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Biomedical subjects

R L Coffman

Publications and source records attributed to R L Coffman.

At least 19 recordsLinked to original sources
PubMed2005

Airway generation-specific differences in the spatial distribution of immune cells and cytokines in allergen-challenged rhesus monkeys.

BACKGROUND: Accumulation of immune cell populations and their cytokine products within tracheobronchial airways contributes to the pathogenesis of allergic asthma. It has been postulated that peripheral regions of the lung play a more significant role than proximal airways with regard to inflammatory events and airflow obstruction. OBJECTIVE: To determine whether immune cell populations and associated cytokines are uniformly distributed throughout the conducting airway tree in a non-human primate model of allergic asthma. METHODS: We used a stereologic approach with a stratified sampling scheme to measure the volume density of immune cells within the epithelium and interstitium of trachea and 4-5 intrapulmonary airway generations from house dust mite (HDM) (Dermatophagoides farinae)-challenged adult monkeys. In conjunction with immune cell distribution profiles, mRNA levels for 21 cytokines/chemokines and three chemokine receptors were evaluated at four different airway generations from microdissected lungs. RESULTS: In HDM-challenged monkeys, the volume of CD1a+ dendritic cells, CD4+ T helper lymphocytes, CD25+ cells, IgE+ cells, eosinophils, and proliferating cells were significantly increased within airways. All five immune cell types accumulated within airways in unique patterns of distribution, suggesting compartmentalized responses with regard to trafficking. Although cytokine mRNA levels were elevated throughout the conducting airway tree of HDM-challenged animals, the distal airways (terminal and respiratory bronchioles) exhibited the most pronounced up-regulation. CONCLUSION: These findings demonstrate that key effector immune cell populations and cytokines associated with asthma differentially accumulate within distinct regions and compartments of tracheobronchial airways from allergen-challenged primates.

Animals↗
PubMed2001

Modulation of inhaled antigen-induced IgE tolerance by ongoing Th2 responses in the lung.

The normal response to inhaled Ag is the absence of Ag-specific IgE and cytokine production to later Ag challenges. Although the mechanism of this aerosol-induced IgE tolerance is not completely understood, it may prevent sensitization to inhaled Ags, which could otherwise lead to allergy and asthma. We examined the consequences of ongoing Th1 and Th2 responses in the lungs of mice during OVA inhalation to mimic conditions that may subvert tolerance and lead to sensitization. We found that concurrent, secondary Th2 lung responses to keyhole limpet hemocyanin or primary responses to Nippostrongylus larvae or Asperigillus fumagatus extract prevented establishment of IgE tolerance to aerosolized OVA. Intranasal rIL-4 given before OVA aerosolization also prevented establishment of tolerance, whereas concurrent Th1 responses to influenza virus or Mycobacterium bovis bacillus Calmette-Guérin had no effect. However, once established, aerosol tolerance to OVA could not be completely broken by OVA rechallenge concurrent with a secondary Th2 response to keyhole limpet hemocyanin or A. fumagatus extract, or by intranasal rIL-4. These data suggest that the immune status of the lung of an individual may profoundly influence the initial response to inhaled Ag, and that aerosol-induced IgE tolerance may not be appropriately established in individuals undergoing concurrent, Th2-mediated responses to Ags or pathogens.

Administration, Inhalation↗
PubMed2001

Central nervous system expression of IL-10 inhibits autoimmune encephalomyelitis.

Multiple sclerosis, an inflammatory, demyelinating disease of the CNS currently lacks an effective therapy. We show here that CNS inflammation and clinical disease in experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis, could be prevented completely by a replication-defective adenovirus vector expressing the anti-inflammatory cytokine IL-10 (replication-deficient adenovirus expressing human IL-10), but only upon inoculation into the CNS where local infection and high IL-10 levels were achieved. High circulating levels of IL-10 produced by i. v. infection with replication-deficient adenovirus expressing human IL-10 was ineffective, although the immunological pathways for disease are initiated in the periphery in this disease model. In addition to this protective activity, intracranial injection of replication-deficient adenovirus expressing human IL-10 to mice with active disease blocked progression and accelerated disease remission. In a relapsing-remitting disease model, IL-10 gene transfer during remission prevented subsequent relapses. These data help explain the varying outcomes previously reported for systemic delivery of IL-10 in experimental autoimmune encephalomyelitis and show that, for optimum therapeutic activity, IL-10 must either access the CNS from the peripheral circulation or be delivered directly to it by strategies including the gene transfer described here.

Adenoviridae↗
PubMed2001

Interleukin-10 and the interleukin-10 receptor.

Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Animals↗
PubMed2000

T regulatory cells 1 inhibit a Th2-specific response in vivo.

We recently described a new population of CD4(+) regulatory T cells (Tr1) that inhibits proliferative responses of bystander T cells and prevents colitis induction in vivo through the secretion of IL-10. IL-10, which had been primarily described as a Th2-specific cytokine inhibiting Th1 responses, has displayed in several models a more general immune suppression on both types of effector T cell responses. Using an immediate hypersensitivity model in which BALB/c mice immunized with OVA (alum) normally generate Th2-dominated responses, we examined the ability of OVA-specific Tr1 T cell clones to inhibit OVA-specific cytokines and Ab responses. In contrast to Th2 or Th1 T cell clones, transfer of Tr1 T cell clones coincident with OVA immunization inhibited Ag-specific serum IgE responses, whereas IgG1 and IgG2a synthesis were not affected. This specific inhibition was mediated in part through IL-10 secretion as anti-IL-10 receptor Abs treatment reverted the inhibitory effect of Tr1 T cell clones. Although specifically targeted to IgE responses, Tr1 clones' inhibitory effects were more profound as they affected Ag-specific Th2 cell priming both in term of proliferative responses and cytokine secretion. These results suggest that regulatory T cells may play a fundamental role in maintaining the balance of the immune system to prevent allergic disorders.

Adoptive Transfer↗
PubMed2000

Interferon gamma signaling alters the function of T helper type 1 cells.

One mechanism regulating the ability of different subsets of T helper (Th) cells to respond to cytokines is the differential expression of cytokine receptors. For example, Th2 cells express both chains of the interferon gamma receptor (IFN-gammaR), whereas Th1 cells do not express the second chain of the IFN-gammaR (IFN-gammaR2) and are therefore unresponsive to IFN-gamma. To determine whether the regulation of IFN-gammaR2 expression, and therefore IFN-gamma responsiveness, is important for the differentiation of naive CD4(+) T cells into Th1 cells or for Th1 effector function, we generated mice in which transgenic (TG) expression of IFN-gammaR2 is controlled by the CD2 promoter and enhancer. CD4(+) T cells from IFN-gammaR2 TG mice exhibit impaired Th1 polarization potential in vitro. TG mice also display several defects in Th1-dependent immunity in vivo, including attenuated delayed-type hypersensitivity responses and decreased antigen-specific IFN-gamma production. In addition, TG mice mount impaired Th1 responses against Leishmania major, as manifested by increased parasitemia and more severe lesions than their wild-type littermates. Together, these data suggest that the sustained expression of IFN-gammaR2 inhibits Th1 differentiation and function. Therefore, the acquisition of an IFN-gamma-unresponsive phenotype in Th1 cells plays a crucial role in the development and function of these cells.

Animals↗
PubMed2000

Self and nonself stimulatory molecules induce preferential expansion of CD5+ B cells or activated T cells of chagasic patients, respectively.

It has previously been demonstrated that Trypanosoma cruzi-derived antigens (TRP) and human parasite-specific antibodies (Id) stimulate proliferation of cells from Chagasic patients. More recently, we have shown that activated T cells and CD5+ B cells are present in elevated levels in the peripheral blood of Chagasic patients. Upon in vitro exposure to these two different types of stimulatory molecules (TRP, Id), we now show that each of these elevated populations respond differentially to TRP or Id. We found that stimulation with TRP led to preferential expansion of activated T cells, while Id preferentially stimulated CD5+ B cells and CD8+ T cells. Moreover, this expansion of CD5+ B cells by Id was even more pronounced in cultures of cells from Chagasic patients with the severe, cardiac form of the disease, as compared to indeterminate patients. CD8+ T cells comprise approximately 50% of the total T cells in cultures stimulated by Id while in TRP-stimulated cultures their frequency is proportionally lower. Since parasite antigens and antiparasite antibodies are always present in the host during the chronic phase of the disease, they may also be involved with differential activation mechanisms of these cell populations in vivo.

Adult↗
PubMed2000

Effects of interleukin-4 deprivation and treatment on resistance to Trypanosoma cruzi.

