Novel mechanisms of immune activation following allogeneic, hematopoietic stem ce

Summary

Principal Investigator: JOHN JAMES LETTERIO
Abstract: DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for many patients with hematologic malignancies and other blood disorders. In addition to delivering effective anti-cancer treatment, the therapeutic potential of allogeneic HSCT relies on graft-versus-tumor (GVT) effects, which eradicate residual malignant cells via immunologic mechanisms. Unfortunately, GVT effects are closely associated with the development of graft-versus-host disease (GVHD). GVHD and malignant relapse are the two primary contributors to mortality, which remains unacceptably high. Standard therapy for GVHD is often therapeutically sub-optimal and predisposes to opportunistic infections and relapse of the underlying disease. Thus, the development of novel strategies that reduce GVHD and enhance survival after allogeneic HSCT remains the most significant challenge facing physician-scientists and our patients. The pathophysiology of GVHD is complex and fundamentally depends upon interactions between donor T cells and host antigen presenting cells. Experimental and clinical data support the hypothesis that cytokine dysregulation during GVHD occurs in three distinct phases including: 1) the effects of conditioning regimens on host tissues, 2) activation of donor T cells by host antigen presenting cells and 3) the generation of cellular and inflammatory effectors. While simplistic, this 3-step hypothesis uncovers opportunities to regulate this disease process. We have recently explored the role of cyclin dependent kinase 5 (Cdk5) in immune cells. Cdk5 is a ubiquitously expressed serine-threonine kinase that is predominantly active in post-mitotic neurons where the expression of its obligate partner proteins (p35 and p39) is most abundant. Cdk5 activity is essential in various neuronal processes, and as such, current paradigms suggest that Cdk5 function is largely restricted to the CNS. Activation of the Cdk5/p35 complex is however associated with inflammatory disorders, but the contribution of Cdk5 activity to lymphocyte biology has not been fully appreciated. Recently, our group was the first to implicate a role for Cdk5 in lymphocyte activation by 1) developing a new chimeric mouse model in which hematopoietic stem cells from Cdk5 deficient (Cdk5-/-) embryos are used to reconstitute lethally irradiated adult mouse recipients (CDK5-/-C), 2) showing the rapid induction of both Cdk5 and its obligate partner p35 during T cell activation, 3) revealing defects in activation and migration of Cdk5-/- T cells from adult chimeric CDK5-/-C mice;and 4) demonstrating a resistance to the induction of experimental autoimmune encephalomyelitis in CDK5-/-C mice immunized with a MOG peptide. Exciting preliminary data strongly suggest a role for Cdk5 in modulating GVHD severity as well. However, the mechanisms for this protective effect must be further defined. These findings are significant because they identify potential targets for novel cellular therapeutic strategies that are non-cross reactive with standard immuno-suppressive approaches and therefore have the potential to reduce GVHD severity while maintaining immune reconstitution and GVT effects.
Funding Period: 2013-08-19 - 2017-05-31
more information: NIH RePORT

Research Grants

  1. Therapeutic Opportunities for Pediatric Astrocytoma
    Rosalind A Segal; Fiscal Year: 2013
  2. Martin Delaney Collaboratory to Eradicate HIV-1 Infection
    David M Margolis; Fiscal Year: 2013
  3. Center for Interdisciplinary Research on Nicotine Addiction (CIRNA)
    Caryn Lerman; Fiscal Year: 2013
  4. P53 - REGULATORS AND EFFECTORS
    Stuart A Aaronson; Fiscal Year: 2013
  5. Biology &Transplantation of the Human Stem Cell
    John E Wagner; Fiscal Year: 2013
  6. Mayo SPORE in Brain Cancer
    BRIAN PATRICK O'NEILL; Fiscal Year: 2013
  7. Failed Regeneration in the Muscular Dystrophies: Inflammation, Fibrosis and Fat
    H Lee Sweeney; Fiscal Year: 2013
  8. IMPROVING CORD BLOOD TRANSPLANTATION
    Elizabeth J Shpall; Fiscal Year: 2013
  9. Optical Technologies and Molecular Imaging for Cervical Neoplasia
    Michele Follen; Fiscal Year: 2013
  10. Bone Marrow Transplantation in Human Disease
    Richard J Jones; Fiscal Year: 2013

