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 x 10(6) HSC/kg), at days 5 and 11 posttransplant, without ablative conditioning. An 'Edmonton-like' immunosuppression was administered, with a single dose of anti-TNFalpha 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.
authors.affiliation: Clinical Islet Transplant Program (CITP), Diabetes Research Institute, L. Miller School of Medicine, University of Miami, FL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mineo
authors.forename: C
authors.initials: C
authors.lastname: Ricordi
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: A
authors.initials: A
authors.lastname: Pileggi
authors.forename: R
authors.initials: R
authors.lastname: Garcia-Morales
authors.forename: A
authors.initials: A
authors.lastname: Khan
authors.forename: D A
authors.initials: DA
authors.lastname: Baidal
authors.forename: D
authors.initials: D
authors.lastname: Han
authors.forename: K
authors.initials: K
authors.lastname: Monroy
authors.forename: J
authors.initials: J
authors.lastname: Miller
authors.forename: A
authors.initials: A
authors.lastname: Pugliese
authors.forename: T
authors.initials: T
authors.lastname: Froud
authors.forename: L
authors.initials: L
authors.lastname: Inverardi
authors.forename: N S
authors.initials: NS
authors.lastname: Kenyon
authors.forename: R
authors.initials: R
authors.lastname: Alejandro
mesh_terms: D000328:Adult; D018952:Antigens, CD34 / Q000276:immunology; D046528:Chimerism; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D018952:Antigens, CD34