Trypanosoma cruzi (Y strain)-infected interleukin-4(-/-) (IL-4(-/-)) mice of strains 129/J, BALB/c, and C57BL/6 showed no significant difference in parasitemia levels or end point mortality rates compared to wild-type (WT) mice. Higher production of gamma interferon (IFN-gamma) by parasite antigen (Ag)-stimulated splenocytes was observed only for C57BL/6 IL-4(-/-) mice. Treatment of 129/J WT mice with recombinant IL-4 (rIL-4), rIL-10, anti-IL-4, and/or anti-IL-10 monoclonal antibodies (MAbs) did not modify parasitism. However, WT mice treated with rIL-4 and rIL-10 had markedly increased parasitism and suppressed IFN-gamma synthesis by spleen cells stimulated with parasite Ag, concanavalin A, or anti-CD3. Addition of anti-IL-4 MAbs to splenocyte cultures from infected WT 129/J, BALB/c, or C57BL/6 mice failed to modify IFN-gamma synthesis levels; in contrast, IL-10 neutralization increased IFN-gamma production and addition of rIL-4 and/or rIL-10 diminished IFN-gamma synthesis. We conclude that endogenous IL-4 is not a major determinant of susceptibility to Y strain T. cruzi infection but that IL-4 can, in association with IL-10, modulate IFN-gamma production and resistance.

Animals↗
PubMed1999

An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation.

A T helper cell type 1-mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RB(high) CD4(+) T cells and can be prevented by cotransfer of the CD45RB(low) subset. The immune-suppressive activities of the CD45RB(low) T cell population can be reversed in vivo by administration of an anti-transforming growth factor beta antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RB(low) population. This population isolated from IL-10-deficient (IL-10(-/-)) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti-murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RB(low) CD4(+) cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RB(high) CD4(+) cells, as CD45RB(low) CD4(+) cells from WT mice were able to inhibit colitis induced by IL-10(-/-) CD45RB(high) CD4(+) cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.

Animals↗
PubMed1999

Cutting edge: mouse IgG1 antibodies comprise two functionally distinct types that are differentially regulated by IL-4 and IL-12.

IL-4-dependent and -independent IgG1 Abs differ in their ability to induce mast cell degranulation as measured by passive cutaneous anaphylaxis (PCA). Mice immunized with OVA or PIII (fraction of Ascaris suum) produced high titers of IgG1 as shown by ELISA and PCA. In contrast, another A. suum fraction, PI, elicited IgG1 Abs with no PCA activity. IgG1 with anaphylactic activity required IL-4, as IgG1 responses to OVA and PIII in IL-4-/- mice gave no PCA. PI-specific IgG1 was IL-4-independent, because no difference was found between the responses of IL-4-/- and IL-4+/+ mice. Significant PCA reactions were elicited, however, with PI-specific IgG1 from IL-12-/- or anti-IFN-gamma Ab-treated mice, although less Ab was measured by ELISA. These results indicate that one type of IgG1 has anaphylactic activity and its synthesis is IL-4-dependent, being inhibited by IL-12 or IFN-gamma; the other lacks this activity and its synthesis is stimulated by IL-12 or IFN-gamma.

Adjuvants, Immunologic↗
PubMed1999

Lungkine, a novel CXC chemokine, specifically expressed by lung bronchoepithelial cells.

We describe a novel mouse CXC chemokine that is selectively expressed in lung epithelial cells and up-regulated in various lung inflammation models. Although this chemokine clusters with other ELR-CXC chemokines, none of them can confidently be assigned to be its human homologue based on sequence identity. In addition, the highly restricted mRNA tissue distribution of this chemokine differentiates it from all previously described chemokines: Lungkine could not be detected in any of the 70 cDNA libraries analyzed corresponding to specific murine cell populations and tissues. High levels of Lungkine mRNA were specifically detected in the lung and at lower levels in fetal lung tissue by Northern blot and in situ hybridization, suggesting a potential role for this chemokine during lung development. Moreover, Lungkine protein is secreted into the airway spaces and induces the in vitro and in vivo migration of neutrophils, suggesting that it is involved in lung-specific neutrophil trafficking. Using fluorescent in situ hybridization, we show that Lungkine maps to mouse chromosome 5.

Amino Acid Sequence↗
PubMed1999

Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis.

The effectiveness of interleukin 10 (IL-10) in the treatment of autoimmune-mediated central nervous system inflammation is controversial. Studies of the model system, experimental autoimmune encephalomyelitis (EAE), using various routes, regimens, and delivery methods of IL-10 suggest that these variables may affect its immunoregulatory function. To study the influence of these factors on IL-10 regulation of EAE pathogenesis, we have analyzed transgenic mice expressing human IL-10 (hIL-10) transgene under the control of a class II major histocompatibility complex (MHC) promoter. The hIL-10 transgenic mice are highly resistant to EAE induced by active immunization, and this resistance appears to be mediated by suppression of autoreactive T cell function. Myelin-reactive T helper 1 cells are induced but nonpathogenic in the IL-10 transgenic mice. Antibody depletion confirmed that EAE resistance is dependent on the presence of the transgenic IL-10. Mice expressing the hIL-10 transgene but not the endogenous murine IL-10 gene demonstrated that transgenic IL-10 from MHC class II-expressing cells is sufficient to block induction of EAE. This study demonstrates that IL-10 can prevent EAE completely if present at appropriate levels and times during disease induction.

