Induction of Donor Specific Tolerance in Recipients of Live Donor Kidney Allografts by Donor Stem Cell Infusion

Study Overview
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Brief Summary
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The goal of this research study is to establish chimerism and avoid graft-versus-host disease in patients with kidney failure allowing a reduction or cessation of immune-suppressive therapy.

Detailed Description
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At the present time, kidney transplant recipients must take anti-rejection medication to prevent rejection of the donated kidney. Even with this medication, chronic rejection is the most common cause of late graft loss. The anti-rejection agents themselves are significantly toxic, with side effects including kidney damage, infection and an increased incidence of cancer. The goal of this study is to allow the patient to develop tolerance to the transplanted kidney while maintaining a competent immune system. Tolerance enables the transplant recipient's body to recognize the transplanted organ as self rather than foreign tissue. The recipient will not try to reject the donor kidney and the need for anti-rejection medication could be dramatically decreased or eliminated entirely. To accomplish this, patients in this study will receive specially treated bone marrow taken from their kidney donor. Bone marrow transplant has been shown in animal studies and in humans to induce tolerance following organ transplant. Two factors limit the application of donor marrow transplant to induce tolerance: 1) preparing the patient for transplant (conditioning); and 2) graft-versus-host disease (GVHD). Traditional conditioning destroys the recipient's immune system and requires that the marrow transplant be successful because the patient is unable to fight off infection if the donor cells do not survive. GVHD occurs when donor immune cells recognize the recipient's cells as foreign tissue and attack them. Severe GVHD can result in death. This study utilizes a new approach to conditioning which leaves the patient's immune system intact. The transplant product is depleted of GVHD-producing cells but retains tolerance-promoting facilitating cells, which are intended to ensure the donor and recipient cells coexists peacefully, a state called mixed chimerism. The toxicity of conditioning and transplantation is significantly reduced. In this study, we will determine the appropriate cell dose to safely establish mixed chimerism following partial conditioning in living donor or deceased donor kidney transplant recipients. The study takes a gradual approach to increasing the cell dose to achieve mixed chimerism. We believe this study will provide a breakthrough in the approach to kidney transplantation. Our goal is to evaluate the potential of safely establishing mixed chimerism to induce tolerance following kidney transplant and reduce or eliminate the need for anti-rejection therapy.

Official Title
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Induction of Donor Specific Tolerance in Recipients of Living Kidney Allografts by Donor FCRx Infusion

Conditions
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Renal Failure

Intervention / Treatment
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* Biological: Enriched Hematopoietic Stem Cell Infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be between the ages of 18 and 65 years and meet the institution's criteria for renal transplantation for end-organ failure Patient is receiving first renal transplant Patient is receiving a renal transplant only The crossmatch is negative between donor and recipient Women who are of child bearing potential must have a negative pregnancy test (urine test is acceptable) within 48 hours of initiating total body irradiation (TBI) and agree to use reliable contraception for 1 year following transplant Note: The subjects do not need to be local residents in order to be eligible for this trial, but must be willing to reside in the area, or within a four hour drive, for the first three months of the protocol so that we can monitor them closely in the early post transplant period. As long as there is insurance or funding that will cover the cost of the transplant and any research related complications, it is not necessary for the subjects to be US citizens to participate in this trial. Exclusion Criteria: Clinically active bacterial, fungal, viral or parasitic infection Pregnancy Clinical or serologic evidence of viral infection which would preclude the recipient from receiving a kidney transplant Previous radiation therapy at a dose which would preclude TBI Positive crossmatch between donor and recipient Evidence for immunologic memory against donor BMI >35 or <18

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Living or Deceased Donor Kidney Allograft<br>Recipients with the need for a living kidney allograft are treated with an enriched hematopoetic stem cell infusion from the same living donor. Recipients with the need for a deceased donor kidney allograft are treated with an enriched hematopoetic stem cell infusion from the same deceased donor | Biological: Enriched Hematopoietic Stem Cell Infusion<br>* Enriched Hematopoietic Stem Cell Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of Donor Chimerism from Enriched Hematopoietic Stem Cell Engraftment | Tests are done at key time points to monitor for donor chimerism by evaluating presence of bone marrow-derived hematopoietic stem cells. | one month to three years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney transplant, Tolerance, Marrow/stem cell transplant