Biomedical subjects

F D Finkelman

Publications and source records attributed to F D Finkelman.

At least 37 records · Page 2Linked to original sources

PubMed1999

The role of IL-13 in helminth-induced inflammation and protective immunity against nematode infections.

Helminth infections induce the production of type 2 cytokines, which contribute both to expulsion of the worms and inflammatory responses that can either protect or damage the host. Although IL-4 has been considered the most critical cytokine for both inflammation and protective immunity, recent observations indicate that IL-13 - a related cytokine - can have equal or even greater importance than IL-4 in inflammatory responses and host protection against infection.

Animals↗

PubMed1999

Development of an assay to measure in vivo cytokine production in the mouse.

The short in vivo lifespan of many cytokines can make measurement of in vivo cytokine production difficult. A method was developed to measure in vivo IL-4 and IFN-gamma production that eliminates this problem. Mice are injected with a biotin-labeled neutralizing IgG anti-IL-4 or anti-IFN-gamma mAb and bled 2-24 h later. Secreted cytokine is captured by the biotin-labeled mAb to produce a complex that has a relatively long in vivo half-life and consequently accumulates in serum. Serum concentrations of the complex are determined by ELISA, using wells coated with an antibody to a second epitope on the same cytokine to capture the complex. This technique is specific and increases sensitivity of detection of secreted IL-4 at least 1000-fold. The amount of cytokine measured is directly proportional to the amount produced and relatively independent of the site of cytokine production. Furthermore, because mice are injected with small quantities of biotin-labeled anti-cytokine mAb, which sample, rather than neutralize, all secreted cytokines, cytokine-dependent responses are not inhibited. The in vivo half-lives of the cytokine-anti-cytokine mAb complexes are sufficiently short to allow cytokine production to be measured every 2-3 days in the same mice. Thus, use of this assay provides a practical and relatively simple and inexpensive way to measure ongoing in vivo cytokine production. Furthermore, the techniques that have been developed to measure in vivo production of IL-4 and IFN-gamma can be applied to in vivo measurement of other molecules that have a short in vivo lifespan, including other cytokines.

Animals↗

PubMed1998

In vivo IL-4 responses to anti-IgD antibody are MHC class II dependent and beta 2-microglobulin independent and develop normally in the absence of IL-4 priming of T cells.

A crucial role for CD1-responsive, MHC class II-unrestricted T cells in the generation of T cell IL-4 responses is suggested by the: 1) requirement for IL-4 to prime in vitro IL-4 responses by naive CD4+ T cells; 2) ability of TCR cross-linking to induce CD1-responsive T cells, but not conventional naive T cells, to produce IL-4; 3) failure of anti-IgD Ab to induce an IL-4-dependent IgE response in beta 2-microglobulin-deficient mice, which lack CD1; and 4) reported ability of MHC class II-deficient mice to make IgE responses to anti-IgD Ab. In contrast, the Ag specificity of cytokine and Ab responses in anti-IgD-injected mice and the normal IgE responses made by anti-IgD-treated CD1-deficient mice are difficult to reconcile with this view. We now find that the failure of beta 2-microglobulin-deficient mice to make an IgE response to anti-IgD Ab is caused by their rapid degradation of anti-IgD; sustained anti-IgD treatment induces them to make relatively normal IL-4 and IgE responses. Furthermore, in our study, MHC class II-deficient mice make little or no IL-4 or IgE responses to anti-IgD Ab and beta 2-microglobulin-deficient mice make large in vivo IL-4 responses to anti-CD3 mAb. Finally, although IL-4 priming of T cells for IL-4 production is Stat6 dependent, Stat6-deficient mice make normal IL-4 responses to anti-IgD. Thus, CD1-responsive T cells and other beta 2-microglobulin-dependent T cells are not required to prime conventional CD4+ T cells to make IL-4 responses to anti-IgD in vivo; in fact, the large IL-4 response made in this system does not require IL-4 priming.