Detail Information

Research Grants30

  1. 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. ..
  2. Martin Delaney Collaboratory to Eradicate HIV-1 Infection
    David M Margolis; Fiscal Year: 2013
    ..We are convinced that together we will catalyze advances that will ultimately lead to the eradication of HIV infection. ..
  3. Center for Interdisciplinary Research on Nicotine Addiction (CIRNA)
    Caryn Lerman; Fiscal Year: 2013
    ..The CIRNA is proposed to replace the TTURC, since this NIH initiative is ending. ..
  4. P53 - REGULATORS AND EFFECTORS
    Stuart A Aaronson; Fiscal Year: 2013
    ..This Program brings together a senior group of investigators from different disciplines and with complementary expertise focused on important and novel aspects of p53 biology. ..
  5. Biology &Transplantation of the Human Stem Cell
    John E Wagner; Fiscal Year: 2013
    ..abstract_text> ..
  6. Mayo SPORE in Brain Cancer
    BRIAN PATRICK O'NEILL; Fiscal Year: 2013
    ..D.) D. Animal Core (Director: J.N. Sarkaria, M.D.;Co-Director: I.F. Parney, M.D., Ph.D.) E. Clinical Research Core (Director: J.C. Buckner, M.D.;Co-Director: D. H. Lachance, M.D.) Developmental Research Portfolio ..
  7. Failed Regeneration in the Muscular Dystrophies: Inflammation, Fibrosis and Fat
    H Lee Sweeney; Fiscal Year: 2013
    ..A Physiological Assessment Core (Core C) will support Project 1 and continue as a national source for evaluating therapeutic inten/entions in mouse models of Muscular Dystrophy. ..
  8. IMPROVING CORD BLOOD TRANSPLANTATION
    Elizabeth J Shpall; Fiscal Year: 2013
    ....
  9. Optical Technologies and Molecular Imaging for Cervical Neoplasia
    Michele Follen; Fiscal Year: 2013
    ..abstract_text> ..
  10. Bone Marrow Transplantation in Human Disease
    Richard J Jones; Fiscal Year: 2013
    ..abstract_text> ..
  11. Adoptive Transfer of Donor Tregs Specific Against Host Alloantigens for Presentio
    Claudio Anasetti; Fiscal Year: 2013
    ..By trace-labeling the Tregs, we will also assess Treg repopulation and survival after adoptive transfer to allograft recipients. ..
  12. Host Defense Against HIV-related Pulmonary Infections
    Judd E Shellito; Fiscal Year: 2013
    ..abstract_text> ..
  13. T CELL MEMORY TO PATHOGENS: GENERATION AND FUNCTION
    Susan L Swain; Fiscal Year: 2013
    ..abstract_text> ..
  14. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
    ..By pooling our data, specimens, and importantly, expertise to investigate these synergist hypotheses, we will elucidate much of the etiology of aggressive, early onset breast cancers in AA women. ..
  15. PAPOVA VIRUS TRANSFORMING MECHANISMS
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
    ..The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies. ..
  16. Targeting CC-Chemokine Receptor 7 for the prevention of graft-versus-host disease
    JAMES M COGHILL; Fiscal Year: 2013
    ..Through these experiences, Dr. Coghill will obtain the skills necessary to transition to an independent, NIH funded laboratory investigator. ..
  17. 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. ..
  18. MOLECULAR BASIS OF CHOLESTEROL METABOLISM
    Joseph L Goldstein; Fiscal Year: 2013
    ..Such an integrated interdisciplinary approach is possible only through continued support of this PPG. ..
  19. Directing Tumor-specific T cells to Tumors
    Pawel Kalinski; Fiscal Year: 2013
    ..abstract_text> ..
  20. MOLECULAR BASIS OF VIRAL AND CELLULAR TRANSFORMATION
    DANIEL C DIMAIO; Fiscal Year: 2013
    ..abstract_text> ..
  21. Immuno/Immuno-Gene Therapies for Thoracic Malignancies
    STEVEN MARK ALBELDA; Fiscal Year: 2013
    ..Core C will provide biostatistical and data management services. The goal of this P01 is to alter the treatment paradigm for MPM and advance the entire field of adoptive T cell transfer. ..
  22. Radiation Bystander Effects: Mechanisms
    Tom K Hei; Fiscal Year: 2013
    ..abstract_text> ..
  23. Herpesviral, Oncogenesis, Latency and Reactivation
    NANCY JOAN RAAB-TRAUB; Fiscal Year: 2013
    ..abstract_text> ..