach A., Dong J., Dorner T., Dress R. J., Dutertre C. -A., Eckle S. B. G., Eede P., Evrard M., Falk C. S., Feuerer M., Fillatreau S., Fiz-Lopez A., Follo M., Foulds G. A., Frobel J., Gagliani N., Galletti G., Gangaev A., Garbi N., Garrote J. A., Geginat J., Gherardin N. A., Gibellini L., Ginhoux F., Godfrey D. I., Gruarin P., Haftmann C., Hansmann L., Harpur C. M., Hayday A. C., Heine G., Hernandez D. C., Herrmann M., Hoelsken O., Huang Q., Huber S., Huber J. E., Huehn J., Hundemer M., Hwang W. Y. K., Iannacone M., Ivison S. M., Jack H. -M., Jani P. K., Keller B., Kessler N., Ketelaars S., Knop L., Knopf J., Koay H. -F., Kobow K., Kriegsmann K., Kristyanto H., Krueger A., Kuehne J. F., Kunze-Schumacher H., Kvistborg P., Kwok I., Latorre D., Lenz D., Levings M. K., Lino A. C., Liotta F., Long H. M., Lugli E., MacDonald K. N., Maggi L., Maini M. K., Mair F., Manta C., Manz R. A., Mashreghi M. -F., Mazzoni A., McCluskey J., Mei H. E., Melchers F., Melzer S., Mielenz D., Monin L., Moretta L., Multhoff G., Munoz L. E., Munoz-Ruiz M., Muscate F., Natalini A., Neumann K., Ng L. G., Niedobitek A., Niemz J., Almeida L. N., Notarbartolo S., Ostendorf L., Pallett L. J., Patel A. A., Percin G. I., Peruzzi G., Pinti M., Pockley A. G., Pracht K., Prinz I., Pujol-Autonell I., Pulvirenti N., Quatrini L., Quinn K. M., Radbruch H., Rhys H., Rodrigo M. B., Romagnani C., Saggau C., Sakaguchi S., Sallusto F., Sanderink L., Sandrock I., Schauer C., Scheffold A., Scherer H. U., Schiemann M., Schildberg F. A., Schober K., Schoen J., Schuh W., Schuler T., Schulz A. R., Schulz S., Schulze J., Simonetti S., Singh J., Sitnik K. M., Stark R., Starossom S., Stehle C., Szelinski F., Tan L., Tarnok A., Tornack J., Tree T. I. M., van Beek J. J. P., van de Veen W., van Gisbergen K., Vasco C., Verheyden N. A., von Borstel A., Ward-Hartstonge K. A., Warnatz K., Waskow C., Wiedemann A., Wilharm A., Wing J., Wirz O., Wittner J., Yang J. H. M., Yang J., Cossarizza, A, Chang, H, Radbruch, A, Abrignani, S, Addo, R, Akdis, M, Andra, I, Andreata, F, Annunziato, F, Arranz, E, Bacher, P, Bari, S, Barnaba, V, Barros-Martins, J, Baumjohann, D, Beccaria, C, Bernardo, D, Boardman, D, Borger, J, Bottcher, C, Brockmann, L, Burns, M, Busch, D, Cameron, G, Cammarata, I, Cassotta, A, Chang, Y, Chirdo, F, Christakou, E, Cicin-Sain, L, Cook, L, Corbett, A, Cornelis, R, Cosmi, L, Davey, M, De Biasi, S, De Simone, G, del Zotto, G, Delacher, M, Di Rosa, F, Santo, J, Diefenbach, A, Dong, J, Dorner, T, Dress, R, Dutertre, C, Eckle, S, Eede, P, Evrard, M, Falk, C, Feuerer, M, Fillatreau, S, Fiz-Lopez, A, Follo, M, Foulds, G, Frobel, J, Gagliani, N, Galletti, G, Gangaev, A, Garbi, N, Garrote, J, Geginat, J, Gherardin, N, Gibellini, L, Ginhoux, F, Godfrey, D, Gruarin, P, Haftmann, C, Hansmann, L, Harpur, C, Hayday, A, Heine, G, Hernandez, D, Herrmann, M, Hoelsken, O, Huang, Q, Huber, S, Huber, J, Huehn, J, Hundemer, M, Hwang, W, Iannacone, M, Ivison, S, Jack, H, Jani, P, Keller, B, Kessler, N, Ketelaars, S, Knop, L, Knopf, J, Koay, H, Kobow, K, Kriegsmann, K, Kristyanto, H, Krueger, A, Kuehne, J, Kunze-Schumacher, H, Kvistborg, P, Kwok, I, Latorre, D, Lenz, D, Levings, M, Lino, A, Liotta, F, Long, H, Lugli, E, Macdonald, K, Maggi, L, Maini, M, Mair, F, Manta, C, Manz, R, Mashreghi, M, Mazzoni, A, Mccluskey, J, Mei, H, Melchers, F, Melzer, S, Mielenz, D, Monin, L, Moretta, L, Multhoff, G, Munoz, L, Munoz-Ruiz, M, Muscate, F, Natalini, A, Neumann, K, Ng, L, Niedobitek, A, Niemz, J, Almeida, L, Notarbartolo, S, Ostendorf, L, Pallett, L, Patel, A, Percin, G, Peruzzi, G, Pinti, M, Pockley, A, Pracht, K, Prinz, I, Pujol-Autonell, I, Pulvirenti, N, Quatrini, L, Quinn, K, Radbruch, H, Rhys, H, Rodrigo, M, Romagnani, C, Saggau, C, Sakaguchi, S, Sallusto, F, Sanderink, L, Sandrock, I, Schauer, C, Scheffold, A, Scherer, H, Schiemann, M, Schildberg, F, Schober, K, Schoen, J, Schuh, W, Schuler, T, Schulz, A, Schulz, S, Schulze, J, Simonetti, S, Singh, J, Sitnik, K, Stark, R, Starossom, S, Stehle, C, Szelinski, F, Tan, L, Tarnok, A, Tornack, J, Tree, T, van Beek, J, van de Veen, W, van Gisbergen, K, Vasco, C, Verheyden, N, von Borstel, A, Ward-Hartstonge, K, Warnatz, K, Waskow, C, Wiedemann, A, Wilharm, A, Wing, J, Wirz, O, Wittner, J, Yang, J, Cossarizza A., Chang H. -D., Radbruch A., Abrignani S., Addo R., Akdis M., Andra I., Andreata F., Annunziato F., Arranz E., Bacher P., Bari S., Barnaba V., Barros-Martins J., Baumjohann D., Beccaria C. G., Bernardo D., Boardman D. A., Borger J., Bottcher C., Brockmann L., Burns M., Busch D. H., Cameron G., Cammarata I., Cassotta A., Chang Y., Chirdo F. G., Christakou E., Cicin-Sain L., Cook L., Corbett A. J., Cornelis R., Cosmi L., Davey M. S., De Biasi S., De Simone G., del Zotto G., Delacher M., Di Rosa F., Santo J. D., Diefenbach A., Dong J., Dorner T., Dress R. J., Dutertre C. -A., Eckle S. B. G., Eede P., Evrard M., Falk C. S., Feuerer M., Fillatreau S., Fiz-Lopez A., Follo M., Foulds G. A., Frobel J., Gagliani N., Galletti G., Gangaev A., Garbi N., Garrote J. A., Geginat J., Gherardin N. A., Gibellini L., Ginhoux F., Godfrey D. I., Gruarin P., Haftmann C., Hansmann L., Harpur C. M., Hayday A. C., Heine G., Hernandez D. C., Herrmann M., Hoelsken O., Huang Q., Huber S., Huber J. E., Huehn J., Hundemer M., Hwang W. Y. K., Iannacone M., Ivison S. M., Jack H. -M., Jani P. K., Keller B., Kessler N., Ketelaars S., Knop L., Knopf J., Koay H. -F., Kobow K., Kriegsmann K., Kristyanto H., Krueger A., Kuehne J. F., Kunze-Schumacher H., Kvistborg P., Kwok I., Latorre D., Lenz D., Levings M. K., Lino A. C., Liotta F., Long H. M., Lugli E., MacDonald K. N., Maggi L., Maini M. K., Mair F., Manta C., Manz R. A., Mashreghi M. -F., Mazzoni A., McCluskey J., Mei H. E., Melchers F., Melzer S., Mielenz D., Monin L., Moretta L., Multhoff G., Munoz L. E., Munoz-Ruiz M., Muscate F., Natalini A., Neumann K., Ng L. G., Niedobitek A., Niemz J., Almeida L. N., Notarbartolo S., Ostendorf L., Pallett L. J., Patel A. A., Percin G. I., Peruzzi G., Pinti M., Pockley A. G., Pracht K., Prinz I., Pujol-Autonell I., Pulvirenti N., Quatrini L., Quinn K. M., Radbruch H., Rhys H., Rodrigo M. B., Romagnani C., Saggau C., Sakaguchi S., Sallusto F., Sanderink L., Sandrock I., Schauer C., Scheffold A., Scherer H. U., Schiemann M., Schildberg F. A., Schober K., Schoen J., Schuh W., Schuler T., Schulz A. R., Schulz S., Schulze J., Simonetti S., Singh J., Sitnik K. M., Stark R., Starossom S., Stehle C., Szelinski F., Tan L., Tarnok A., Tornack J., Tree T. I. M., van Beek J. J. P., van de Veen W., van Gisbergen K., Vasco C., Verheyden N. A., von Borstel A., Ward-Hartstonge K. A., Warnatz K., Waskow C., Wiedemann A., Wilharm A., Wing J., Wirz O., Wittner J., Yang J. H. M., and Yang J.

