Studies are proposed to enhance and improve the immune monitoring of the peripheral blood mononuclear cells (PBMCs) of patients enrolled in two parent clinical trials;one designed to induce immune tolerance to combined kidney and hematopoietic cell transplants and another designed to prevent graft versus host disease (GVHD) after hematopoietic cell transplantation (HCT) for the treatment of leukemia and lymphoma. The goals of the proposed immune monitoring are to use serial analyses of gene microarrays and patterns of intracellular cytokine production to predict which patients can be safely withdrawn from all immunosuppressive drugs at 6 months after transplantation without the subsequent development of rejection episodes in the case of the kidney transplant patients and without the development of GVHD in the case of the hematolymphoid cancer patients. The gene microarray studies build upon recent cross sectional studies that show a """"""""tolerance"""""""" gene expression pattern in kidney transplant patients with good graft function off drugs, and a """"""""GVHD"""""""" expression pattern that differentiates patients with and without chronic GVHD. We plan to apply the microarray assays to serial longitudinal monitoring of patients in the two trials. In addition, our preclinical and clinical studies of the monitoring of cytokine production patterns of T cell subsets has delineated an IL-4 and IL-10 increase pattern that is associated with the successful induction of tolerance and prevention of GVHD. We will apply the serial monitoring of the changed cytokine patterns to help guide the safe withdrawal of all immunosuppressive drugs in concert with the gene array studies in the future. In addition to providing information about guidance of drug withdrawal, the studies are designed to provide further insight into the cellular and molecular immune mechanisms of tolerance and GVHD protection.

Public Health Relevance

The goal of the proposed immune monitoring studies are to help safely guide the complete withdrawal of immunosuppressive drugs from patients enrolled in two parent clinical trials;one designed to remove the lifelong use of these drugs from patients given kidney transplants and the other designed to remove these drugs that are used to prevent graft versus host disease in patients given transplants of cells derived from the bone marrow of donors as a treatment for leukemia and lymphoma. We will use two assays that can help guide the safe withdrawal of drugs. One is based on the use of gene chips that can determine which genes are expressed in the immune cells of patients, and the other is based on which cytokines (immune hormones) are expressed. By performing serial monitoring of these assays, it is expected that the immune changes that prevent kidney graft rejection and GVHD can be predicted and help in management of the withdrawal process to improve the future safety of these patients.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1-PA-I (M6))
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Hayes, Deborah
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Roedder, Silke; Li, Li; Alonso, Michael N et al. (2015) A Three-Gene Assay for Monitoring Immune Quiescence in Kidney Transplantation. J Am Soc Nephrol 26:2042-53
Kohrt, Holbrook E; Tian, Lu; Li, Li et al. (2013) Identification of gene microarray expression profiles in patients with chronic graft-versus-host disease following allogeneic hematopoietic cell transplantation. Clin Immunol 148:124-35
Scandling, J D; Busque, S; Dejbakhsh-Jones, S et al. (2012) Tolerance and withdrawal of immunosuppressive drugs in patients given kidney and hematopoietic cell transplants. Am J Transplant 12:1133-45