Animals↗

PubMed1998

Development of murine allergic asthma is dependent upon B7-2 costimulation.

Allergic asthma is thought to be mediated by CD4+ T lymphocytes producing the Th2-associated cytokines, IL-4, and IL-5. Recently, the costimulatory molecules B7-1 and B7-2, which are expressed on the surface of APC, have been suggested to influence the development of Th1 vs Th2 immune responses. We examined the in vivo role of these costimulatory molecules in the pathogenesis of Th2-mediated allergen-induced airway hyperresponsiveness in a murine model of asthma. In this model, OVA-sensitized A/J mice develop significant increases in airway responsiveness, pulmonary eosinophilia, and pulmonary Th2 cytokine expression following aspiration challenge with OVA as compared with PBS-control animals. Strikingly, administration of anti-B7-2 mAb to OVA-treated mice abolished allergen-induced airway hyperresponsiveness, pulmonary eosinophilia, and elevations in serum IgG1 and IgE levels. Anti-B7-2 treatment of OVA-treated mice reduced both total lung IL-4 and IL-5 mRNA and bronchoalveolar lavage fluid IL-4 and IL-5 protein levels, with no significant changes in IFN-gamma message or protein levels. In contrast, treatment with anti-B7-1 mAbs had no effect on allergen-induced airway hyperresponsiveness, IgE production, or cytokine production, however, it significantly suppressed pulmonary eosinophilia. We conclude that B7-2 provides the necessary costimulatory signal required for the development of in vivo allergic responses to inhaled allergen exposure.

Animals↗

PubMed1998

Exogenous interleukin 7 as a proliferative stimulant of early precursor B cells in mouse bone marrow: efficacy of IL-7 injection, IL-7 infusion and IL-7-anti-IL-7 antibody complexes.

B lymphocyte development in mouse bone marrow (BM) occurs in association with stromal cells which provide essential growth factors, notably interleukin 7 (IL-7). The ability of recombinant IL-7 given systemically by several modes of administration to stimulate proliferation of precursor B cells at successive stages of development was examined. Using immunofluorescence labelling and mitotic arrest, the in vivo proliferative cell dynamics of phenotypically defined B lineage cells was quantitated. Single injections of murine IL-7 (muIL-7) in low and intermediate doses stimulated production both of pro-B cells preceeding the expression of mu heavy chains and large pre-B cells expressing cytoplasmic mu. In contrast, higher doses were not stimulatory. Infusion of muIL-7 from subcutaneous micro-osmotic pumps produced a proliferative wave of TdT+ pro-B cells and pre-B cells followed by elevated numbers of postmitotic small pre-B cells and B cells. Stimulation tended to be followed by secondary oscillations of B lymphopoiesis or an IL-7 refractory state. Pronounced increases in TdT+ pro-B and pre-B cell production resulted from injecting small doses of either muIL-7 or human IL-7 (hIL-7), complexed with anti-IL-7 antibody as carrier protein. The results indicate that exogenous IL-7 at optimal dose can markedly stimulate in vivo B lymphopoiesis from the earliest detectable TdT+ pro-B cell stage onward, and is effective when delivered as a cytokine-anticytokine complex.

Animals↗

PubMed1998

Intestinal nematode parasites, cytokines and effector mechanisms.

Laboratory models of intestinal nematode infection have played an important role in developing our understanding of the immune mechanisms that operate against infectious agents. The type of helper T cell response that develops following infection with intestinal nematode parasites is critical to the outcome of infection. The early events that mediate polarisation of the helper T cell subsets towards either Th1 or Th2 during intestinal nematode infection are not well characterised, but it is likely that multiple factors influence the induction of a Th1 or Th2 type response, just as multiple effector mechanisms are involved in worm expulsion. Costimulatory molecules have been shown to be important in driving T helper cell development down a specific pathway as has the immediate cytokine environment during T cell activation. If helper T cells of the Th2 type gain ascendancy then a protective immune response ensues, mediated by Th2 type cytokines and the effector mechanisms they control. In contrast, if an inappropriate Th1 type response predominates the ability to expel infection is compromised. Equally important is the observation that multiple potential effector mechanisms are stimulated by nematode infection, with a unique combination operating against the parasite depending on nematode species and its life cycle stage. Despite the close association between intestinal nematode infection and the generation of eosinophilia, mastocytosis and IgE it has been difficult to consistently demonstrate a role for these effector cells/molecules in resistance to nematode parasites, although mast cells are clearly important in some cases. It therefore seems that, in general, less classical Th2 controlled effector mechanisms, which remain poorly defined, are probably important in resistance to nematode parasites. Thus, our understanding of both the induction and effector phases remains incomplete and will remain an intense area of interest in the coming years.

