Clinical trial NCT02447926: Procurement of Leukapheresis Products From End Stage Liver Disease (ESLD) Patients for Immunological Studies
Official title: Procurement of Leukapheresis Products From End Stage Liver Disease (ESLD) Patients for Immunological Studies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: End Stage Liver Disease
Keywords: leukapheresis
regulatory T cells
liver transplantation
Lead sponsor: Northwestern University
Sponsor class: OTHER
First posted: 2015-05-19
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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).

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,
* subjects who do not meet all inclusion criteria.

Primary outcomes:
measure: Number of Regulatory CD4+CD25+ T Cells Obtained From 150 ml of Peripheral Blood in an ESLD Patient
timeFrame: 21 days
measure: Suppressive Function of Expanded Cells Will be Assessed Using in Vitro Assays of Alloreactivity (Mixed Lymphocyte Culture)
timeFrame: 21 days
Secondary outcomes:
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University Comprehensive Transplant Center
state: Illinois
Study officials:
affiliation: Northwestern University
name: Josh Levitsky, MD
role: PRINCIPAL_INVESTIGATOR
References: