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 × 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-TNFa 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.

Evaluation of the tolerogenic effects of donor bone marrow cells using a severe combined immunodeficient mouse–human islet transplant model

“…In contrast, however, a recent clinical trial from our group indicated that combined islet and hematopoietic stem cell (HSC) allotransplantation using an “Edmonton-like” immunosuppression, without ablative conditioning, did not lead to stable peripheral chimerism and graft tolerance [41]. This could be caused by a number of factors, including the possible presence of residual anti-islet autoimmunity that could not be abrogated by the HSC or the failure to attain stable chimerism resulting from suboptimal treatment regimen in the type-1 diabetic patients.…”

Hematopoietic Chimerism and Transplantation Tolerance: A Role for Regulatory T Cells

“…Less promising results were obtained in a study in which HLA-mismatched pancreatic islets were transplanted into type I diabetes patients (Mineo et al, 2008). The conditioning regimen used was very mild but nevertheless led to transient hematopoietic chimerism.…”

Re-engineering islet cell transplantation

“…A growing body of literature supports the potential beneficial impact of the use of hematopoietic stem cells (HSC) and of regulatory immune cell subsets ( i.e ., T regulatory cells, Tregs; Mesenchymal Stromal Cells, MSC; Dendritic Cells, DC; amongst others) to achieve such goal in patients with T1D [48–52] and in organ transplant recipients [53–60]. In the context of clinical islet transplantation, the use of donor-specific HSC was shown to associate with the achievement of graft function and transient hematopoietic chimerism, though the discontinuation of immunosuppression by protocol (in the absence of tests predictive of immunomodulation) invariably resulted in loss of graft function [4,54,61]. Combination of islets with MSC treatment was shown to improve islet engraftment in rodents [62–65] and large animal models [66], and is currently under evaluation in the clinical settings (Table 1).…”