DC-ASGPR as Novel Target for Controlling GVHD and Allograft Rejection

Information

  • Research Project
  • 9452864
  • ApplicationId
    9452864
  • Core Project Number
    R01AI105066
  • Full Project Number
    5R01AI105066-05
  • Serial Number
    105066
  • FOA Number
    PA-11-260
  • Sub Project Id
  • Project Start Date
    4/1/2014 - 10 years ago
  • Project End Date
    3/31/2019 - 5 years ago
  • Program Officer Name
    NABAVI, NASRIN N
  • Budget Start Date
    4/1/2018 - 6 years ago
  • Budget End Date
    3/31/2019 - 5 years ago
  • Fiscal Year
    2018
  • Support Year
    05
  • Suffix
  • Award Notice Date
    3/16/2018 - 6 years ago

DC-ASGPR as Novel Target for Controlling GVHD and Allograft Rejection

DESCRIPTION (provided by applicant): Allograft survival with no adverse effects is an ultimate goal in transplantation. Over the past several decades, a large array of immunosuppressive agents has been developed and used for patients. However, immunosuppression does not guarantee the prevention of alloreaction over time in patients who receive organs, tissues, and hematopoietic stem cell (HPSC) transplantation. As a consequence, patients succumb to graft-versus-host disease (GVHD) as well as serious side effects from life-long immunosuppression. Furthermore, controlling GVHD with nonspecific immunosuppression neither spares pre-existing memory cells nor discriminates between alloreactive and non-alloreactive T cells. Thus, although GVHD could be controlled in some degrees by immunosuppression, it is at the cost of increased incidence of graft failure, leukemia relapse, and compromised immunity to post-transplant infections, such as cytomegalovirus (CMV). Therefore, a novel therapeutic strategy that prevents GVHD, while preserving host immunity to infections and graft versus leukemia (GVL) effects will bring great benefit to patients. We have recently found that human dendritic cells (DCs) activated via different lectin-like receptors (LLRs) can program the quality and quantity of antigen-specific T cells in different ways. Of the LLRs tested, DC-asialoglycoprotein receptor (DC-ASGPR) has a unique function to generate antigen-specific Tregs that produce IL-10. Small numbers of such Tregs were sufficient to suppress the same antigen-specific effector T cell proliferation and inflammatory cytokine expression. DCs activated via DC-ASGPR with anti-DC-ASGPR antibody express IL-10, which promotes antigen-specific Treg responses. In addition, anti-DC-ASGPR antibody significantly reduces allogeneic T cell proliferation. Thus, DC-ASGPR could be a novel target to mount alloantigen-specific Tregs in patients without interfering with host immunity to pathogens and GVL effects. In this study, therefore, we propose to investigate the molecular (Aim 1) and cellular (Aim 2) mechanisms of DC-ASGPR-induced alloantigen-specific tolerance and the effectiveness of our novel anti-DC-ASGPR antibody in GVHD (Aim 3) and allograft rejection (Aim 4). At the end of this R01 study, we will understand the molecular and cellular mechanisms of DC-ASGPR-induced alloantigen-specific immune tolerance. The results of this study will have immediate implications for the rational design and development of novel immunotherapeutics for patients who undergo transplantation in the near future.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R01
  • Administering IC
    AI
  • Application Type
    5
  • Direct Cost Amount
    250000
  • Indirect Cost Amount
    142000
  • Total Cost
    392000
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:392000\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    TTT
  • Study Section Name
    Transplantation, Tolerance, and Tumor Immunology
  • Organization Name
    BAYLOR RESEARCH INSTITUTE
  • Organization Department
  • Organization DUNS
    145745022
  • Organization City
    DALLAS
  • Organization State
    TX
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    752046165
  • Organization District
    UNITED STATES