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

At the present time, heart transplant recipients must take anti-rejection medication to
prevent rejection of the donated heart. 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 heart 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 heart 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 heart
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 heart 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 heart transplantation. Our goal is to
evaluate the potential of safely establishing mixed chimerism to induce tolerance following
heart transplant and reduce or eliminate the need for anti-rejection therapy.

Inclusion Criteria:

- Subject must be between the ages of 18 and 70 years and meet the institution's
criteria for cardiac transplantation.

- Subjects must have acceptable negative results for infectious disease markers done
within two weeks of the bone marrow infusion.

- Subject is receiving a first cardiac transplant.

- Subjects receiving a multi-organ transplant (i.e., heart/kidney) may be included at
the discretion of the PI and investigators.

Note: These multi-organ subjects will have identical criteria with the exception of
adequate function of the affected organ to be transplanted (i.e., kidney). They are
included in the total of thirty subjects to be transplanted.

- Subject's panel reactive antibody (PRA) is <40. If the patient is plasmapheresed
prior to the heart transplant, then the pre-transplant PRA will not be a
consideration for inclusion/exclusion.

- Subject must have a negative crossmatch with the donor.

- Women who are of child bearing potential must have a negative pregnancy test (urine
test within 48 hours) before TBI and agree to use reliable contraception for one year
following transplant.

- Subject is able to give informed consent.

Exclusion Criteria:

- Clinically active bacterial, fungal, viral or parasitic infection

- Pregnancy

- Previous radiation therapy at a dose that would preclude TBI

- Subject is unable to give informed consent

- If the procedures associated with the study (i.e., delivering TBI) would
significantly extend the cold ischemia time of the heart, the protocol will be
abandoned and the patient will receive a conventional heart transplant.