Animals↗

PubMed1998

IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis.

Although IL-4 induces expulsion of the gastrointestinal nematode parasite, Nippostrongylus brasiliensis, from immunodeficient mice, this parasite is expelled normally by IL-4-deficient mice. This apparent paradox is explained by observations that IL-4 receptor alpha chain (IL-4Ralpha)-deficient mice and Stat6-deficient mice fail to expel N. brasiliensis, and a specific antagonist for IL-13, another activator of Stat6 through IL-4Ralpha, prevents worm expulsion. Thus, N. brasiliensis expulsion requires signaling via IL-4Ralpha and Stat6, and IL-13 may be more important than IL-4 as an inducer of the Stat6 signaling that leads to worm expulsion. Additional observations made in the course of these experiments demonstrate that Stat6 signaling is not required for IL-4 enhancement of IgG1 production and actually inhibits IL-4-induction of mucosal mastocytosis.

Animals↗

PubMed1997

IL-4 protects against TNF-alpha-mediated cachexia and death during acute schistosomiasis.

To examine the role of the Th2-type response during schistosomiasis mansoni we compared disease progression in wild type (wt), and Th2-response deficient IL-4(-/-) mice. Whereas wt C57BL/6 mice tolerate infection and develop chronic disease, IL-4(-/-) C57BL/6 animals are highly susceptible, exhibiting severe acute cachexia followed by death. Data point toward morbidity in the IL-4(-/-) C57BL/6 mice being mediated by TNF-alpha, possibly through the uncontrolled production of nitric oxide in target organs such as the ileum. We propose that IL-4 prevents severe disease during schistosomiasis by regulating macrophage activation.

Animals↗

PubMed1997

Kinetics of cytokine expression and regulation of host protection following infection with molecularly cloned Venezuelan equine encephalitis virus.

In the mouse model, the arbovirus Venezuelan equine encephalitis virus (VEE) replicates in lymphoid tissues prior to either inducing protective immunity (attenuated VEE mutant) or progressing to lethal encephalitis (virulent parent VEE). To investigate the mechanism of the protective response, cytokine gene expression was examined during the course of the primary in vivo immune response to molecularly cloned, virulent VEE and a single-site attenuated VEE mutant, using a quantitative reverse transcriptase-polymerase chain reaction assay. VEE-induced cytokine gene expression was 100-fold elevated over that of untreated controls for IFN-gamma and IL-6 and 10-fold increased for IL-12, IL-10, and TNF-alpha. There was no qualitative difference in cytokine gene induction comparing mice infected with the attenuated and the virulent VEE; however, there were significant differences in the cytokine gene expression kinetics. In mice infected with the attenuated VEE, elevated cytokine gene expression was delayed 24 hr when compared to mice infected with the virulent parent VEE clone at the same dose. Further, IFN-gamma protein secretion by cells from the draining lymph node mimicked the pattern of IFN-gamma gene induction by cells harvested from the same site. IFN-gamma gene expression was elevated at an earlier time point in mice given virulent V3000 24 hr after attenuated V3032 injection compared to mice infected with virulent V3000 alone. The combined V3000/V3032 infection resulted in host protection. Treatment of mice with IL-12 prior to infection with virulent VEE failed to reduce the severity of infection, while anti-IL-12 antibody did not prevent the early protective effect of attenuated virus. In contrast, administration of anti-IFN-alpha/beta antibody prior to VEE infection worsened virulent VEE disease. These results indicate that the attenuated VEE strain elicits a similar but delayed cytokine response compared to the virulent strain, suggesting that the kinetics of cytokine expression and the particular cytokine produced may influence the development of a host protective response. Furthermore, IFN-alpha/beta, but not IL-12, seems to be a major factor in the induction of early protection against VEE infection and disease.

