Abstract | Investigators | News | Background | Resources

OBJECTIVES: The primary objective of this single-center pilot trial is to evaluate the tolerogenic efficacy of hOKT3γ1 (Ala-Ala) plus sirolimus induction immunotherapy combined with temporary sirolimus maintenance immunosuppression in the clinical setting of intraportal islet transplantation in non-urenic type 1 diabetic recipients. The tolerogenic efficacy, i.e. the ability to induce donor-specific allotolerance and to restore self-tolerance, will be assessed by determining the proportion of islet transplant recipients with rejection-free graft survival during sirolimus maintenance immunosuppression, tapering, and after complete withdrawal.

Secondary objectives include:

1. Predictive Utility of Immune Monitoring Assays: Identify immune monitoring assays predictive of rejection-free islet transplant survival in type 1 diabetic recipients.
2. Diabetes Reversibility: Assess the proportion of type 1 diabetic islet allograft recipients immunosuppressed with a corticosteroid and calcineurin-inhibitor free regimen who achieve full (insulin independence and HbAlc <7%) and partial (insulin dependence, basal or arginine-stimulated C-peptide levels of greater or equal to 0.5 ng/mL and glycated hemoglobin <7%) after the first and any subsequent islet transplants.
3. Immunosuppressive Efficacy: Assess the proportion of type 1 diabetic islet allograft recipients immunosuppressed with hOKT3g1 (Ala-Ala) plus sirolimus induction immunotherapy combined with temporary sirolimus maintenance immunosuppression who maintain full (insulin independence and HbA1c <7%) and partial (insulin dependence, basal or arginine-stimulated C-peptide levels of greater or equal to 0.5 ng/mL and glycated hemoglobin <7%) during the period of maintenance immunosuppression.
4. Protocol Safety: To assess the safety and tolerability of hOKT3g1 (Ala-Ala) antibody and sirolimus induction immunotherapy (and re-treatment should subsequent transplants be necessary), transient sirolimus maintenance immunosuppression, the islet transplant procedure(s), and additional protocol-regulated treatment products in patients with type 1 diabetes.
5. Comparability with Related Approaches: To provide a baseline control group for a concurrent series of patients (to be completed at the University of Alberta in Edmonton under an identical islet processing, testing, transplant, and follow-up protocol) where the FcR-nonbinding anti-CD3 antibody hOKT3g1 (Ala-Ala) is replaced by the anti-CD52 antibody, L-Campath-1H.

BASIS/RATIONALE: Islet transplantation provides a unique transplant model for clinical bioassay of tolerogenic efficacy in both alloimmunity and autoimmunity, as new tolerance protocols are developed for application in solid organ transplantation. The consequence of return to insulin, or undergoing islet re-transplantation under an immunosuppressive protocol, would not lead to the loss of a life-sustaining graft.

In an ongoing clinical trial, insulin independence has been restored and maintained for more than 12 in four out of six single-donor islet allograft recipients with long-standing type 1 diabetes immunosuppressed with hOKT3γ1 (Ala-Ala), sirolimus, and delayed low-dose tacrolimus. It is unknown whether donor-specific tolerance has been induced or self-tolerance has been restored in any of these recipients. Preclinical studies suggest the tolerogenic efficacy of sirolimus in allotransplant models, and of non-mitogenic anti-CD3 antibodies both in autoimmunity and allotransplantation. The proposed clinical trial seeks to translate this tolerogenic potential to the clinical setting of islet allotransplantation in autoimmune type 1 diabetes.

Development of tolerogenic protocols will have a major impact on advancement of clinical islet transplantation, strengthening the role that islet transplantation would play in the treatment of type 1 diabetes. The proposed trial in this clinical population will enable a robust test of tolerance in a favorable risk/benefit setting with implications beyond islet transplantation. The proposed study will provide a platform for assessing state-of-the-art mechanistic studies as a guide to the withdrawal of immunosuppression following induction immunotherapy and transient maintenance therapy. This trial represents an extension to the ongoing immunosuppression-based Edmonton Protocol currently funded by the Immune Tolerance Network, by formally assessing the tolerogenic efficacy of a potentially tolerogenic protocol.

PROTOCOL SUMMARY: A total of 12 patients with type I diabetes complicated by hypoglycemia unawareness that persist despite intensive insulin management efforts will undergo islet transplantation with induction immunotherapy with hOKT3γ1 (Ala-Ala) and sirolimus and will receive sirolimus maintenance immunosuppression for the first year post-transplant. Immune tolerance assays will include autoantibodies, donor-specific alloantibodies, serum cytokines, cytokine gene polymorphism, , frequency and cytokine profile of auto- and alloreactive T cells, frequency of GAD/DR4 tetramer-reactive T cells, peripheral blood cytotoxic T lymphocyte effector transcripts, and peripheral blood mononuclear cell gene microarray analysis. At the end of this first year following transplantation, sirolimus will be withdrawn over 4 months as directed by trial stopping rules. In Phase A of this study, regardless of tolerance assay findings, three groups of two subjects will be weaned, with a three-month follow-up period of therapy prior to initiation of the next group of subjects. In Phase B, the initiation of weaning will be subject to recommendations of regulatory bodies and the ITN and will include an analysis of tolerance assay findings from this and related clinical trials.

MECHANISTIC STUDIES:

• Donor-specific alloantibody titers
• Epitope- and isotype specific autoantibody titers
• Serum cytokine levels
• hOKT3g1 (Ala-Ala) serum and sirolimus trough levels
• CD3 coating and modulation
• Phenotypes of circulating T cell subsets
• CD4+CD25+ T regulatory cell function
• Frequency of GAD/DR4 tetramer-reactive T cells
• Frequency of donor-specific, direct pathway memory T cells
• Frequency of T cells with indirect anti-donor alloreactivity
• Frequency of IFN-g secreting T cells reactive to immunodominat peptide sequences from GAD65
• Cytotoxic lymphocyte effector transcripts
• Cytokine gene polymorphism
• Global patterns of PBMC gene expression

Participating Investigators

	David E. R. Sutherland, University of Minnesota, Minneapolis, Minn.
	Raja Kandaswamy, University of Minnesota, Minneapolis, Minn.
	David W. Hunter, University of Minnesota, Minneapolis, Minn
	Camillo Ricordi, Diabetes Research Institute, University of Miami, Miami, PL
	James Shapiro, University of Alberta, Edmonton, Canada
	Jeffrey A. Bluestone, University of California, San Francisco, CA

News & Recent Developments

	Islet Transplants Allow More Insulin-Independence in Diabetics - Medscape [go]
	Clinical outcomes with Edmonton Protocol - Diabetes [go]

Background Articles

	Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus - NEJM [go]
	Phase I results of hOKT3γ1 (ala-ala) in renal transplantation - Transplantation [go]
	hOKT3γ1 (ala-ala) delivers partial TCR signal - J Immunol [go]
	Pancreatic islet transplantation in the treatment of diabetes mellitus - Best Pract Res Clin Endocrinol Metab [go]
	Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen - NEJM [go]

Resources & Interesting Links

	Eighty years after insulin: parallels with modern islet transplantation - CMAJ [go]
	Clinical islet transplant––state of the art - Transplant Proc [go]