Role of CCR2+ monocytes and Mo-DCs in defense against IA and GVHD development

Summary

Principal Investigator: Amariliz Rivera
Abstract: DESCRIPTION (provided by applicant): Allogeneic bone marrow transplantation (ABMT) can be a life-saving procedure as therapy against a variety of hematologic malignancies. The broad application of ABMT has been hampered by serious complications including life-threatening fungal infections (especially invasive aspergillosis, IA) and graft versus host disease (GVHD) development. The curative effects of ABMT could be more broadly exploited by ameliorating infection and GVHD side effects through novel therapeutic interventions. A detailed understanding of basic biological aspects of ABMT would facilitate the identification of relevant targets for the development of innovative therapies. In this application we seek to further our current knowledge of ABMT by examining the specific contributions of CCR2+ inflammatory monocytes and CCR2+ monocyte-derived dendritic cells (Mo-DCs) in defense against fungal infection in the context of ABMT with our without GVHD. In preliminary studies we have employed a novel mouse strain that allows for the selective depletion of CCR2+monocytes to uncover a previously unidentified essential role for CCR2+inflmmatory monocytes in defense against IA. Based on our published and unpublished observations the proposed studies will test two main hypothesis: 1) ABMT leads to enhanced susceptibility to IA due to impairments in CCR2+monocyte reconstitution and/or function 2) ABMT and GVHD lead to enhanced susceptibility to IA due to impairments in the activation of protective fungus- specific CD4 T cell responses. The proposed studies will be made possible by employing novel mouse strains that facilitate the selective tracking and depletion of CCR2+ inflammatory monocytes and Mo-DCs. We will also exploit our previously developed model for tracking the in vivo development of fungus-specific CD4 T cell responses to specifically examine the impact of ABMT and GVHD on the development of antifungal immunity. Altogether, the successful completion of the proposed studies would significantly advance our understanding of immune reconstitution after ABMT and identify crucial factors that control susceptibility to fungal infection. Moreover, we believe that our studies will uncover novel mechanisms of susceptibility in the context of ABMT and lay the foundation for future translational studies to exploit inflammatory monocytes in the prevention of life-threatening fungal infections in ABMT patients.
Funding Period: 2013-04-01 - 2013-06-30
more information: NIH RePORT

Top Publications

  1. pmc Inflammatory monocytes orchestrate innate antifungal immunity in the lung
    Vanessa Espinosa
    Rutgers, New Jersey Medical School, Department of Pediatrics, Center for Immunity and Inflammation, Newark, New Jersey, United States of America Rutgers, Graduate School of Biomedical Sciences, Newark, New Jersey, United States of America
    PLoS Pathog 10:e1003940. 2014
  2. ncbi When PRRs collide: mincle meddles with dectin and toll
    Amariliz Rivera
    Department of Pediatrics, Center for Immunity and Inflammation, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07101, USA Electronic address
    Cell Host Microbe 15:397-9. 2014

Detail Information

Publications2

  1. pmc Inflammatory monocytes orchestrate innate antifungal immunity in the lung
    Vanessa Espinosa
    Rutgers, New Jersey Medical School, Department of Pediatrics, Center for Immunity and Inflammation, Newark, New Jersey, United States of America Rutgers, Graduate School of Biomedical Sciences, Newark, New Jersey, United States of America
    PLoS Pathog 10:e1003940. 2014
    ..Our findings illustrate both indirect and direct functions for CCR2⁺Mo and their derivatives in innate antifungal immunity in the lung...
  2. ncbi When PRRs collide: mincle meddles with dectin and toll
    Amariliz Rivera
    Department of Pediatrics, Center for Immunity and Inflammation, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07101, USA Electronic address
    Cell Host Microbe 15:397-9. 2014
    ..Wevers et al. (2014) uncover a mechanism of PRR antagonism where fungal-induced Mincle signaling suppresses IL-12 transcription induced by other PRRs and thereby abates antifungal immunity. ..

Research Grants30

  1. Immunobioogy for Marrow Allografts for Leukemia
    RICHARD JOHN O'REILLY; Fiscal Year: 2013
    ..The 3 cores include: Core A which provides all patient samples and evaluate grafts pre and post HSCT, Core B Biostatistics and Core C administrative support and oversight. ..
  2. MIXED HEMATOPOIETIC CHIMERISM AFTER STEM CELL ALLOGRAFTS
    Rainer F Storb; Fiscal Year: 2013
    ..This is especially important since median ages at diagnosis of patients with most candidate diseases range from 65 to 70 years, which is beyond the age range of inclusion in conventional myeloablative HCT regimens. ..
  3. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  4. Mechanisms of State Switching in Sleep and Sleep Apnea
    Clifford B Saper; Fiscal Year: 2013
    ..This work will help to design interventions for improving the health of patients with OSA. ..
  5. MOLECULAR BASIS OF VIRAL AND CELLULAR TRANSFORMATION
    DANIEL C DIMAIO; Fiscal Year: 2013
    ..abstract_text> ..
  6. Therapeutic Opportunities for Pediatric Astrocytoma
    Rosalind A Segal; Fiscal Year: 2013
    ..The three projects interact with one another and are further unified by economies of scale enabled by an Innovative Neuropathology (INP) core. ..