Animals↗

PubMed1997

CD28 dependence of T cell differentiation to IL-4 production varies with the particular type 2 immune response.

T cell differentiation to effector cell function is required for the development of a type 2 immune response. The T cell surface molecule, CD28, is widely considered to be the principal costimulatory molecule involved in T cell differentiation to effector function, including IL-4 production, although this has been difficult to directly examine in vivo. We have studied in vivo differentiation to T cell effector function during two type 2 immune responses in CD28 knockout mice: the systemic immune response to goat anti-mouse IgD Ab and the mucosal immune response following oral inoculation with the nematode parasite, Heligmosomoides polygyrus. Our results show that in C57BL/6 CD28 knockout mice elevations in IL-4 gene expression and protein secretion are blocked during the immune response to goat anti-mouse IgD, and associated increases in serum IgG1 and IgE are also inhibited to untreated control levels. In marked contrast, T cell differentiation to IL-4 production is comparable in C57BL/6 CD28 -/- and CD28 +/+ H. polygyrus-inoculated mice, and elevations in both serum IgG1 and IgE levels occur. These results indicate that the specific kind of type 2 immune response determines whether T cell differentiation to IL-4 production is CD28 dependent.

Animals↗

PubMed1997

Effects of blocking B7-1 and B7-2 interactions during a type 2 in vivo immune response.

The costimulatory signal provided to T cells through CD28/CTLA-4 interactions is required for in vivo Th cell effector function associated with cytokine production. However, it is uncertain whether the two well-characterized ligands for these molecules, B7-1 and B7-2, differentially influence the consequent development of a type 1 or a type 2 primary response. We have examined the in vivo effects of blocking B7-1 and/or B7-2 ligand interactions on the type 2 mucosal immune response that follows oral infection of mice with the nematode parasite, Heligmosomoides polygyrus. Administration of the combination of anti-B7-1 and anti-B7-2 Abs inhibited H. polygyrus-induced increases in serum IgG1 and IgE levels, the expansion of mesenteric lymph node (MLN) germinal centers, in situ CD4+ T cell expansion, elevated blood eosinophils, and increased intestinal mucosal mast cells. Similarly, both Abs blocked MLN and Peyer's patch cytokine gene expression and elevations in MLN T cell-derived IL-4 protein secretion. However, in the same experiments, administration of either anti-B7-1 or anti-B7-2 Abs alone had little effect on any of these parameters. T cell and B cell activation was also blocked by the combination of anti-B7-2 and a B7-1-specific mutant Y100F CTLA-4Ig construct. These results suggest that to the extent that anti-B7-1 and anti-B7-2 mAbs block B7 interactions, either B7-1 or B7-2 ligand interactions can provide the required costimulatory signals that lead to T cell effector function during a type 2 in vivo immune response.

Animals↗

PubMed1997

Oral but not parenteral interleukin (IL)-12 redirects T helper 2 (Th2)-type responses to an oral vaccine without altering mucosal IgA responses.

