Immunosuppression, Kidney Transplantation
Conditions
Keywords
Transplants, Kidney Transplantation, Immunosuppression, Assay, Graft Rejection
Brief summary
The study is a laboratory investigation comparing the regulatory effects of different immunosuppressive therapies in an in vitro human MLR assay of selecting specific immunosuppressive therapy to promote a regulatory profile and determining possibly newer accepted dosing and drug concentrations for agents most associated with this regulatory profile.
Detailed description
Life-long immunosuppressive (IS) therapy is typically required in the great majority of organ transplants. Immunobiologically correct IS dosing, tapering to low levels and/or monotherapy could lower the incidence of complications related to IS and improve long term graft and patient survival. The current standard of IS care for liver transplant recipients are the calcineurin-inhibitors (CNIs) tacrolimus (TAC) and cyclosporine (CSA), although alternative IS drugs such as mycophenolate mofetil (MMF) and sirolimus (SRL) are available for use in select patients. This is also true for kidney, pancreas and heart transplant recipients, with TAC being favored in each case. The ideal IS agent is one that can be given at low levels such that both rejection and long term toxicity are minimized. Directly related to IS minimization might be the development of a regulatory, tolerance profile, as assessed by ex vivo immunophenotyping and functional assays that might test these specific IS agents singly, in combination or even in sequence. Human Tregs and DCregs can be more predominantly generated in the presence of one of three IS agents with different modes of action, i.e., TAC, MMF or SRL, and in different conditions of antigen presentation and alloimmune incompatibility. This is a bench protocol studying the effects of TAC, MMF and SRL on pre operative living renal recipient donor pair.
Interventions
None listed
Sponsors
Astellas Pharma US, Inc.
Northwestern University
Study design
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults 18 years of Age or Older * Undergoing living donor renal transplant
Exclusion criteria
* No active infection or history of malignancy * No HIV infection * No Hepatitis C (HCV) infection * No prior transplant (kidney or other organ) * No chromic use of immunosuppressive therapy or history of autoimmune disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CD4+CD25 High FOXP3+ Cell Levels in Mixed Lymphocyte Reactions (MLRs) of Renal Pre-transplant Recipients/Donors | 3 months | CD4+CD25 high FOXP3+ cell levels in mixed lymphocyte reactions (MLRs) of Renal Pre-transplant Recipients/Donors were measured in the presence of 1) No Drug/Control; 2) 0.05-0.2, 0.3-3 and \> 5 ng/ml Tacrolimus (TAC); OR 3) 0.05-0.2, 0.3-3 and \> 5 ng/ml Sirolimus (SRL). CD4+CD25 high FOXP3+ cell levels in the MLRs with TAC or SRL are expressed as the percentage of CD4+CD25 high FOXP3+ cell levels in the MLRs with no drug. |
Countries
United States
Participant flow
Recruitment details
Recruit donor/recipient renal transplant subjects for blood draw before renal transplant surgery. Peripheral mononuclear cells (PBMC) were isolated from the blood, and were cultured in the following combinations: Recipient PMBC + Donor PBMC + No drug Recipient PMBC + Donor PBMC + Tacrolimus (TAC) Recipient PMBC + Donor PBMC + Sirolimus (SRL)
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants (6 donors, 6 recipients) had blood drawn before renal transplant surgery. Peripheral mononuclear cells (PBMC) were isolated from the blood, and were cultured in the following combination:
Recipient PMBC + Donor PBMC + No drug Recipient PMBC + Donor PBMC + Tacrolimus (TAC) Recipient PMBC + Donor PBMC + Sirolimus (SRL) | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 2 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age Continuous | 47.08 years STANDARD_DEVIATION 10.5 |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
CD4+CD25 High FOXP3+ Cell Levels in Mixed Lymphocyte Reactions (MLRs) of Renal Pre-transplant Recipients/Donors
CD4+CD25 high FOXP3+ cell levels in mixed lymphocyte reactions (MLRs) of Renal Pre-transplant Recipients/Donors were measured in the presence of 1) No Drug/Control; 2) 0.05-0.2, 0.3-3 and \> 5 ng/ml Tacrolimus (TAC); OR 3) 0.05-0.2, 0.3-3 and \> 5 ng/ml Sirolimus (SRL). CD4+CD25 high FOXP3+ cell levels in the MLRs with TAC or SRL are expressed as the percentage of CD4+CD25 high FOXP3+ cell levels in the MLRs with no drug.
Time frame: 3 months
Population: For each arm, blood samples from 5 donor/recipient pairs (i.e., 10 participants) were used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLRs in the Presence of TAC | CD4+CD25 High FOXP3+ Cell Levels in Mixed Lymphocyte Reactions (MLRs) of Renal Pre-transplant Recipients/Donors | Cell Levels in 0.05-0.2 ng/mL TAC or SRL | 90 Percentage of Control Cells | Standard Deviation 20 |
| MLRs in the Presence of TAC | CD4+CD25 High FOXP3+ Cell Levels in Mixed Lymphocyte Reactions (MLRs) of Renal Pre-transplant Recipients/Donors | Cell Levels in 0.3-3 ng/mL TAC or SRL | 25 Percentage of Control Cells | Standard Deviation 15 |
| MLRs in the Presence of TAC | CD4+CD25 High FOXP3+ Cell Levels in Mixed Lymphocyte Reactions (MLRs) of Renal Pre-transplant Recipients/Donors | Cell Levels in > 5 ng/mL TAC or SRL | 10 Percentage of Control Cells | Standard Deviation 5 |
| MLRs in the Presence of SRL | CD4+CD25 High FOXP3+ Cell Levels in Mixed Lymphocyte Reactions (MLRs) of Renal Pre-transplant Recipients/Donors | Cell Levels in 0.05-0.2 ng/mL TAC or SRL | 85 Percentage of Control Cells | Standard Deviation 5 |
| MLRs in the Presence of SRL | CD4+CD25 High FOXP3+ Cell Levels in Mixed Lymphocyte Reactions (MLRs) of Renal Pre-transplant Recipients/Donors | Cell Levels in 0.3-3 ng/mL TAC or SRL | 50 Percentage of Control Cells | Standard Deviation 10 |
| MLRs in the Presence of SRL | CD4+CD25 High FOXP3+ Cell Levels in Mixed Lymphocyte Reactions (MLRs) of Renal Pre-transplant Recipients/Donors | Cell Levels in > 5 ng/mL TAC or SRL | 45 Percentage of Control Cells | Standard Deviation 10 |