The Cellular Immunology Laboratory is studying the development of the hematopoietic and innate immune system in response to microbial and nutrient immune activators and basic mechanisms of host defense against viruses and microbes. Studies focus on regulatory control of the cytokine response during postnatal development, and in primary and secondary immune deficiency.

Beta glucans and hematopoiesis: Glucans are known to be reticuloendothelial system activators. Glucan is a major constituent of yeasts and fungi as well as mushrooms and barley, and is the pharmacologically active agent of zymosan particles from yeast cell walls. The beta-glucan receptors, dectin-1, dectin-2, are present on mammalian leukocytes and initiate phagocytosis of particulate yeast beta-glucans, such as zymosan particles.

Recent studies have shown that glucan binding to dectin ?1 drives production of IL-17 made by a distinctive class of T cells that is emerging as an interesting new class of regulatory T cells and is also involved in hematopoiesis. The laboratory has developed a series of studies in collaboration with the MSKCC Botanical Research Center and the Cornell CNRU nutrition and cancer prevention program on the effects of Maitake beta glucan (MBG). The first studies using mouse bone marrow cells showed a dose dependent increase on a granulocyte-monocyte colony forming (CFU-GM) colonies that was associated with enhanced viability of progenitor cells. MBG also enhanced the human CFU-GM colony forming response in human umbilical cord blood cells over essentially the same dose range observed in the mouse. MBG protected both mouse bone marrow and cord blood cells from doxorubicin toxicity. MBG directly activated cord blood CD33+ monocytes to produce G-CSF. Current studies are ongoing using the NOD/SCID mouse model to determine effects on hematopoiesis and the signaling pathways.

Microbial modulation of neonatal immune response: The development of both innate and adaptive immune response in the neonate occurs in the context of post natal commensal microbial colonization and exposure to environmental antigens. Neonates are more vulnerable to potential microbial pathogens in this period due to immaturity of the immune system. Response to bacterial antigens requires antigen binding to toll-like receptors (TLRs) that recognize conserved molecular products derived from various classes of pathogens, including gram positive (TLR-2) and gram negative (TLR-4) bacteria to initiate production of inflammatory cytokines and chemokines. The mechanisms and role of different bacterial antigens in specific responses are largely unknown.

The laboratory is studying immune response to physiologically relevant bacterial antigens in term and preterm infants to determine if cytokine response is stereotyped according TLR usage. Initial studies examined response of monocytes, memory and na•ve T-cells and subsets of natural killer (NK), cells to specific microbial activators, L. plantarum 299v, S. epidermidis, Group B streptococcus and E. coli. Preliminary data show that neonatal lymphocyte response to microbial activators differs both qualitatively and quantitatively from that of adults and is characterized by a strong cytokine response toward selected microbes. Monocytes from term neonates compared to preterm neonates show a down regulated anti-inflammatory response to specific bacteria. High neonatal response to pathogenic E. coli in the preterm infant could lead to uncontrolled inflammatory response while the lower levels of IL-6 response to S. epi in both infant groups may indicate a basis for vulnerability to S. epi infection.

In collaboration with the Division of Neonatology other emerging studies suggest that immature and deficient immune response is also linked to hyper responsiveness that may be associated with an uncontrolled inflammatory response.

HCV Interactions in Hemophilia: The laboratory is investigating HCV pathogenesis in the HIV infected transfusion recipient and the evolution of host defense in this setting. HIV-1 frequently infected hemophiliacs who received non-heat-treated clotting factor concentrates prior to 1985 and more than 80% became chronically infected with HCV. The laboratory is focusing on the interaction between the innate and adaptive immune response in controlling HCV infection in the HCV and the HIV/HCV infected host. Cellular immune studies are based on repository specimens collected over seven years. The overall goal is to examine CD4+ T cell phenotype and NK cell subsets in relationship to cellular immune function and viral load and to correlate these findings with genetic polymorphisms that might affect Th1/Th2 cytokine differentiation.