Our past studies have shown that the mucosal adjuvant cholera toxin (CT) induces T helper type 2 (Th2) responses with systemic IgG1, IgE and mucosal secretory IgA (S-IgA) antibodies (Abs). In this study, recombinant murine IL-12 (rmIL-12) was given either parenterally or orally to mice orally immunized with tetanus toxoid (TT) and CT to determine whether this cytokine could redirect the CT-induced Th2-type responses and what effect this shift would have on S-IgA Ab responses. Intraperitoneal administration of rmIL-12 shifted TT-specific responses toward Th1-type and resulted in CD4+ T cells producing IFN-gamma and IL-2 with markedly reduced levels of Th2-type cytokines. This cytokine profile was accompanied by increased delayed-type hypersensitivity (DTH) and shifts in serum IgG1 to IgG2a and IgG3 anti-TT Ab responses. Further, serum IgE and S-IgA Ab responses were markedly reduced by parenteral IL-12. When IL-12 complexed to liposomes was given orally both shifts to IgG2a and IgG3 and low IgE Abs again occurred concomitant with enhanced serum IFN-gamma and DTH responses. Interestingly, oral rmIL-12 did not result in significant levels of serum IL-12 nor altered S-IgA Ab responses and resulted in higher levels of some Th2-type cytokines both in vitro and in vivo when compared with parenteral IL-12. Our results show that the shifts in systemic immune responses with intact S-IgA Abs which occur after oral delivery of IL-12-liposomes are due to cytokine effects in the Peyer's patches and suggest new strategies for the targeted manipulation of Th1- and Th2-type responses to mucosal vaccines.

Administration, Oral↗

PubMed1997

The function of costimulatory molecules and the development of IL-4-producing T cells.

The development of IL-4-producing effector T cells during a type 2 immune response requires signaling through B7 ligands, but probably not CD40 ligands. Here, William Gause and colleagues review the still controversial role of CD28 and CTLA-4 on T cells, and B7-1 and B7-2 on antigen-presenting cells, and provide a model to incorporate recent findings.

Abatacept↗

PubMed1997

Cytokine regulation of host defense against parasitic gastrointestinal nematodes: lessons from studies with rodent models.

Studies with rodents infected with Trichinella spiralis, Heligmosomoides polygyrus, Nippostronglyus brasiliensis, and Trichuris muris have provided considerable information about immune mechanisms that protect against parasitic gastrointestinal nematodes. Four generalizations can be made: 1. CD4+ T cells are critical for host protection; 2. IL-12 and IFN-gamma inhibit protective immunity; 3. IL-4 can: (a) be required for host protection, (b) limit severity of infection, or (c) induce redundant protective mechanisms; and 4. Some cytokines that are stereotypically produced in response to gastrointestinal nematode infections fail to enhance host protection against some of the parasites that elicit their production. Host protection is redundant at two levels: 1. IL-4 has multiple effects on the immune system and on gut physiology (discussed in this review), more than one of which may protect against a particular parasite; and 2. IL-4 is often only one of multiple stimuli that can induce protection. Hosts may have evolved the ability to recognize features that characterize parasitic gastrointestinal nematodes as a class as triggers for a stereotypic cytokine response, but not the ability to distinguish features of individual parasites as stimuli for more specific protective cytokine responses. As a result, hosts deploy a set of defense mechanisms against these parasites that together control infection by most members of that class, even though a specific defense mechanism may not be required to defend against a particular parasite and may even damage a host infected with that parasite.

Animals↗

PubMed1997

Interleukin-4 modulates cholinergic neural control of mouse small intestinal longitudinal muscle.

Interleukin-4 contributes to expulsion of certain gastrointestinal parasites and causes intestinal mucosal mastocytosis. Because mast cell-derived mediators are spasmogenic, potentially causing parasitic expulsion, we investigated the effect of interleukin-4 on smooth muscle and the mast cell and mediator dependency of this effect. BALB/c, mast cell-deficient W/Wv mice, 5-lipoxygenase-efficient mice, and their littermate controls were injected with interleukin-4-anti-interleukin-4 antibody complexes that chronically increase serum interleukin-4 levels. Mid-small intestinal segments, hung longitudinally in organ baths, were stimulated electrically or by agonists. The cholinergic response to electrical field stimulation was significantly increased by interleukin-4 treatment in BALB/c but not W/Wv mice. The enhanced cholinergic contraction was not due to increased acetylcholine responsiveness but was dependent on leukotriene D4, since it was reversed by leukotriene D4 receptor antagonism, and not observed in 5-lipoxygenase knock-out mice. Leukotriene D4 responsiveness was unaffected by interleukin-4 treatment. We conclude that interleukin-4 amplifies cholinergic excitation through a mast cell and leukotriene D4-dependent mechanism.