Abstract

The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers.

Published
2021

4. Identification of Donor Origin and Condition of Transplanted Islets in Situ in the Liver of a Type 1 Diabetic Recipient

Author

Cornelis R. Van Der Torren, Jessica S. Suwandi, Dahae Lee, Ernst-Jan T. Van't Wout, Gaby Duinkerken, Godelieve Swings, Arend Mulder, Frans H. J. Claas, Zhidong Ling, Pieter Gillard, Bart Keymeulen, Peter In't Veld, and Bart O. Roep

Subjects
Medicine
Abstract

Transplantation of islet allografts into type 1 diabetic recipients usually requires multiple pancreas donors to achieve insulin independence. This adds to the challenges of immunological monitoring of islet transplantation currently relying on surrogate immune markers in peripheral blood. We investigated donor origin and infiltration of islets transplanted in the liver of a T1D patient who died of hemorrhagic stroke 4 months after successful transplantation with two intraportal islet grafts combining six donors. Immunohistological staining for donor HLA using a unique panel of human monoclonal HLA-specific alloantibodies was performed on liver cryosections after validation on cryopreserved kidney, liver, and pancreas and compared with auto- and alloreactive T-cell immunity in peripheral blood. HLA-specific staining intensity and signal-to-noise ratio varied between tissues from very strong on kidney glomeruli, less in liver, kidney tubuli, and endocrine pancreas to least in exocrine pancreas, complicating the staining of inflamed islets in an HLA-disparate liver. Nonetheless, five islets from different liver lobes could be attributed to donors 1, 2, and 5 by staining patterns with multiple HLA types. All islets showed infiltration with CD8 + cytotoxic T cells that was mirrored by progressive alloreactive responses in peripheral blood mononuclear cells (PBMCs) to donors 1, 2, and 5 after transplantation. Stably low rates of peripheral islet autoreactive T-cell responses after islet infusion fit with a complete HLA mismatch between grafts and recipient and exclude the possibility that the islet-infiltrating CD8 T cells were autoreactive. HLA-specific immunohistochemistry can identify donor origin in situ and differentiate graft dysfunction and immunological destruction.

Published
2017
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7. Serum Cytokines as Biomarkers in Islet Cell Transplantation for Type 1 Diabetes.

Author

Cornelis R van der Torren, Annemarie A Verrijn Stuart, DaHae Lee, Jenny Meerding, Ursule van de Velde, Daniel Pipeleers, Pieter Gillard, Bart Keymeulen, Wilco de Jager, and Bart O Roep

Subjects
Medicine, Science
Abstract

Islet cell transplantation holds a potential cure for type 1 diabetes, but many islet recipients do not reach long-lasting insulin independence. In this exploratory study, we investigated whether serum cytokines, chemokines and adipokines are associated with the clinical outcome of islet transplantation.Thirteen islet transplant patients were selected on basis of good graft function (reaching insulin independence) or insufficient engraftment (insulin requiring) from our cohort receiving standardized grafts and immune suppressive therapy. Patients reaching insulin independence were divided in those with continued (>12 months) versus transient (

Published
2016
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9. Possible role of minor h antigens in the persistence of donor chimerism after stem cell transplantation; relevance for sustained leukemia remission.