Animals↗
PubMed1999

A transgenic model to analyze the immunoregulatory role of IL-10 secreted by antigen-presenting cells.

IL-10 is a cytokine secreted by a wide variety of cells type that has pleiotropic stimulatory and suppressive activities on both lymphoid and myeloid cells in vitro. To analyze the consequences of high IL-10 secretion by APCs in immune responses, we produced transgenic mice expressing human IL-10 directed by the MHC class II Ea promoter. Despite alterations in the development of T and B cells, no gross abnormalities were detected in peripheral lymphocyte populations or serum Ig levels. However, when immunized using conditions that give either a Th2-type or a Th1-type response, IL-10 transgenic mice failed to mount a significant T or B cell immune response to OVA. IL-10 transgenic mice were also highly susceptible to infection with intracellular pathogens like Listeria monocytogenes or Leishmania major, in contrast to IL-10 transgenic mice, where the transgene was express in T cells. Finally, the recently described stimulatory effect of IL-10 on CD8+ T cells was confirmed by the ability of IL-10 transgenic mice to limit the growth of immunogenic tumors by a CTL-mediated mechanism. These results demonstrate, that, depending on the type of immune response, IL-10 can mediate immunosuppressive or immunostimulatory activities in vivo.

Animals↗
PubMed1999

Ability of macrophage subsets to transfer resistance to murine leishmaniasis is dependent on IL-12 production.

Leishmania major, which causes cutaneous leishmaniasis in humans, can also infect mice, in which can cause either a local cutaneous lesion or a fatal disseminated infection. We have previously shown that BALB/c mice injected with antigen-pulsed macrophages derived from bone marrow with granulocyte-macrophage colony-stimulating factor (GMMphi), but not other types of macrophages, were protected from an otherwise lethal infection with L. major The protection induced by GMMphi was shown to be antigen specific and correlated with the induction of a Th1-like response characterized by production of high levels of IFN-gamma, delayed-type hypersensitivity reactivity and long-lived resistance to reinfection. In this report, we show that the protection induced in this disease model correlates with the sustained production of IL-12 synthesis by GMMphi in vitro and in vivo. Moreover, GMMphi deficient in the production of IL-12 were unable to induce protection in this model. Our data, therefore, suggest that a defect in macrophage activation or differentiation may play a significant role in the inability of BALB/c mice to respond effectively to L. major, and this mechanism may also be important in determining resistance to other intracellular parasites.

Animals↗
PubMed1999

Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3).

We have generated rat monoclonal antibodies specific for the mouse eotaxin receptor, C-C chemokine receptor 3 (CCR3). Several anti-CCR3 mAbs proved to be useful for in vivo depletion of CCR3-expressing cells and immunofluorescent staining. In vivo CCR3 mAbs of the IgG2b isotype substantially depleted blood eosinophil levels in Nippostrongyus brasiliensis-infected mice. Repeated anti-CCR3 mAb treatment in these mice significantly reduced tissue eosinophilia in the lung tissue and bronchoalveolar lavage fluid. Flow cytometry revealed that mCCR3 was expressed on eosinophils but not on stem cells, dendritic cells, or cells from the thymus, lymph node, or spleen of normal mice. Unlike human Th2 cells, mouse Th2 cells did not express detectable levels of CCR3 nor did they give a measurable response to eotaxin. None of the mAbs were antagonists or agonists of CCR3 calcium mobilization. To our knowledge, the antibodies described here are the first mAbs reported to be specific for mouse eosinophils and to be readily applicable for the detection, isolation, and in vivo depletion of eosinophils.

3T3 Cells↗
PubMed1999

Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells.

Naive Itk-deficient CD4+ T cells were unable to establish stable IL-4 production, even when primed in Th2-inducing conditions. In contrast, IFNgamma production was little affected. Failure to express IL-4 occurred even among cells that had gone through multiple cell divisions and was associated with a delay in the kinetics and magnitude of NFATc nuclear localization. IL-4 production was restored genetically by retroviral reconstitution of Itk or biochemically by augmenting the calcium flux with ionomycin. In vivo, Itk-deficient mice were unable to establish functional Th2 cells. Development of protective Th1 cells was unimpeded. These data define a nonredundant role for Itk in modulating signals from the TCR/CD28 pathways that are specific for the establishment of stable IL-4 but not IFNgamma expression.

Animals↗