Research Summaries

Department of Surgery
Brigham and Women’s Hospital and Harvard Medical School
Julian & Eunice Cohen Laboratory for Surgical Research
75 Francis Street
Boston, MA 02115
Tel: (617) 732-7399
Fax: (617) 264-5222
jlederer@rics.bwh.harvard.edu

Laboratory Staff: 

3 postdoctoral fellows, 2 technicians; 1 associate professor; 1 professor

Research Profile

It is well recognized that serious injury induces perturbations of the immune system manifested initially as a systemic inflammatory response syndrome (SIRS), which is followed after several days by a compensatory anti-inflammatory response syndrome (CARS), which in turn is associated with diminished resistance to infection by nosocomial organisms. Either the initial SIRS response or a later invasive infection subsequent to the CARS response can induce the multiple organ dysfunction syndrome (MODS), which is the leading cause of death in injured patients who survive initial resuscitation. Beyond the clinical importance of this problem, recent research has focused on the basic mechanisms through which the mammalian immune system copes with injury.

Our laboratory is devoted to the study of interactions between the innate and adaptive immune systems involved in initiating both the SIRS and CARS responses to injury. Circulating mononuclear cells in the blood of injured patients and blood, lymph nodes and spleens from a mouse model of burn or sham burn injury are utilized in these studies. In order to substantiate and expand the findings obtained in studies of patients and wild type (WT) animals, we use a number of genetically altered mice including T-cell receptor transgenics, Rag 1 deficient animals (lacking an adaptive immune system), mice genetically deficient in beta2 microglobulin (MHCI), CD4 or CD8 cells, Fas or Fas ligand, IL-10, toll-like receptor (TLR) 4, or the IL-1 TLR family signaling adapter protein, MyD88. Readout systems include response to infectious challenge in the form of cecal ligation and puncture, cytokine production and antibody isotypes measured by immunoassay; transgenic T-cell receptor expression, T-cell receptor Vbeta chain expression, costimulatory receptor expression, activation marker expression, phenotypic markers, and intracellular cytokine content by flow cytometry, gene expression by real-time PCR and microarray technology, and in vivo siRNA-mediated gene knockdown technology.

Recent findings of interest include the demonstration that cells of both the innate and adaptive immune systems participate in the early SIRS response to injury and that interaction of T-cells of the adaptive immune system with antigen presenting cells of the innate immune system at or near the time of injury is necessary for the induction of the regulatory T-cell phenotype, which plays a major role in the compensatory anti-inflammatory CARS response and diminished resistance to infection.

Current projects in which students and research  fellows can participate include:

1. Studies addressing the influence of injury on TLR expression and reactivity by cells of the innate and adaptive immune systems and their response to TLR agonists as determined by expression of activation markers, cytokine excretion and intracellular cytokine staining.
2. Use of TCR transgenic mice and adoptive transfer of transgenic T-cells to WT mice, in order to delineate the effects of injury on T-cell responses to specific antigen at serial intervals following burn or sham burn injury.
3. Study of the interactions of cells of the innate and adaptive immune systems after injury through in vitro study of antigen presenting cells, harvested from burn or sham injured mice, cultured with naïve transgenic T-cells.
4. Utilization of Rag 1 deficient mice (mice that lack an adaptive immune system) to determine the effects of adoptive transfer of various WT adaptive immune cell types on the response to injury and resistance to infection.
5. Immediate ex vivo measurement by flow cytometry of the in vivo effects of injury on expression of TCR Vbeta chains to determine T-cell clonal expansion or deletion at serial intervals after injury as well as T-cell proliferation and activation marker expression.
6. Use of microarrays and real-time PCR to determine the effects of injury on gene expression in the lymphoid organs of burn and sham injured mice at serial intervals.
7. Functional genomics experiments addressing the effect of transient gene knockdown on the host immune response to injury.

