Combined islet and hematopoietic stem cell allotransplantation

A clinical pilot trial to induce chimerism and graft tolerance

D. Mineo, Camillo Ricordi, X. Xu, A. Pileggi, R. Garcia-Morales, A. Khan, David Baidal, D. Han, K. Monroy, J. Miller, Alberto Pugliese, Tatiana Froud, Luca A Inverardi, Norma S Kenyon, Rodolfo Alejandro

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

To prevent graft rejection and avoid immunosuppression-related side-effects, we attempted to induce recipient chimerism and graft tolerance in islet transplantation by donor CD34+hematopoietic stem cell (HSC) infusion. Six patients with brittle type 1 Diabetes Mellitus received a single-donor allogeneic islet transplant (8611 ± 2113 IEQ/kg) followed by high doses of donor HSC (4.3 ± 1.9 × 106 HSC/kg), at days 5 and 11 posttransplant, without ablative conditioning. An 'Edmonton-like' immunosuppression was administered, with a single dose of anti-TNFα antibody (Infliximab) added to induction. Immunosuppression was weaned per protocol starting 12 months posttransplant. After transplantation, glucose control significantly improved, with 3 recipients achieving insulin-independence for a short time (24 ± 23 days). No severe hypoglycemia or protocol-related adverse events occurred. Graft function was maximal at 3 months then declined. Two recipients rejected within 6 months due to low immunosuppressive trough levels, whereas 4 completed 1-year follow-up with functioning grafts. Graft failure occurred within 4 months from weaning (478 ± 25 days posttransplant). Peripheral chimerism, as donor leukocytes, was maximal at 1-month (5.92 ± 0.48%), highly reduced at 1-year (0.20 ± 0.08%), and was undetectable at graft failure. CD25+T-lymphocytes significantly decreased at 3 months, but partially recovered thereafter. Combined islet and HSC allotransplantation using an 'Edmonton-like' immunosuppression, without ablative conditioning, did not lead to stable chimerism and graft tolerance.

Original languageEnglish
Pages (from-to)1262-1274
Number of pages13
JournalAmerican Journal of Transplantation
Volume8
Issue number6
DOIs
StatePublished - Jun 1 2008

Fingerprint

Transplantation Tolerance
Chimerism
Hematopoietic Stem Cells
Immunosuppression
Clinical Trials
Transplants
Tissue Donors
Type 1 Diabetes Mellitus
Islets of Langerhans Transplantation
Graft Rejection
Immunosuppressive Agents
Weaning
Hypoglycemia
Anti-Idiotypic Antibodies
Leukocytes
Transplantation
Insulin
T-Lymphocytes
Glucose

Keywords

  • Chimerism
  • Graft tolerance
  • Hematopoietic stem cells
  • Islet transplantation
  • Type 1 diabetes

ASJC Scopus subject areas

  • Immunology

Cite this

Combined islet and hematopoietic stem cell allotransplantation : A clinical pilot trial to induce chimerism and graft tolerance. / Mineo, D.; Ricordi, Camillo; Xu, X.; Pileggi, A.; Garcia-Morales, R.; Khan, A.; Baidal, David; Han, D.; Monroy, K.; Miller, J.; Pugliese, Alberto; Froud, Tatiana; Inverardi, Luca A; Kenyon, Norma S; Alejandro, Rodolfo.

In: American Journal of Transplantation, Vol. 8, No. 6, 01.06.2008, p. 1262-1274.

Research output: Contribution to journalArticle

Mineo, D. ; Ricordi, Camillo ; Xu, X. ; Pileggi, A. ; Garcia-Morales, R. ; Khan, A. ; Baidal, David ; Han, D. ; Monroy, K. ; Miller, J. ; Pugliese, Alberto ; Froud, Tatiana ; Inverardi, Luca A ; Kenyon, Norma S ; Alejandro, Rodolfo. / Combined islet and hematopoietic stem cell allotransplantation : A clinical pilot trial to induce chimerism and graft tolerance. In: American Journal of Transplantation. 2008 ; Vol. 8, No. 6. pp. 1262-1274.
@article{14859f57e809413a978557268b0f853b,
title = "Combined islet and hematopoietic stem cell allotransplantation: A clinical pilot trial to induce chimerism and graft tolerance",
abstract = "To prevent graft rejection and avoid immunosuppression-related side-effects, we attempted to induce recipient chimerism and graft tolerance in islet transplantation by donor CD34+hematopoietic stem cell (HSC) infusion. Six patients with brittle type 1 Diabetes Mellitus received a single-donor allogeneic islet transplant (8611 ± 2113 IEQ/kg) followed by high doses of donor HSC (4.3 ± 1.9 × 106 HSC/kg), at days 5 and 11 posttransplant, without ablative conditioning. An 'Edmonton-like' immunosuppression was administered, with a single dose of anti-TNFα antibody (Infliximab) added to induction. Immunosuppression was weaned per protocol starting 12 months posttransplant. After transplantation, glucose control significantly improved, with 3 recipients achieving insulin-independence for a short time (24 ± 23 days). No severe hypoglycemia or protocol-related adverse events occurred. Graft function was maximal at 3 months then declined. Two recipients rejected within 6 months due to low immunosuppressive trough levels, whereas 4 completed 1-year follow-up with functioning grafts. Graft failure occurred within 4 months from weaning (478 ± 25 days posttransplant). Peripheral chimerism, as donor leukocytes, was maximal at 1-month (5.92 ± 0.48{\%}), highly reduced at 1-year (0.20 ± 0.08{\%}), and was undetectable at graft failure. CD25+T-lymphocytes significantly decreased at 3 months, but partially recovered thereafter. Combined islet and HSC allotransplantation using an 'Edmonton-like' immunosuppression, without ablative conditioning, did not lead to stable chimerism and graft tolerance.",
keywords = "Chimerism, Graft tolerance, Hematopoietic stem cells, Islet transplantation, Type 1 diabetes",
author = "D. Mineo and Camillo Ricordi and X. Xu and A. Pileggi and R. Garcia-Morales and A. Khan and David Baidal and D. Han and K. Monroy and J. Miller and Alberto Pugliese and Tatiana Froud and Inverardi, {Luca A} and Kenyon, {Norma S} and Rodolfo Alejandro",
year = "2008",
month = "6",
day = "1",
doi = "10.1111/j.1600-6143.2008.02230.x",
language = "English",
volume = "8",
pages = "1262--1274",
journal = "American Journal of Transplantation",
issn = "1600-6135",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Combined islet and hematopoietic stem cell allotransplantation

