Transplant Tolerance by Combinatorial Therapy with Donor Stem Cells and Expanded Recipient Regulatory T Cells in HLA Mismatched Kidney Recipients

Project: Research project

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previously shown that about 80% of 26 fully HLA matched patients developed persistent chimerism and were completely withdrawn from IS drugs without evidence of subsequent rejection using an IND approved protocol with observation of up to 8 years.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 evidence has shown that the addition of autologous Tregs to donor hematopoietic stem cell (DHSC) infusion can promote the successful establishment of stable mixed chimerism in the face of MHC mismatch and may represent a more successful path to establishment of stable mixed chimerism that the continued escalation of donor T cell dosing. The ability to successfully manufacture clinical grade Tregs and safely administer them to KTx recipients has been established at Northwestern. This current proposal will test whether combinatorial cell therapy using donor and recipient derived cells can achieve high levels of stable donor T cell and whole blood chimerism in HLA mismatched living donor KTx recipients. This will be achieved through our established TLI conditioning regimen, followed by injecting a donor cell inoculum containing sufficient purified CD34+ hematopoietic progenitor cells and T cells (DHSC), along with polyclonally expanded recipient regulatory T cells (Tregs) in an effort to induce persistent mixed chimerism and immune tolerance.. Our goal over the 4 year CIRM grant period is to enhance our ability to achieve persistent chimerism and allow for complete IS drug withdrawal in recipients of HLA haploidentical living donor KTx. All regulatory approvals for conducting this combinatorial cell therapy trial (INDs and FDA approval to proceed) are in place. This study will include a total of 24 recipients accrued over 4 years that meet the criteria for enrollment as described for KTx at Stanford or Northwestern. The addition of Northwestern University, which has one of th
StatusFinished
Effective start/end date3/1/1912/31/20

Funding

  • Stanford University (005436803//CLIN2-11400)
  • California Institute for Regenerative Medicine (005436803//CLIN2-11400)

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.