Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation

Volkert A. L. Huurman; Robert Hilbrands; Gabrielle G. M. Pinkse; Pieter Gillard; Gaby Duinkerken; Pieter van de Linde; Petronella M. W. van der Meer-Prins; Minke F. J. Versteeg-van der Voort Maarschalk; Koen Verbeeck; Behrooz Z. Alizadeh; Chantal Mathieu; Frans K. Gorus; Dave L. Roelen; Frans H. J. Claas; Bart Keymeulen; Daniel G. Pipeleers; Bart O. Roep

doi:10.1371/journal.pone.0002435

Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation

Volkert A. L. Huurman^*, Robert Hilbrands, Gabrielle G. M. Pinkse, Pieter Gillard, Gaby Duinkerken, Pieter van de Linde, Petronella M. W. van der Meer-Prins, Minke F. J. Versteeg-van der Voort Maarschalk, Koen Verbeeck, Behrooz Z. Alizadeh, Chantal Mathieu, Frans K. Gorus, Dave L. Roelen, Frans H. J. Claas, Bart Keymeulen, Daniel G. Pipeleers, Bart O. Roep

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background: Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.

Methodology/Principal Findings: Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto-and alloantigens was measured before and during one year after transplantation. Cellular auto-and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto-and alloantibodies. Clinical outcome parameters-including time until insulin independence, insulin independence at one year, and C-peptide levels over one year-remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.

Conclusions/Significance: In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.

Trial Registration: Clinicaltrials.gov NCT00623610

Original language	English
Article number	2435
Number of pages	10
Journal	PLoS ONE
Volume	3
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0002435
Publication status	Published - 18-Jun-2008
Externally published	Yes

Keywords

NCT00623610
alloantibody
alloantigen
autoantibody
autoantigen
C peptide
gene product
insulin
lymphocyte antigen
mycophenolate mofetil
protein GAD
protein ia 2
tacrolimus
thymocyte antibody
adult
alloimmunity
article
autoimmunity
cell assay
cell culture
cellular immunity
clinical article
clinical trial
cohort analysis
controlled clinical trial
controlled study
correlation analysis
cytotoxic T lymphocyte
donor selection
female
graft rejection
human
humoral immunity
immunological parameters
immunosuppressive treatment
insulin dependence
insulin dependent diabetes mellitus
lymphocyte activation
male
metabolic regulation
multivariate analysis
outcome assessment
pancreas islet transplantation
postoperative period
protein blood level
treatment response

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Huurman, V. A. L., Hilbrands, R., Pinkse, G. G. M., Gillard, P., Duinkerken, G., van de Linde, P., van der Meer-Prins, P. M. W., Maarschalk, M. F. J. V. D. V., Verbeeck, K., Alizadeh, B. Z., Mathieu, C., Gorus, F. K., Roelen, D. L., Claas, F. H. J., Keymeulen, B., Pipeleers, D. G., & Roep, B. O. (2008). Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation. PLoS ONE, 3(6), Article 2435. https://doi.org/10.1371/journal.pone.0002435

@article{bd27c9ac6e264e1f94d7f5c3e9aac310,

title = "Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation",

abstract = "Background: Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.Methodology/Principal Findings: Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto-and alloantigens was measured before and during one year after transplantation. Cellular auto-and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto-and alloantibodies. Clinical outcome parameters-including time until insulin independence, insulin independence at one year, and C-peptide levels over one year-remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.Conclusions/Significance: In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.Trial Registration: Clinicaltrials.gov NCT00623610",

keywords = "NCT00623610, alloantibody, alloantigen, autoantibody, autoantigen, C peptide, gene product, insulin, lymphocyte antigen, mycophenolate mofetil, protein GAD, protein ia 2, tacrolimus, thymocyte antibody, adult, alloimmunity, article, autoimmunity, cell assay, cell culture, cellular immunity, clinical article, clinical trial, cohort analysis, controlled clinical trial, controlled study, correlation analysis, cytotoxic T lymphocyte, donor selection, female, graft rejection, human, humoral immunity, immunological parameters, immunosuppressive treatment, insulin dependence, insulin dependent diabetes mellitus, lymphocyte activation, male, metabolic regulation, multivariate analysis, outcome assessment, pancreas islet transplantation, postoperative period, protein blood level, treatment response",

