Procurement of Leukapheresis Products From End Stage Liver Disease (ESLD) Patients for Immunological Studies
| Status: | Enrolling by invitation |
|---|---|
| Conditions: | Gastrointestinal |
| Therapuetic Areas: | Gastroenterology |
| Healthy: | No |
| Age Range: | 18 - 89 |
| Updated: | 4/21/2016 |
| Start Date: | July 2014 |
| End Date: | December 2017 |
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).
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).
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).
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).
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.
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