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Papers by David Leitenberg

The Journal of Immunology, 2004

Parasitic helminths induce chronic infections in their hosts although, with most human helminthia... more Parasitic helminths induce chronic infections in their hosts although, with most human helminthiases, protective immunity gradually develops with age or exposure of the host. One exception is infection with the human hookworm, Necator americanus, where virtually no protection ensues over time. Such observations suggest these parasites have developed unique mechanisms to evade host immunity, leading us to investigate the role of the excretory/secretory (ES) products of adult N. americanus in manipulating host immune responses. Specifically, we found that a protein(s) from ES products of adult N. americanus bound selectively to mouse and human NK cells. Moreover, incubation of purified NK cells with N. americanus ES products stimulated the production of augmented (4-to 30-fold) levels of IFN-␥. This augmentation was dependent on the presence of both IL-2 and IL-12 and was endotoxin-independent. This is the first report of a pathogen protein that binds exclusively to NK cells and the first report of a nematode-derived product that induces abundant levels of cytokines from NK cells. Such an interaction could provide a means of cross-regulating deleterious Th2 immune responses in the host, thereby contributing to the long-term survival of N. americanus.

The Journal of Immunology, 2006

Extracellular cyclophilins have been well described as chemotactic factors for various leukocyte ... more Extracellular cyclophilins have been well described as chemotactic factors for various leukocyte subsets. This chemotactic capacity is dependent upon interaction of cyclophilins with the cell surface signaling receptor CD147. Elevated levels of extracellular cyclophilins have been documented in several inflammatory diseases. We propose that extracellular cyclophilins, via interaction with CD147, may contribute to the recruitment of leukocytes from the periphery into tissues during inflammatory responses. In this study, we examined whether extracellular cyclophilin-CD147 interactions might influence leukocyte recruitment in the inflammatory disease allergic asthma. Using a mouse model of asthmatic inflammation, we show that 1) extracellular cyclophilins are elevated in the airways of asthmatic mice; 2) mouse eosinophils and CD4 ؉ T cells express CD147, which is up-regulated on CD4 ؉ T cells upon activation; 3) cyclophilins induce CD147-dependent chemotaxis of activated CD4 ؉ T cells in vitro; 4) in vivo treatment with anti-CD147 mAb significantly reduces (by up to 50%) the accumulation of eosinophils and effector/memory CD4 ؉ T lymphocytes, as well as Ag-specific Th2 cytokine secretion, in lung tissues; and 5) anti-CD147 treatment significantly reduces airway epithelial mucin production and bronchial hyperreactivity to methacholine challenge. These findings provide a novel mechanism whereby asthmatic lung inflammation may be reduced by targeting cyclophilin-CD147 interactions.

Journal of Experimental Medicine, 2001

Rac2 is a hematopoietic-specific GTPase acting as a molecular switch to mediate both transcriptio... more Rac2 is a hematopoietic-specific GTPase acting as a molecular switch to mediate both transcriptional activation and cell morphological changes. We have examined the effect of Rac2 deficiency during T cell activation. In Rac2−/− T cells, proliferation was reduced upon stimulation with either plate-bound anti-CD3 or T cell receptor–specific antigen. This defect is accompanied with decreased activation of mitogen activated protein kinase extracellular signal–regulated kinase (ERK)1/2 and p38, and reduced Ca2+ mobilization. TCR stimulation–induced actin polymerization is also reduced. In addition, anti-CD3 cross-linking–induced T cell capping is reduced compared with wild-type T cells. These results indicate that Rac2 is important in mediating both transcriptional and cytoskeletal changes during T cell activation. The phenotypic similarity of Rac2−/− to Vav−/− cells implicates Rac2 as a downstream mediator of Vav signaling.

Immunology, 2010

Tumour pathogenesis is characterized by an immunosuppressive microenvironment that limits the dev... more Tumour pathogenesis is characterized by an immunosuppressive microenvironment that limits the development of effective tumour-specific immune responses. This is in part the result of tumour-dependent recruitment and activation of regulatory cells, such as myeloid-derived suppressor cells and regulatory T cells in the tumour microenvironment and draining lymph nodes. Shedding of gangliosides by tumour cells has immunomodulatory properties, suggesting that gangliosides may be a critical factor in initiating an immunosuppressive microenvironment. To better define the immunomodulatory properties of gangliosides on antigen-specific T-cell activation and development we have developed an in vitro system using ganglioside-treated murine bone-marrow-derived dendritic cells to prime and activate antigen-specific CD4 + T cells from AND T-cell receptor transgenic mice. Using this system, ganglioside treatment promotes the development of a dendritic cell population characterized by decreased CD86 (B7-2) expression, and decreased interleukin-12 and interleukin-6 production. When these cells are used as antigenpresenting cells, CD4 T cells are primed to proliferate normally, but have a defect in T helper (Th) effector cell development. This defect in Th effector cell responses is associated with the development of regulatory T-cell activity that can suppress the activation of previously primed Th effector cells in a contact-dependent manner. In total, these data suggest that ganglioside-exposed dendritic cells promote regulatory T-cell activity that may have long-lasting effects on the development of tumour-specific immune responses.

The Journal of Immunology, 2005

Cell surface gangliosides are shed by tumors into their microenvironment. In this study they inhi... more Cell surface gangliosides are shed by tumors into their microenvironment. In this study they inhibit cellular immune responses, including APC development and function, which is critical for Th1 and Th2 cell development. Using human dendritic cells (DCs) and naive CD4 ؉ T cells, we separately evaluated Th1 and Th2 development under the selective differentiating pressures of DC1-inducing pertussis toxin (PT) and DC2-inducing cholera toxin (CT). High DC IL-12 production after PT exposure and high DC IL-10 production after CT exposure were observed, as expected. However, when DCs were first preincubated with highly purified G D1a ganglioside, up-regulation of costimulatory molecules was blunted, and PT-induced IL-12 production was reduced, whereas CT-induced IL-10 production was increased. The combination of these effects could contribute to a block in the Th1 response. In fact, when untreated naive T cells were coincubated with ganglioside-preincubated, Ag-exposed DCs, naive Th cell differentiation into Th effector cells was reduced. Both the subsequent DC1-induced T cell production of IFN-␥ (Th1 marker) and DC2-induced T cell IL-4 production (Th2) were inhibited. Thus, ganglioside exposure of DC impairs, by at least two distinct mechanisms, the ability to induce Th differentiation, which could adversely affect the development of an effective cellular antitumor immune response.

Abstract. Vascular endothelial cells (ECs) can undergo dramatic phenotypic and functional alterat... more Abstract. Vascular endothelial cells (ECs) can undergo dramatic phenotypic and functional alterations in response to humoral and cellular stimuli. These changes promote endothelial participation in the inflammatory response through active recruitment of immune effector cells, increased vascular permeability, and alteration in vascular tone. In an attempt to define early events in lymphocyte-mediated EC signaling, we investigated cytosolic-free calcium (Ca 2+) changes in single, Fluo-3-1abeled human umbilical vein ECs (HUVECs), using an ACAS interactive laser cytometer. Of all lymphocyte subsets tested, allogeneic CD3-, CD56+ natural killer (NK) cells uniquely elicited oscillatory EC Ca 2 ÷ signals in cytokine (interleukin [IL]-I- or tumor necrosis factor [TNF])-treated

We present a case of del(14)(q21) as a sole abnormality in a 4-year-old boy diagnosed with precur... more We present a case of del(14)(q21) as a sole abnormality in a 4-year-old boy diagnosed with precursor B-cell acute lymphoblastic leukemia (pre-B ALL). To our knowledge, this is the first case of isolated del(14)(q21) in pre-B ALL. Two pretreatment bone marrow samples obtained 5 days apart were analyzed by cytogenetics. The G-banded karyotypes of the two samples were similar, differing only in the ratio of normal/abnormal metaphases detected. Both samples showed a del(14)(q21) as the only abnormality. Fluorescence in situ hybridization performed using the probes TEL/AML1 and immunoglobulin heavy chain (IGH) showed no fusion involving the TEL and AML1 genes and only a singleIGH signal in 20% of the interphase cells analyzed. 2005 Elsevier Inc. All rights reserved.

The Journal of Immunology, Aug 1, 1998

The Journal of Immunology, Apr 1, 2010

The Journal of Immunology, May 15, 1999

Tissue Engineering Part A, 2015

Background: Rapidly improving protocols for the derivation of autologous cells from stem cell sou... more Background: Rapidly improving protocols for the derivation of autologous cells from stem cell sources is a welcome development. However, there are many circumstances when off-the-shelf universally immunocompatible cells may be needed. Embryonic stem cells (ESCs) provide a unique opportunity to modify the original source of differentiated cells to minimize their rejection by nonautologous hosts. Hypothesis: Immune rejection of nonautologous human embryonic stem cell (hESC) derivatives can be reduced by downregulating human leukocyte antigen (HLA) class I molecules, without affecting the ability of these cells to differentiate into specific lineages. Methods and Results: Beta-2-microglobulin (B2M) expression was decreased by lentiviral transduction using human anti-HLA class I light-chain B2M short hairpin RNA. mRNA levels of B2M were decreased by 90% in a RUES2-modified hESC line, as determined by quantitative real time-polymerase chain reaction analysis. The transduced cells were selected under puromycin pressure and maintained in an undifferentiated state. The latter was confirmed by Oct4 and Nanog expression, and by the formation of characteristic round-shaped colonies. B2M downregulation led to diminished HLA-I expression on the cell surface, as determined by flow cytometry. When used as target cells in a mixed lymphocyte reaction assay, transduced hESCs and their differentiated derivatives did not stimulate allogeneic T-cell proliferation. Using a cardiac differentiation protocol, transduced hESCs formed a confluent layer of cardiac myocytes and maintained a low level of B2M expression. Transduced hESCs were also successfully differentiated into a hepatic lineage, validating their capacity to differentiate into multiple lineages. Conclusions: HLA-I depletion does not preclude hESC differentiation into cardiac or hepatic lineages. This methodology can be used to engineer tissue from nonautologous hESC sources with improved immunocompatibility.

Journal of immunology (Baltimore, Md. : 1950), 1996

Activation of T lymphocytes through their TCR is regulated by a delicate balance of phosphorylati... more Activation of T lymphocytes through their TCR is regulated by a delicate balance of phosphorylation and dephosphorylation of protein substrates by protein tyrosine kinases (PTKs) and phosphotyrosyl phosphatases, respectively. One of the earliest steps in the activation pathway is thought to involve the Src family PTKs, p56(lck) (Lck) and p59(fyn) (Fyn); however, the precise contribution of each PTK in TCR-mediated signaling remains incompletely understood. To study the role of Lck in mature T cells, antisense RNA was used to inhibit its expression in a nontransformed Th2 clone. In this report, we demonstrate that specific inhibition of Lck expression in Th2 cells, in the presence of normal levels of functional Fyn PTK, has profound consequences on multiple events following TCR stimulation, including an altered pattern of tyrosine-phosphorylated substrates, defective phosphorylation of TCR-zeta and ZAP-70, defective Ca2+ mobilization, and a approximately 90% reduction in proliferativ...