Author

Cornelis R van der Torren, Yvette van Hensbergen, Susanne Luther, Zohara Aghai, Zuzana Stachová Rychnavská, Manon Slot, Sicco Scherjon, Nicolaus Kröger, Arnold Ganser, Eva M Weissinger, Els Goulmy, and Lothar Hambach

Subjects
Medicine, Science
Abstract

Persistent complete donor chimerism is an important clinical indicator for remissions of hematological malignancies after HLA-matched allogeneic stem cell transplantation (SCT). However, the mechanisms mediating the persistence of complete donor chimerism are poorly understood. The frequent coincidence of complete donor chimerism with graft-versus-leukemia effects and graft-versus-host disease suggests that immune responses against minor histocompatibility antigens (mHags) are playing an important role in suppressing the host hematopoiesis after allogeneic SCT. Here, we investigated a possible relationship between donor immune responses against the hematopoiesis-restricted mHag HA-1 and the long-term kinetics of host hematopoietic chimerism in a cohort of 10 patients after allogeneic HLA-matched, HA-1 mismatched SCT. Functional HA-1 specific CTLs (HA-1 CTLs) were detectable in 6/10 patients lysing host-type hematopoietic cells in vitro. Presence of HA-1 CTLs in the peripheral blood coincided with low host hematopoiesis levels quantified by highly sensitive mHag specific PCR. Additionally, co-incubation of host type CD34+ cells with HA-1 CTLs isolated after allogeneic SCT prevented progenitor and cobblestone area forming cell growth in vitro and human hematopoietic engraftment in immunodeficient mice. Conversely, absence or loss of HA-1 CTLs mostly coincided with high host hematopoiesis levels and/or relapse. In summary, in this first study, presence of HA-1 CTLs paralleled low host hematopoiesis levels. This coincidence might be supported by the capacity of HA-1 CTLs isolated after allogeneic SCT to specifically eliminate host type hematopoietic stem/progenitor cells. Additional studies involving multiple mismatched mHags in more patients are required to confirm this novel characteristic of mHag CTLs as factor for the persistence of complete donor chimerism and leukemia remission after allogeneic SCT.

Published
2015
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34. Immunogenicity of human embryonic stem cell-derived beta cells

Author

Cornelis R. van der Torren, Bart O. Roep, Arnaud Zaldumbide, Mark Peakman, Gaby Duinkerken, Laura Martinson, Eugene P. Brandon, Geert Stange, Simone H. Brand-Schaaf, Daniel Pipeleers, Evert Kroon, Medicine and Pharmacy academic/administration, Pathology/molecular and cellular medicine, Diabetes Pathology & Therapy, and Vriendenkring VUB

Subjects
0301 basic medicine, Embryonic stem cells, Endocrinology, Diabetes and Metabolism, Human Embryonic Stem Cells, 030209 endocrinology & metabolism, Autoimmunity, Adaptive Immunity, Biology, Article, Allograft rejection, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Immune system, Insulin-Secreting Cells, HLA-A2 Antigen, Internal Medicine, Humans, Cells, Cultured, reproductive and urinary physiology, Stem cell transplantation for articular cartilage repair, geography, Transplantation, geography.geographical_feature_category, Stem Cells, Immunogenicity, Beta cells, Allografts, equipment and supplies, Islet, Embryonic stem cell, Immunity, Innate, Immunity, Humoral, 3. Good health, Cell biology, 030104 developmental biology, embryonic structures, Immunology, biological phenomena, cell phenomena, and immunity, Stem cell, Adult stem cell
Abstract

