Procurement of Leukapheresis Products From End Stage Liver Disease (ESLD) Patients for Immunological Studies

NCT ID: NCT02447926

Last Updated: 2019-09-25

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: NA
• Total Enrollment: 1 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-07-31
• Study Completion Date: 2016-07-31

Brief Summary

Regulatory CD4+CD25+ T cells (Treg) derived from the thymus and/or periphery can control immune responsiveness to auto- and allo-antigens. However, there have been few efforts to harness the therapeutic potential of isolated Tregs to control graft rejection and inducing transplantation tolerance in solid organ recipients. In order for Tregs to be used as a clinical treatment, the following properties are necessary: ex vivo generation of sufficient numbers of cells, migration in vivo to sites of antigenic reactivity, ability to suppress rejection in an alloantigen-specific manner, and survival/expansion after infusion. The and others have demonstrated 1) the feasibility of expanding Treg ex vivo, 2) the ability of these cells to down-regulate allogeneic immune responses in vitro, and 3) the efficacy of Treg for prevention of allograft rejection in animal models. In kidney transplant, the investigators have developed strategies for the ex vivo expansion of naturally occurring human Tregs (nTregs) from leukapheresis products that would allow for the clinical employment of this cellular therapy. The investigators are also interested in this approach in patients with end stage liver disease (ESLD) undergoing liver transplantation (LT). Our central hypothesis is that alloreactive human nTreg with suppressive action can be expanded ex vivo from ESLD patients (this proposal) and used to both prevent liver transplant rejection and facilitate the minimization and withdrawal of drug-based immunosuppression (future proposals). This application will further define and validate efficient methods for ex vivo expansion of human CD4+CD25+CD127- FOXP3+nTregs cells in ESLD. The investigators herein propose to use leukapheresis products obtained from patients with ESLD to further refine and optimize protocols for expansion of Tregs. Suppressive function of expanded cells will be assessed using in vitro assays of alloreactivity (mixed lymphocyte culture).

Detailed Description

Regulatory CD4+CD25+ T cells (Treg) derived from the thymus and/or periphery can control immune responsiveness to auto- and allo-antigens. However, there have been few efforts to harness the therapeutic potential of isolated Tregs to control graft rejection and inducing transplantation tolerance in solid organ recipients. In order for Tregs to be used as a clinical treatment, the following properties are necessary: ex vivo generation of sufficient numbers of cells, migration in vivo to sites of antigenic reactivity, ability to suppress rejection in an alloantigen-specific manner, and survival/expansion after infusion. We and others have demonstrated 1) the feasibility of expanding Treg ex vivo, 2) the ability of these cells to down-regulate allogeneic immune responses in vitro, and 3) the efficacy of Treg for prevention of allograft rejection in animal models. In kidney transplant, we have developed strategies for the ex vivo expansion of naturally occurring human Tregs (nTregs) from leukapheresis products that would allow for the clinical employment of this cellular therapy. We are also interested in this approach in patients with end stage liver disease (ESLD) undergoing liver transplantation (LT). Our central hypothesis is that alloreactive human nTreg with suppressive action can be expanded ex vivo from ESLD patients (this proposal) and used to both prevent liver transplant rejection and facilitate the minimization and withdrawal of drug-based immunosuppression (future proposals). This application will further define and validate efficient methods for ex vivo expansion of human CD4+CD25+CD127- FOXP3+nTregs cells in ESLD. We herein propose to use leukapheresis products obtained from patients with ESLD to further refine and optimize protocols for expansion of Tregs. Suppressive function of expanded cells will be assessed using in vitro assays of alloreactivity (mixed lymphocyte culture).

Conditions

End Stage Liver Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Leaukapheresis of End Stage Liver Disease Patients

Leukapheresis. All subjects will receive the same treatment arm.

Group Type: OTHER

Leukapheresis

Intervention Type: PROCEDURE

Catheter placement will occur for about 1 hour. The research nurse will schedule leukapheresis on the next day following catheter placement.

On the day of leukapheresis, a blood draw will monitor blood counts, kidney function, liver function, and blood clotting ability. Vital signs will be checked three times over the course of intervention.

During the procedure, blood is mixed with anticoagulant and separated (i.e. red blood cells, white blood cells, platelets, and plasma). 1-1.5 cups of white blood cells will be collected. Leukapheresis will last 3-6 hours.

Remaining components, except for 100-200 ml of plasma, are returned through the catheter. Two teaspoons of blood will be drawn to determine when catheter removal can occur. This part of intervention lasts about 2.5-4 hours.

Interventions

Leukapheresis

Catheter placement will occur for about 1 hour. The research nurse will schedule leukapheresis on the next day following catheter placement.

On the day of leukapheresis, a blood draw will monitor blood counts, kidney function, liver function, and blood clotting ability. Vital signs will be checked three times over the course of intervention.

During the procedure, blood is mixed with anticoagulant and separated (i.e. red blood cells, white blood cells, platelets, and plasma). 1-1.5 cups of white blood cells will be collected. Leukapheresis will last 3-6 hours.

Remaining components, except for 100-200 ml of plasma, are returned through the catheter. Two teaspoons of blood will be drawn to determine when catheter removal can occur. This part of intervention lasts about 2.5-4 hours.

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• >18 years old,
• ESLD MELD <25,
• No recent infection,
• no hepatic decompensation,
• no history of HIV,
• weight > 110 lbs,
• platelets > 50,000,
• HGB >10,
• no prior organ transplant

Exclusion Criteria

• Patients ineligible for liver transplant,
• patients who do not understand why the study procedures are being conducted,

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 89 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Northwestern University

OTHER

Sponsor Role: lead

Responsible Party

Josh Levitsky

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Josh Levitsky, MD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Locations

Northwestern University Comprehensive Transplant Center

Chicago, Illinois, United States

Countries

United States

Other Identifiers

STU00097231

Identifier Type: -

Identifier Source: org_study_id