Project Details
Description
The induction of tolerance in kidney transplant (KTx) patients can transform the field of organ transplantation through improvements in health outcomes by eliminating the lifelong need for immunosuppressive (IS) drugs and their attendant side effects, and by improving graft survival by eliminating chronic rejection. The gradual loss of KTx due to chronic rejection and nephrotoxicity occurs even with the most effective IS drugs that are currently available. The goal of the proposed project is to eliminate entirely the lifelong need for immunosuppressive (IS) drugs from recipients of KTx from HLA mismatched living donors through the use of therapeutic cell transfer of donor and recipient derived cell products to establish stable mixed donor hematopoietic cell chimerism. Mixed chimerism is more desirable than full donor chimerism due to a much lower risk of developing graft versus host disease, a condition associated with considerable morbidity and potential mortality for the recipient. At Stanford we have pioneered a tolerance induction protocol wherein recipients are conditioned with total lymphoid irradiation (TLI: 10 doses) and rabbit anti-thymocyte globulin (ATG:5 doses) during the first 11 days after KTx to promote tolerance and acceptance of the allografts. Immediately thereafter, purified donor CD34+ cells and CD3+ T cells are infused from “mobilized” blood apheresis products collected and cryopreserved before KTx. We have previously shown that about 80% of 26 fully HLA matched patients developed persistent chimerism and were completely withdrawn from IS drugs without evidence of subsequent rejection using an IND approved protocol with observation of up to 8 years. However, we have been unable to induce stable, immunosuppression independent mixed chimerism in HLA mismatched donor recipient pairs despite a significant increase in the number of donor CD3+ T cells (from 1 to 100 x 10E6/kg) delivered along with purified CD34+ cells. . Strong preclinical
Status | Finished |
---|---|
Effective start/end date | 3/1/19 → 12/31/20 |
Funding
- Stanford University (005436803 // CLIN2-11400)
- California Institute for Regenerative Medicine (005436803 // CLIN2-11400)
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