Acetylcholine↗

PubMed1997

Interleukin-4 receptor blockade prevents airway responses induced by antigen challenge in mice.

The functional role of interleukin (IL)-4 in the development of airway hyperresponsiveness (AHR) and pulmonary eosinophilia in response to sensitization and challenge of mice with sheep red blood cells (SRBC) was examined. Control- and SRBC-sensitized A/J mice were treated with an antibody to the murine IL-4 receptor (anti-IL-4R) 3 days before intratracheal challenge with the antigen or vehicle only. Blockade of IL-4R significantly reduced antigen-induced AHR and prevented increases in goblet cells and bronchoalveolar lavage (BAL) eosinophils. Treatment with anti-IL-4R did not affect antigen-induced increases in lung mRNA and BAL protein levels of IL-5 and interferon-gamma or IL-4 mRNA but did significantly increase IL-4 protein levels. Antigen-induced AHR was not reduced by treatment with antibodies to the adhesion molecules, vascular cell adhesion molecule-1 and very late activation antigen-4. Administration of IL-4 over a 7-day period did not increase airway reactivity or induce any changes in BAL cell numbers in naive mice. These results demonstrate that IL-4 is necessary for in vivo development of antigen-induced AHR, goblet cell metaplasia, and pulmonary eosinophilia.

Animals↗

PubMed1996

Interleukin-12 alters helper T-cell subsets and antibody profiles induced by the mucosal adjuvant cholera toxin.

We have shown that systemic administration of rmIL-12 could trigger Th1-type responses to a protein antigen delivered orally with CT as mucosal adjuvant. The most striking finding was that IL-12 could retain its regulatory effects when orally administered and could redirect the immune response to the oral vaccine toward a Th1-type. However, regulation by orally administered IL-12 differed from parenteral treatment with IL-12 since only the latter treatment affected mucosal S-IgA responses. These findings have important implications for the development of mucosal vaccines that induce the desired immune response.

Adjuvants, Immunologic↗

PubMed1996

Dendritic cells can present antigen in vivo in a tolerogenic or immunogenic fashion.

Dendritic cells (DC) are unmatched among APCs in their ability to bind, process, and present Ag. Presentation by such potent APCs, if always immunogenic and never tolerogenic, might stimulate pathogenic autoimmune responses. To determine whether Ag presentation by DC can induce tolerance, mice were injected with a rat IgG2b anti-splenic DC mAb, 33D1, and challenged 13 to 28 days later with a stimulatory rat IgG2b mAb. Injection of mice with 1 ng/100 micrograms of 33D1 rarely induced an anti-rat IgG2b Ab response and, in most mice, induced rat IgG2b-specific T cell and B cell tolerance. Tolerant mice had decreased ability to secrete Ab and make both type 1 and type 2 cytokine mRNA and protein in response to immunization with rat IgG2b. 33D1 was 100- to 1000-fold more potent as a tolerogen than an isotype-matched control rat IgG2b mAb. Injecting mice with aggregated 33D1, 33D1 plus anti-IgD mAb, or 33D1 plus IL-1 induced an IgG1 anti-rat IgG2b Ab response rather than tolerance. IL-1 injected 3 days after 33D1 still induced an Ab response rather than tolerance. Not all anti-DC mAbs are tolerogenic. Injection of a DC-specific hamster anti-CD11c mAb (N418) stimulates an IgG anti-hamster response, and injection of 33D1 plus N418 stimulates both anti-hamster and anti-rat IgG2b responses. These observations indicate that DCs can present Ag in either a tolerogenic or stimulatory manner and suggest that inflammatory stimuli can convert an otherwise tolerogenic signal to a stimulatory signal.

Animals↗