Is Aberrant MO Stimulation Pivotal in Post-Trauma MODS?

Summary

Principal Investigator: Carol Miller Graziano
Affiliation: University of Rochester
Country: USA
Abstract: Post-injury morbidity and mortality results from hypo-responsiveness of both the innate and adaptive immune responses resulting in opportunistic infections & multiple organ failure (MOF). Unique tissue damage released mediators including Thrombospondin-1 (TSP-1), and apoptotic cell products pour into the post trauma circulation. Circulating monocytes' (MO) differentiation progeny, macrophage (Mac) & dendritic cells (DC), play key roles in systemic inflammation, induction of specific immunity, and maintenance of self tolerance. Post injury MO differentiation to appropriately activating or dysfunctional DC depends on circulatory mediator upregulation, downregulation, and triggering of constitutively expressed MO receptors. We hypothesize that tissue derived mediators in the post-trauma microenvironment drive aberrant MO->DC differentiation resulting in subsets of defective DC and semi mature inhibitory DC. Emergence of aberrant MO distinguishable by distinctive receptor expression & altered mediator production should correlate to different post injury pathologies. First, we will determine if post trauma MO differentiation to aberrant DC subsets typifies patients developing MOF and bacteremia with 1) MO that express a unique cohorts of interactive, inhibitory mediators/receptors including TSP-1, CD47, SIRP1, 2) inhibitory DC with low costimulatory receptors increased coinhibitory receptors & altered mediators (TSP-1, TGF2, Indoleamine 2-3 dioxygenase) production which inhibit T lymphocyte proliferation and further appropriate MO->DC differentiation. Two trauma relevant model systems for deviating MO differentiation to inhDC (addition of a mimic of TSP-1 or apoptotic T cells to MO differentiating to DC) are assessed for 1) increased coinhibitor/decreased costimulator and elevated inhibitory mediators paralleling pt aberrant DC, 2) emergence of separate inhibitory & stimulatory subsets in the total inhDC populations which can also be detected in pt inhDC, 3) modulation of MO->inhDC differentiation by maturation stimulus or blocade of specific inhibitory mediators/receptors. Successful model inhDC modulation will then be tested for modulation of pt MO differentiating to aberrant DC. These experiments may 1) reveal how novel mediators cause patient MO->DC differentiation dysfunctions, 2) identify pt MO phenotypes indicative of aberrant DC differentiation capacity and immune pathology, and 3) suggest new therapeutic targets for improving post injury recovery. PUBLIC HEALTH RELEVANCE: Infection and multiple organ failure after traumatic injuries are the 8th leading cause of death and are associated with altered differentiation of the blood monocytes (MO) to dendritic cells (DC) and macrophage. These proposed experiments should reveal 1) how trauma-released inhibitory mediators cause patient MO->DC differentiation dysfunctions, 2) delineate detectible MO/DC surface phenotypes that can identify trauma patients developing immune depression, and 3) implicate new therapeutic targets whose modulation can improve post-injury recovery.
Funding Period: 2009-09-24 - 2011-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Simultaneous aberrations in Mphi and T cell function adversely affect trauma patients' clinical outcome: a possible faulty IL-13 feedback loop
    Krzysztof Laudanski
    Department of Surgery, University of Rochester Medical Center, 601 Elmwood Ave SURG, Rochester, NY 14642, USA
    Clin Immunol 118:332-41. 2006
  2. ncbi Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells
    Krzysztof Laudanski
    Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA
    Eur J Immunol 37:2812-24. 2007
  3. ncbi HSP27: an anti-inflammatory and immunomodulatory stress protein acting to dampen immune function
    Carol L Miller-Graziano
    University of Rochester Medical Center, Department of Surgery, 601 Elmwood Avenue SURG, Rochester, NY 14642, USA
    Novartis Found Symp 291:196-208; discussion 208-11, 221-4. 2008

Detail Information

Publications3

  1. ncbi Simultaneous aberrations in Mphi and T cell function adversely affect trauma patients' clinical outcome: a possible faulty IL-13 feedback loop
    Krzysztof Laudanski
    Department of Surgery, University of Rochester Medical Center, 601 Elmwood Ave SURG, Rochester, NY 14642, USA
    Clin Immunol 118:332-41. 2006
    ..These data suggest that immunodepressed patients' aberrant monokine and depressed T cell IL-13 production are independent but synergistic contributors to emergence of MOF...
  2. ncbi Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells
    Krzysztof Laudanski
    Department of Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA
    Eur J Immunol 37:2812-24. 2007
    ..This suggests that endogenous HSP-27 has immunoregulatory activities which could contribute to immunopathology...
  3. ncbi HSP27: an anti-inflammatory and immunomodulatory stress protein acting to dampen immune function
    Carol L Miller-Graziano
    University of Rochester Medical Center, Department of Surgery, 601 Elmwood Avenue SURG, Rochester, NY 14642, USA
    Novartis Found Symp 291:196-208; discussion 208-11, 221-4. 2008
    ..These data suggest HSP27 belongs to a new group of 'anti-danger signals'...