Aims/hypothesis To overcome the donor shortage in the treatment of advanced type 1 diabetes by islet transplantation, human embryonic stem cells (hESCs) show great potential as an unlimited alternative source of beta cells. hESCs may have immune privileged properties and it is important to determine whether these properties are preserved in hESC-derived cells. Methods We comprehensively investigated interactions of both innate and adaptive auto- and allo-immunity with hESC-derived pancreatic progenitor cells and hESC-derived endocrine cells, retrieved after in-vivo differentiation in capsules in the subcutis of mice. Results We found that hESC-derived pancreatic endodermal cells expressed relatively low levels of HLA endorsing protection from specific immune responses. HLA was upregulated when exposed to IFNγ, making these endocrine progenitor cells vulnerable to cytotoxic T cells and alloreactive antibodies. In vivo-differentiated endocrine cells were protected from complement, but expressed more HLA and were targets for alloreactive antibody-dependent cellular cytotoxicity and alloreactive cytotoxic T cells. After HLA compatibility was provided by transduction with HLA-A2, preproinsulin-specific T cells killed insulin-producing cells. Conclusions/interpretation hESC-derived pancreatic progenitors are hypoimmunogenic, while in vivo-differentiated endocrine cells represent mature targets for adaptive immune responses. Our data support the need for immune intervention in transplantation of hESC-derived pancreatic progenitors. Cell-impermeable macro-encapsulation may suffice. Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-4125-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Published
2017
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36. The EU network on trace element speciation in full swing

Author

Cornelis, R, Cámara, C, Ebdon, L, Pitts, L, Sperling, M, Morabito, R, Donard, O.F.X, Crews, H, Larsen, E.H, Neidhart, B, Ariese, F, Rosenberg, E, Berrouiguet, O, Morrison, G.M, Cordier, G, Adams, F, Dero, B, Marshall, J, Stojanik, B, Ekvall, A, and Quevauviller, Ph

Published
2000
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40. Pretransplantation GAD-Autoantibody Status to Guide Prophylactic Antibody Induction Therapy in Simultaneous Pancreas and Kidney Transplantation

Author

Paul J M van der Boog, Ezio Bonifacio, Marko J.K. Mallat, Jan Ringers, Johan W. de Fijter, Pieter van de Linde, Cornelis R. van der Torren, and Bart O. Roep

Subjects
Adult, Graft Rejection, Male, medicine.medical_specialty, Daclizumab, medicine.medical_treatment, Pancreas transplantation, Kidney, Antibodies, Monoclonal, Humanized, Induction therapy, Gastroenterology, Young Adult, Predictive Value of Tests, Risk Factors, Prednisone, Internal medicine, medicine, Humans, Transplantation, Homologous, Prospective Studies, Pancreas, Kidney transplantation, Antilymphocyte Serum, Autoantibodies, Retrospective Studies, Transplantation, Glutamate Decarboxylase, business.industry, Autoantibody, Middle Aged, medicine.disease, Kidney Transplantation, Diabetes Mellitus, Type 1, Immunoglobulin G, Acute Disease, Immunology, Monoclonal, Prednisolone, Female, Pancreas Transplantation, business, Immunosuppressive Agents, medicine.drug
Abstract

Background Daclizumab and antithymocyte globulin (ATG) have been shown to reduce allograft rejection. We assessed the safety and efficacy of daclizumab or ATG prophylaxis in combination with triple immunotherapy in simultaneous pancreas-kidney transplant (SPKT) recipients. Methods Thirty-nine type 1 diabetic patients scheduled for primary SPKT were randomized to receive prophylactic therapy with either daclizumab or ATG. A group of 27 patients without prophylactic antibodies was used for retrospective comparison. All patients received cyclosporine and mycophenolate mofetil and gradually tapered prednisone. Autoantibodies and cellular autoreactivity were measured to assess recurrent autoreactive responses. Results Baseline and transplant characteristics were comparable among groups. Both daclizumab and ATG therapy resulted in a significant reduction in acute rejection episodes. The incidence of rejection episodes was significantly higher in pretransplantation GAD autoantibody-positive daclizumab-treated recipients compared with GAD autoantibody-negative or ATG-treated recipients. IA-2 islet autoantibodies showed no association with rejection. There were no significant differences between the groups for in vitro autoreactivity, clinical outcome, or functional parameters. Conclusions Daclizumab or ATG combined with a maintenance immunosuppressive regime consisting of cyclosporine, mycophenolate mofetil, and prednisolone were well tolerated and equally effective in reducing the incidence of acute rejection episodes in SPKT recipients. Up to 3 years, no adverse sequelae of the immunoprophylaxis or clinical and ex vivo recurrent autoimmunity were observed. We propose that the pretransplantation existence of GAD65 autoantibodies serves as a marker guiding the choice for prophylactic therapy in pancreas transplantation.