Recent Publications:

1. Guo, Z., E. Kavanagh, Y. Zang, S. M. Dolan, S. J. Kriynovich, J. A. Mannick, and J. A. Lederer. 2003. Burn injury promotes antigen-driven th2-type responses in vivo. J Immunol 171:3983-3990.
2. Murphy, T., H. Paterson, S. Rogers, J. A. Mannick, and J. A. Lederer. 2003. Use of intracellular cytokine staining and bacterial superantigen to document suppression of the adaptive immune system in injured patients. Ann Surg 238:401-410; discussion 410-401.
3. Paterson, H. M., T. J. Murphy, E. J. Purcell, O. Shelley, S. J. Kriynovich, E. Lien, J. A. Mannick, and J. A. Lederer. 2003. Injury primes the innate immune system for enhanced Toll-like receptor reactivity. J Immunol 171:1473-1483.
4. Shelley, O., T. Murphy, H. Paterson, J. A. Mannick, and J. A. Lederer. 2003. Interaction between the innate and adaptive immune systems is required to survive sepsis and control inflammation after injury. Shock 20:123-129.
5. Shelley, O., T. Murphy, J. A. Lederer, J. A. Mannick, and M. L. Rodrick. 2003. Mast cells and resistance to peritoneal sepsis after burn injury. Shock 19:513-518.
6. Murphy, T. J., H. M. Paterson, J. A. Mannick, and J. A. Lederer. 2004. Injury, sepsis, and the regulation of Toll-like receptor responses. J Leukoc Biol 75:400-407.
7. NiChoileain, N., Y. Zang, S. Dolan, M. Miller, J. A. Mannick, and J. A. Lederer. 2004. Injury effects on the CD25-expressing CD4+ T-cell subset. Shock 21:51.
8. Zang, Y., S. M. Dolan, N. N. Choileain, S. J. Kriynovich, T. J. Murphy, P. Sayles, J. A. Mannick, and J. A. Lederer. 2004. Burn injury initiates a shift in superantigen-induced T cell responses and host survival. J Immunol 172:4883-4892.
9. Lederer, J. A. 2005. Does nitric oxide control the counter-inflammatory response in endotoxic shock? Crit Care Med 33:896-898.
10. Maung, A. A., S. Fujimi, L. M. M, M. P. Macconmara, J. A. Mannick, and J. A. Lederer. 2005. Enhanced TLR4 reactivity following injury is mediated by increased p38 activation. J Leukoc Biol.
11. Maung, A. A., S. Fujimi, M. L. Miller, M. P. Macconmara, J. A. Mannick, and J. A. Lederer. 2005. Enhanced TLR4 reactivity following injury is mediated by increased p38 activation. J Leukoc Biol 78:565-573.
12. Murphy, T. J., N. N. Choileain, Y. Zang, J. A. Mannick, and J. A. Lederer. 2005. CD4+CD25+ regulatory T cells control innate immune reactivity after injury. J Immunol 174:2957-2963.
13. Murphy, T. J., H. M. Paterson, S. Kriynovich, Y. Zang, E. A. Kurt-Jones, J. A. Mannick, and J. A. Lederer. 2005. Linking the "two-hit" response following injury to enhanced TLR4 reactivity. J Leukoc Biol 77:16-23.
14. Purcell, E. M., S. M. Dolan, S. Kriynovich, J. A. Mannick, and J. A. Lederer. 2006. Burn injury induces an early activation response by lymph node cd4+ T cells. Shock 25:135-140.
15. Fujimi, S., M. P. Macconmara, A. A. Maung, Y. Zang, J. A. Mannick, J. A. Lederer, and P. H. Lapchak. 2006. Platelet depletion in mice increases mortality after thermal injury. Blood.
16. Choileain, N. N., M. Macconmara, Y. Zang, T. J. Murphy, J. A. Mannick, and J. A. Lederer. 2006. Enhanced Regulatory T Cell Activity Is an Element of the Host Response to Injury. J Immunol 176:225-236.
17. Brownstein, B. H., T. Logvinenko, J. A. Lederer, J. P. Cobb, W. J. Hubbard, I. H. Chaudry, D. G. Remick, H. V. Baker, W. Xiao, and J. A. Mannick and the Inflammation and Host Response to Injury Investigators.. 2006. Commonality and differences in leukocyte gene expression patterns among three models of inflammation and injury. Physiol Genomics 24:298-309.