T2 - A clinical pilot trial to induce chimerism and graft tolerance

AU - Mineo, D.

AU - Ricordi, Camillo

AU - Xu, X.

AU - Pileggi, A.

AU - Garcia-Morales, R.

AU - Khan, A.

AU - Baidal, David

AU - Han, D.

AU - Monroy, K.

AU - Miller, J.

AU - Pugliese, Alberto

AU - Froud, Tatiana

AU - Inverardi, Luca A

AU - Kenyon, Norma S

AU - Alejandro, Rodolfo

PY - 2008/6/1

Y1 - 2008/6/1

N2 - To prevent graft rejection and avoid immunosuppression-related side-effects, we attempted to induce recipient chimerism and graft tolerance in islet transplantation by donor CD34+hematopoietic stem cell (HSC) infusion. Six patients with brittle type 1 Diabetes Mellitus received a single-donor allogeneic islet transplant (8611 ± 2113 IEQ/kg) followed by high doses of donor HSC (4.3 ± 1.9 × 106 HSC/kg), at days 5 and 11 posttransplant, without ablative conditioning. An 'Edmonton-like' immunosuppression was administered, with a single dose of anti-TNFα antibody (Infliximab) added to induction. Immunosuppression was weaned per protocol starting 12 months posttransplant. After transplantation, glucose control significantly improved, with 3 recipients achieving insulin-independence for a short time (24 ± 23 days). No severe hypoglycemia or protocol-related adverse events occurred. Graft function was maximal at 3 months then declined. Two recipients rejected within 6 months due to low immunosuppressive trough levels, whereas 4 completed 1-year follow-up with functioning grafts. Graft failure occurred within 4 months from weaning (478 ± 25 days posttransplant). Peripheral chimerism, as donor leukocytes, was maximal at 1-month (5.92 ± 0.48%), highly reduced at 1-year (0.20 ± 0.08%), and was undetectable at graft failure. CD25+T-lymphocytes significantly decreased at 3 months, but partially recovered thereafter. Combined islet and HSC allotransplantation using an 'Edmonton-like' immunosuppression, without ablative conditioning, did not lead to stable chimerism and graft tolerance.

AB - To prevent graft rejection and avoid immunosuppression-related side-effects, we attempted to induce recipient chimerism and graft tolerance in islet transplantation by donor CD34+hematopoietic stem cell (HSC) infusion. Six patients with brittle type 1 Diabetes Mellitus received a single-donor allogeneic islet transplant (8611 ± 2113 IEQ/kg) followed by high doses of donor HSC (4.3 ± 1.9 × 106 HSC/kg), at days 5 and 11 posttransplant, without ablative conditioning. An 'Edmonton-like' immunosuppression was administered, with a single dose of anti-TNFα antibody (Infliximab) added to induction. Immunosuppression was weaned per protocol starting 12 months posttransplant. After transplantation, glucose control significantly improved, with 3 recipients achieving insulin-independence for a short time (24 ± 23 days). No severe hypoglycemia or protocol-related adverse events occurred. Graft function was maximal at 3 months then declined. Two recipients rejected within 6 months due to low immunosuppressive trough levels, whereas 4 completed 1-year follow-up with functioning grafts. Graft failure occurred within 4 months from weaning (478 ± 25 days posttransplant). Peripheral chimerism, as donor leukocytes, was maximal at 1-month (5.92 ± 0.48%), highly reduced at 1-year (0.20 ± 0.08%), and was undetectable at graft failure. CD25+T-lymphocytes significantly decreased at 3 months, but partially recovered thereafter. Combined islet and HSC allotransplantation using an 'Edmonton-like' immunosuppression, without ablative conditioning, did not lead to stable chimerism and graft tolerance.

KW - Chimerism

KW - Graft tolerance

KW - Hematopoietic stem cells

KW - Islet transplantation

KW - Type 1 diabetes

UR - http://www.scopus.com/inward/record.url?scp=44449155884&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44449155884&partnerID=8YFLogxK

U2 - 10.1111/j.1600-6143.2008.02230.x

DO - 10.1111/j.1600-6143.2008.02230.x

M3 - Article

VL - 8

SP - 1262

EP - 1274

JO - American Journal of Transplantation

JF - American Journal of Transplantation

SN - 1600-6135

IS - 6

ER -