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

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.

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