Published
2013
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43. Innate and adaptive immunity to human beta cell lines: implications for beta cell therapy

Author

Mark Peakman, Bart O. Roep, Philippe Ravassard, Raphael Scharfmann, Cornelis R. van der Torren, Dave L. Roelen, Paul Czernichow, Arnaud Zaldumbide, Gaby Duinkerken, and Simone H. Brand-Schaaf

Subjects
0301 basic medicine, Genotype, Cell Transplantation, Short Communication, Endocrinology, Diabetes and Metabolism, Adaptive immunity, Human leukocyte antigen, Antibodies, Cell Line, 03 medical and health sciences, Immune system, HLA Antigens, Insulin-Secreting Cells, Internal Medicine, Humans, Beta (finance), Inflammation, Innate immunity, Transplantation, Innate immune system, biology, Complement System Proteins, Th1 Cells, Acquired immune system, Immunity, Innate, 3. Good health, Killer Cells, Natural, Beta cell, Diabetes Mellitus, Type 1, 030104 developmental biology, Hyperglycemia, Immune System, Immunology, Leukocytes, Mononuclear, Cancer research, biology.protein, Cytokines, Antibody, Genetic Engineering, HeLa Cells, T-Lymphocytes, Cytotoxic
Abstract

Aims/hypothesis Genetically engineered human beta cell lines provide a novel source of human beta cells to study metabolism, pharmacology and beta cell replacement therapy. Since the immune system is essentially involved in beta cell destruction in type 1 diabetes and after beta cell transplantation, we investigated the interaction of human beta cell lines with the immune system to resolve their potential for immune intervention protocol studies. Methods Human pancreatic beta cell lines (EndoC-βH1 and ECi50) generated by targeted oncogenesis in fetal pancreas were assessed for viability after innate and adaptive immune challenges. Beta cell lines were pre-conditioned with T helper type 1 (Th1) cytokines or high glucose to mimic inflammatory and hyperglycaemia-stressed conditions. Beta cells were then co-cultured with auto- and alloreactive cytotoxic T cells (CTL), natural killer (NK) cells, supernatant fraction from activated autoreactive Th1 cells, or alloantibodies in the presence of complement or effector cells. Results Low HLA expression protected human beta cell lines from adaptive immune destruction, but it was associated with direct killing by activated NK cells. Autoreactive Th1 cell inflammation, rather than glucose stress, induced increased beta cell apoptosis and upregulation of HLA, increasing beta cell vulnerability to killing by auto- and alloreactive CTL and alloreactive antibodies. Conclusions/interpretation We demonstrate that genetically engineered human beta cell lines can be used in vitro to assess diverse immune responses that may be involved in the pathogenesis of type 1 diabetes in humans and beta cell transplantation, enabling preclinical evaluation of novel immune intervention strategies protecting beta cells from immune destruction. Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3779-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Published
2016
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44. Serum Cytokines as Biomarkers in Islet Cell Transplantation for Type 1 Diabetes

Author

Jenny Meerding, Annemarie A. Verrijn Stuart, Cornelis R. van der Torren, Pieter Gillard, Wilco de Jager, Bart Keymeulen, DaHae Lee, Daniel Pipeleers, Bart O. Roep, Ursule Van de Velde, von Herrath, Matthias G, Public Health Sciences, Pathology/molecular and cellular medicine, Diabetes Pathology & Therapy, and Vriendenkring VUB

