Based on experimental animal studies, a compelling rationale has emerged for the clinical testing of regulatory dendritic cells (DCreg) to improve organ transplant survival. Importantly, using a robust, clinically-relevant, non- human primate model and minimal immunosuppression, we have shown that infusion of DCreg, one week before transplant, can safely prolong renal allograft survival, without evidence of host sensitization. This therapeutic effect is associated with selective attenuation of donor-specific T memory cell responses, an important barrier to the promotion of long-term graft survival. We have generated GMP grade human DCreg from elutriated blood monocytes and demonstrated both their stable resistance to maturation under inflammatory conditions and their ability to negatively regulate alloreactive T cell responses. We have also established release criteria for clinical testing. Based on these accomplishments, we will now plan to conduct a clinical trial of donor-derived DCreg in adult, de novo live donor renal transplantation. This is a novel and unique approach to regulatory immune cell therapy in organ transplantation. The purpose of this R34 application is to complete the clinical trial protocol, finalize scale-up and manufacturing SOPs for DCreg production, complete design of the mechanistic studies, obtain the requisite approvals from the FDA and IRB, and establish the framework for clinical trial operation and management. We hypothesize that donor-derived DCreg, generated ex vivo and administered prospectively to live donor renal transplant recipients treated with conventional immunosuppression, will be safe and induce immunological changes conducive to improved graft survival. We have two Specific Aims:
Aim 1 : To plan a first-in-human, open label, single center phase 1 dose escalation safety study in adult recipients of de novo, live donor renal transplants. Patients will receive standard-of-care immunosuppression. One week before transplantation, they will receive a single infusion of donor-derived DCreg in combination with Mycophenolic Acid (MPA). While this is a safety trial, data that we acquire during the course of the trial may enable us to conduct a preliminary examination of efficacy.
Aim 2 : To plan sequential immunological analyses of the DCreg recipients. We will plan to conduct detailed mechanistic studies critical to understanding the outcome of the study and the potential effects of the infused cells on the alloimmune response.

Public Health Relevance

Dendritic leukocytes with ability to regulate adaptive immune responses (regulatory DC; DCreg) are highly- promising, novel cellular therapeutic agents to improve long-term transplant survival. We will plan to evaluate their safety in a first-in-human phase 1 trial in live donor renal transplantation and plan to analyze underlying immunologic mechanisms. Our proposed strategy may induce immunological changes conducive to improved graft survival and reduced patient dependence on immunosuppressive drugs that have severe side effects.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Planning Grant (R34)
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Special Emphasis Panel (ZAI1-PA-I (S1))
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Bridges, Nancy D
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University of Pittsburgh
Schools of Medicine
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Thomson, Angus W; Humar, Abhinav; Lakkis, Fadi G et al. (2018) Regulatory dendritic cells for promotion of liver transplant operational tolerance: Rationale for a clinical trial and accompanying mechanistic studies. Hum Immunol 79:314-321
Zahorchak, Alan F; Macedo, Camila; Hamm, David E et al. (2018) High PD-L1/CD86 MFI ratio and IL-10 secretion characterize human regulatory dendritic cells generated for clinical testing in organ transplantation. Cell Immunol 323:9-18
Thomson, Angus W; Zahorchak, Alan F; Ezzelarab, Mohamed B et al. (2016) Prospective Clinical Testing of Regulatory Dendritic Cells in Organ Transplantation. Front Immunol 7:15