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Research in our laboratory centers on innate immunity of immunocompromised patients to microbial infection. Our interest in this area traces to my doctoral training during which I isolated and studied human neutrophil-derived antimicrobial proteins and peptides including cathelicidins and the bactericidal/permeability-increasing protein (BPI) that possesses antibacterial and endotoxin-neutralizing activity against Gram-negative bacteria. Spurred by an interest in the functional immaturity of neutrophil function at birth, we have discovered that neutrophils of human newborns are deficient in BPI, that possesses cytotoxic and endotoxin-neutralizing activity towards Gram-negative bacteria. Supplementing human newborn cord blood with recombinant BPI in vitro enhances bactericidal activity against Gram-negative bacteria and markedly reduces bacteria-induced cytokine release, raising the possibility that BPI might represent a potential therapy for newborns with invasive Gram-negative bacterial infection and/or endotoxemia.
Translational work in our lab has recently demonstrated the importance of endotoxin-directed innate immunity in triggering graft-versus-host-disease in neutropenic pediatric and adult patients undergoing myeloablative chemotherapy for hematopoietic stem cell transplantation (bone marrow transplantation). Together with collaborators at the Dana Farber Cancer Institute, we are currently conducting a clinical trial of recombinant BPI (rBPI21, XOMA (U.S.) LLC) as a novel endotoxin antagonist, assessing safety, pharmacokinetics, and impact on endotoxin-directed innate immunity.

Another major innate immune focus of our laboratory is the expression and function of the Toll-like receptor (TLR) system in human newborns. Greater than 2,000,000 infants under the age of 6 months die every year of infection and therefore characterizing mechanisms of susceptibility and approaches to modulating neonatal host defense to prevent and or treat infection are global health priorities. We have discovered a marked impairment in TLR-mediated production of the Th1-polarizing cytokine TNF by human newborn blood monocytes. Remarkably, newborn plasma inhibits TLR2-mediated TNF production from monocytes, reflecting the presence of adenosine, an endogenous purine metabolite. Adenosine induces the secondary messenger cyclic adenosine monophosphate (cAMP), that suppresses TLR-induced TNF production but preserves synthesis of the anti-inflammatory and Th2-polarizing cytokine IL-6. Skewed TLR-induced cytokine responses may significantly contribute to immature neonatal immunity.

In marked contrast to impaired neonatal responses to most TLR agonists, we have discovered that TLR8 agonists, including single stranded viral RNAs and synthetic nucleoside imidazoquinoline compounds, fully activate robust production of TNF and IL-12 by human neonatal antigen-presenting cells, corresponding to robust activation of NF-kB and p38 MAP kinase pathways. Preservation of responses to TLR8 agonists may present unique opportunities for augmenting immunity in the human newborn, particularly as novel vaccine adjuvants that may be active at
birth- a major public health priority. We have recently expanded this work to include a tissue engineering approach for in vitro modeling of neonatal antigen-presenting cell and lymphocyte responses to novel vaccine formulations incorporating TLR agonists and nanoparticles.

The overall goal of our work is to identify innate immune pathway defects as potential targets of immunomodulatory therapies to prevent and treat infection in newborns and those exposed to chemoradio-therapy.

Last Update: 8/22/2013

Publications

Guinan EC, Barbon CM, Kalish LA, Parmar K, Kutok J, Mancuso CJ, Stoler-Barak L, Suter EE, Russell JD, Palmer CD, Gallington LC, Voskertchian A, Vergilio JA, Cole G, Zhu K, D'Andrea A, Soiffer R, Weiss JP, Levy O. Bactericidal/Permeability-Increasing Protein (rBPI21) and Fluoroquinolone Mitigate Radiation-Induced Bone Marrow Aplasia and Death. Sci Trans Med 2011, 3 (11) 110-118.

Philbin, VJ, Dowling, DJ, Gallington, LC, Cortés, G, Tan, Z, Suter, EE, Chi, KW, Shuckett, A, Stoler-Barak, L, Tomai, M, Miller, RL, Mansfield, K, Levy, O. Imidazoquinoline TLR8 agonists activate human newborn monocytes and dendritic cells via adenosine-refractory and caspase-1-dependent pathways. J Allerg Clin Immunol 2012, 130(1):195-204.

Kronforst, KD, Mancuso, CJ, Pettengill, M, Ninkovic, J, Coombs, MRP, Stevens, C, Otto, M, Mallard, C, Wang, X, Goldmann, D, and Levy, O. A Neonatal Model of Intravenous Staphylococcus epidermidis Infection in Mice <24h Old Enables Characterization of Early Innate Immune Responses. PLoS-ONE 2012, 7(9):e4389

© 2013 by the President and Fellows of Harvard College