Subjects
0301 basic medicine, Male, medicine.medical_treatment, Islets of Langerhans Transplantation, Psychologie appliquée, lcsh:Medicine, PROGRESSION, Cohort Studies, MELLITUS, 0302 clinical medicine, RELEVANCE, EFFECTOR T-CELLS, Insulin, lcsh:Science, Non-U.S. Gov't, Multidisciplinary, geography.geographical_feature_category, KIDNEY INJURY MOLECULE-1, Research Support, Non-U.S. Gov't, Immunosuppression, Middle Aged, Sciences bio-médicales et agricoles, Islet, 3. Good health, Multidisciplinary Sciences, Treatment Outcome, DIFFERENTIATION, surgical procedures, operative, 030220 oncology & carcinogenesis, Cytokines, Science & Technology - Other Topics, Female, Chemokines, Biologie, Immunosuppressive Agents, Research Article, Adult, Adipokine, ALLOGRAFT, Research Support, 03 medical and health sciences, Islets of Langerhans, Adipokines, medicine, Journal Article, Humans, INFLAMMATORY CYTOKINES, Immunosuppression Therapy, PANCREAS, Type 1 diabetes, geography, Islet cell transplantation, Science & Technology, business.industry, lcsh:R, Immunotherapy, medicine.disease, Transplantation, 030104 developmental biology, Diabetes Mellitus, Type 1, Immunology, MULTIPLEX IMMUNOASSAY, lcsh:Q, business, Biomarkers
Abstract

Background. Islet cell transplantation holds a potential cure for type 1 diabetes, but many islet recipients do not reach long-lasting insulin independence. In this exploratory study, we investigated whether serum cytokines, chemokines and adipokines are associated with the clinical outcome of islet transplantation. Methods. Thirteen islet transplant patients were selected on basis of good graft function (reaching insulin independence) or insufficient engraftment (insulin requiring) from our cohort receiving standardized grafts and immune suppressive therapy. Patients reaching insulin independence were divided in those with continued (>12 months) versus transient (, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2016

45. Identification of Donor Origin and Condition of Transplanted Islets in Situ in the Liver of a Type 1 Diabetic Recipient

Author

Van Der Torren, Cornelis R., primary, Suwandi, Jessica S., additional, Lee, Dahae, additional, Van't Wout, Ernst-Jan T., additional, Duinkerken, Gaby, additional, Swings, Godelieve, additional, Mulder, Arend, additional, Claas, Frans H. J., additional, Ling, Zhidong, additional, Gillard, Pieter, additional, Keymeulen, Bart, additional, Veld, Peter In't, additional, and Roep, Bart O., additional

Published
2017
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46. Serum Cytokines as Biomarkers in Islet Cell Transplantation for Type 1 Diabetes

Author

van der Torren, Cornelis R, Verrijn Stuart, Annemarie A, Lee, DaHae, Meerding, Jenny, van de Velde, Ursule, Pipeleers, Daniel, Gillard, Pieter, Keymeulen, Bart, de Jager, Wilco, Roep, Bart O, van der Torren, Cornelis R, Verrijn Stuart, Annemarie A, Lee, DaHae, Meerding, Jenny, van de Velde, Ursule, Pipeleers, Daniel, Gillard, Pieter, Keymeulen, Bart, de Jager, Wilco, and Roep, Bart O

Published
2016

47. Serum Cytokines as Biomarkers in Islet Cell Transplantation for Type 1 Diabetes

Author

Endocrinologie, Child Health, CTI Vastert, van der Torren, Cornelis R, Verrijn Stuart, Annemarie A, Lee, DaHae, Meerding, Jenny, van de Velde, Ursule, Pipeleers, Daniel, Gillard, Pieter, Keymeulen, Bart, de Jager, Wilco, Roep, Bart O, Endocrinologie, Child Health, CTI Vastert, van der Torren, Cornelis R, Verrijn Stuart, Annemarie A, Lee, DaHae, Meerding, Jenny, van de Velde, Ursule, Pipeleers, Daniel, Gillard, Pieter, Keymeulen, Bart, de Jager, Wilco, and Roep, Bart O

Published
2016

49. Immunogenicity of human embryonic stem cell-derived beta cells

Author

van der Torren, Cornelis R., primary, Zaldumbide, Arnaud, additional, Duinkerken, Gaby, additional, Brand-Schaaf, Simone H., additional, Peakman, Mark, additional, Stangé, Geert, additional, Martinson, Laura, additional, Kroon, Evert, additional, Brandon, Eugene P., additional, Pipeleers, Daniel, additional, and Roep, Bart O., additional

Published
2016
Full Text
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