author = "Huurman, {Volkert A. L.} and Robert Hilbrands and Pinkse, {Gabrielle G. M.} and Pieter Gillard and Gaby Duinkerken and {van de Linde}, Pieter and {van der Meer-Prins}, {Petronella M. W.} and Maarschalk, {Minke F. J. Versteeg-van der Voort} and Koen Verbeeck and Alizadeh, {Behrooz Z.} and Chantal Mathieu and Gorus, {Frans K.} and Roelen, {Dave L.} and Claas, {Frans H. J.} and Bart Keymeulen and Pipeleers, {Daniel G.} and Roep, {Bart O.}",

year = "2008",

month = jun,

day = "18",

doi = "10.1371/journal.pone.0002435",

language = "English",

volume = "3",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "PUBLIC LIBRARY SCIENCE",

number = "6",

}

Huurman, VAL, Hilbrands, R, Pinkse, GGM, Gillard, P, Duinkerken, G, van de Linde, P, van der Meer-Prins, PMW, Maarschalk, MFJVDV, Verbeeck, K, Alizadeh, BZ, Mathieu, C, Gorus, FK, Roelen, DL, Claas, FHJ, Keymeulen, B, Pipeleers, DG & Roep, BO 2008, 'Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation', PLoS ONE, vol. 3, no. 6, 2435. https://doi.org/10.1371/journal.pone.0002435

TY - JOUR

T1 - Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation

AU - Huurman, Volkert A. L.

AU - Hilbrands, Robert

AU - Pinkse, Gabrielle G. M.

AU - Gillard, Pieter

AU - Duinkerken, Gaby

AU - van de Linde, Pieter

AU - van der Meer-Prins, Petronella M. W.

AU - Maarschalk, Minke F. J. Versteeg-van der Voort

AU - Verbeeck, Koen

AU - Alizadeh, Behrooz Z.

AU - Mathieu, Chantal

AU - Gorus, Frans K.

AU - Roelen, Dave L.

AU - Claas, Frans H. J.

AU - Keymeulen, Bart

AU - Pipeleers, Daniel G.

AU - Roep, Bart O.

PY - 2008/6/18

Y1 - 2008/6/18

N2 - Background: Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.Methodology/Principal Findings: Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto-and alloantigens was measured before and during one year after transplantation. Cellular auto-and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto-and alloantibodies. Clinical outcome parameters-including time until insulin independence, insulin independence at one year, and C-peptide levels over one year-remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.Conclusions/Significance: In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.Trial Registration: Clinicaltrials.gov NCT00623610

AB - Background: Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.Methodology/Principal Findings: Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto-and alloantigens was measured before and during one year after transplantation. Cellular auto-and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto-and alloantibodies. Clinical outcome parameters-including time until insulin independence, insulin independence at one year, and C-peptide levels over one year-remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.Conclusions/Significance: In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.Trial Registration: Clinicaltrials.gov NCT00623610

KW - NCT00623610

KW - alloantibody

KW - alloantigen

KW - autoantibody

KW - autoantigen

KW - C peptide

KW - gene product

KW - insulin

KW - lymphocyte antigen

KW - mycophenolate mofetil

KW - protein GAD

KW - protein ia 2

KW - tacrolimus

KW - thymocyte antibody

KW - adult

KW - alloimmunity

KW - article

KW - autoimmunity

KW - cell assay

KW - cell culture

KW - cellular immunity

KW - clinical article

KW - clinical trial

KW - cohort analysis

KW - controlled clinical trial

KW - controlled study

KW - correlation analysis

KW - cytotoxic T lymphocyte

KW - donor selection

KW - female

KW - graft rejection

KW - human

KW - humoral immunity

KW - immunological parameters

KW - immunosuppressive treatment

KW - insulin dependence

KW - insulin dependent diabetes mellitus

KW - lymphocyte activation

KW - male

KW - metabolic regulation

KW - multivariate analysis

KW - outcome assessment

KW - pancreas islet transplantation

KW - postoperative period

KW - protein blood level

KW - treatment response

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U2 - 10.1371/journal.pone.0002435

DO - 10.1371/journal.pone.0002435

M3 - Article

C2 - 18560516

SN - 1932-6203

VL - 3

JO - PLoS ONE

JF - PLoS ONE

IS - 6

M1 - 2435

ER -

Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation

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Keywords

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