State of the art techniques result in 10-year solid organ graft loss of up to 80% in cardiopulmonary organ transplantation, and re-transplantation is often not possible. Establishment of donor-specific immunological tolerance (DSIT), a condition in which a recipient accepts a transplant without immunosuppression, while retaining the ability to fight infections, would reduce graft loss. The only identified method of inducing robust tolerance involves Hematopoietic Cell Transplantation (HCT), usually in the form of bone marrow transplantation (BMT). Though long recognized experimentally as a means of inducing DSIT, clinical translation has been limited due to the associated complications. A major problem has been the treatment necessary to prepare a recipient for a blood cell transplant. White blood cell counts fall precipitously, resulting in neutropenia and increased susceptibility to infections To reduce infections associated with neutropenia in HCT recipients, unrelated myeloid progenitors (MP) can be injected together with the HCT. This therapy is effective in the laboratory setting in reducing deaths caused by bacterial and fungal infections, and several trials testing a clinical MP product developed by Cellerant Therapeutics (CLT-008) MP in humans are ongoing. We have discovered that injection of MP under these conditions results in MP-specific tolerance, even though there may be only very low-level MP engraftment after the first month. Important, MP from B10;B6-Rag2-/-Il2rg- /- mice, which are incapable of producing functional B, T or NK cells, induce tolerance and clearly show that organ graft-matched lymphoid cells are not essential under these conditions. Uniquely, MP cells induce antigen-specific tolerance in our experimental model system, are clinically available, and have been associated with minimal to no side effects in current clinical trials. MP constitute an ideal and innovative approach in tolerance induction protocols, preferred over efforts aimed at achieving high level donor chimerism. The proposed research in phase I will focus on (Aim 1) testing whether MP can prevent specific lung transplant rejection symptoms, important because lung transplants may be a good patient population for initial trials and (Aim 2) on testing the degree of mismatch allowed between MP and organ graft, as this will affect the production of clinical grade MP for clinical tolerance trils. The design of these trials using a Cellerant produced clinical MP product would be the next stage following this STTR project.
The proposal aims to develop methods that can be used to improve the long-term outcome of clinical organ transplantations. State of the art technology results in up to 80% organ graft loss over ten years mostly due to rejection, and re-transplantation is often not possible. The academic partner has developed preclinical tolerance models and has shown that myeloid cells can induce specific tolerance. The small business partner is currently studying an innovative product (CTL-008, human Myeloid Progenitor Cells) in clinical trials for the prevention of infections. Together we are aiming to test if a commercial Myeloid Progenitor Cell product for the induction of tolerance in solid organ transplantation is feasible and to transfer this technology to the small business partner for further clinical development and application such that it can improve the long-term outcome for patients undergoing transplantation for end-stage organ failure.