Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function

Shereen Sabbah; Aaron Liew; Augustin M. Brooks; Rhiannon Kundu; James L. Reading; Anneliese Flatt; Claire Counter; Pratik Choudhary; Shareen Forbes; Miranda J. Rosenthal; Martin K. Rutter; Stephanie Cairns; Paul Johnson; John Casey; Mark Peakman; James A. Shaw; Timothy I.M. Tree

doi:10.1111/ajt.16285

Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function

Shereen Sabbah, Aaron Liew, Augustin M. Brooks, Rhiannon Kundu, James L. Reading, Anneliese Flatt, Claire Counter, Pratik Choudhary, Shareen Forbes, Miranda J. Rosenthal, Martin K. Rutter, Stephanie Cairns, Paul Johnson, John Casey, Mark Peakman, James A. Shaw^*, Timothy I.M. Tree

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

4 Citations (Scopus)

Abstract

Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1–6 m posttransplant: 38%; 7–12 m: 44%; 13–24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ–dominated response in the pretransplant group replaced by IL-10–dominated response in the 1–6 m posttransplant group, reverting to predominantly IFN-γ–oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10–oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10⁺ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.

Original language	English
Journal	American Journal of Transplantation
DOIs	https://doi.org/10.1111/ajt.16285
Publication status	Accepted/In press - 1 Jan 2020

Keywords

autoantibody
basic (laboratory) research/science
clinical research/practice
immunobiology
islet transplantation
islets of Langerhans
monitoring: immune
T cell biology

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10.1111/ajt.16285

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Sabbah, S., Liew, A., Brooks, A. M., Kundu, R., Reading, J. L., Flatt, A., Counter, C., Choudhary, P., Forbes, S., Rosenthal, M. J., Rutter, M. K., Cairns, S., Johnson, P., Casey, J., Peakman, M., Shaw, J. A., & Tree, T. I. M. (Accepted/In press). Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function. American Journal of Transplantation. https://doi.org/10.1111/ajt.16285

@article{46fa02359c8540d194064c8453bee6e1,

title = "Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function",

abstract = "Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1–6 m posttransplant: 38%; 7–12 m: 44%; 13–24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ–dominated response in the pretransplant group replaced by IL-10–dominated response in the 1–6 m posttransplant group, reverting to predominantly IFN-γ–oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10–oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.",

keywords = "autoantibody, basic (laboratory) research/science, clinical research/practice, immunobiology, islet transplantation, islets of Langerhans, monitoring: immune, T cell biology",

author = "Shereen Sabbah and Aaron Liew and Brooks, {Augustin M.} and Rhiannon Kundu and Reading, {James L.} and Anneliese Flatt and Claire Counter and Pratik Choudhary and Shareen Forbes and Rosenthal, {Miranda J.} and Rutter, {Martin K.} and Stephanie Cairns and Paul Johnson and John Casey and Mark Peakman and Shaw, {James A.} and Tree, {Timothy I.M.}",

year = "2020",

month = jan,

day = "1",

doi = "10.1111/ajt.16285",

language = "English",

journal = "American Journal of Transplantation",

issn = "1600-6135",

publisher = "Wiley-Blackwell",

}

Sabbah, S, Liew, A, Brooks, AM, Kundu, R, Reading, JL, Flatt, A, Counter, C, Choudhary, P, Forbes, S, Rosenthal, MJ, Rutter, MK, Cairns, S, Johnson, P, Casey, J, Peakman, M, Shaw, JA & Tree, TIM 2020, 'Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function', American Journal of Transplantation. https://doi.org/10.1111/ajt.16285

TY - JOUR

T1 - Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function

AU - Sabbah, Shereen

AU - Liew, Aaron

AU - Brooks, Augustin M.

AU - Kundu, Rhiannon

AU - Reading, James L.

AU - Flatt, Anneliese

AU - Counter, Claire

AU - Choudhary, Pratik

AU - Forbes, Shareen

AU - Rosenthal, Miranda J.

AU - Rutter, Martin K.

AU - Cairns, Stephanie

AU - Johnson, Paul

AU - Casey, John

AU - Peakman, Mark

AU - Shaw, James A.

AU - Tree, Timothy I.M.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1–6 m posttransplant: 38%; 7–12 m: 44%; 13–24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ–dominated response in the pretransplant group replaced by IL-10–dominated response in the 1–6 m posttransplant group, reverting to predominantly IFN-γ–oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10–oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.

AB - Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1–6 m posttransplant: 38%; 7–12 m: 44%; 13–24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ–dominated response in the pretransplant group replaced by IL-10–dominated response in the 1–6 m posttransplant group, reverting to predominantly IFN-γ–oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10–oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.

KW - autoantibody

KW - basic (laboratory) research/science

KW - clinical research/practice

KW - immunobiology

KW - islet transplantation

KW - islets of Langerhans

KW - monitoring: immune

KW - T cell biology

UR - http://www.scopus.com/inward/record.url?scp=85091211298&partnerID=8YFLogxK

U2 - 10.1111/ajt.16285

DO - 10.1111/ajt.16285

M3 - Review article

C2 - 32865886

AN - SCOPUS:85091211298

SN - 1600-6135

JO - American Journal of Transplantation

JF - American Journal of Transplantation

ER -

Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function

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Keywords

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