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Biomedical subjects

R L Coffman

Publications and source records attributed to R L Coffman.

At least 91 records · Page 5Linked to original sources
PubMed1994

IgE and eosinophil regulation in a murine model of allergic aspergillosis.

Exposure of BALB/c mice to Aspergillus fumigatus (Af), the antigen responsible for causing allergic bronchopulmonary aspergillosis in humans, caused elevated levels of serum immunoglobulin E (IgE) and peripheral blood and lung eosinophilia similar to that observed in the human disease. We have investigated the role of interleukin-4 (IL-4), IL-5 and interferon-gamma in regulating IgE and eosinophilia in the mouse model. Animals were immunized by intraperitoneal injections of soluble Af antigens adsorbed to alum. These animals developed elevated IgE and Af specific IgG1 and were then treated with anticytokine monoclonal antibodies before the final exposure to particulate Af antigens by the intranasal route. The results showed that anti-IL-5 abrogated eosinophilia in mice, while those treated with anti-IL-4 retained the same or reduced IgE levels compared to pretreatment levels. All anti-IL-5, anti-IFN-gamma, and control antibody-treated animals showed enhanced IgE levels. Anti-IFN-gamma treatment of mice resulted in marked enhancement of eosinophilia compared to all other groups. Eosinophil numbers observed in the histological sections of the lungs confirmed the eosinophilia detected in the peripheral blood. These results indicate that the increase in IgE and eosinophils after exposure to Af antigens in BALB/c mice are due to Af-induced production of IL-4 and IL-5 and that both IgE and eosinophilia are independently regulated.

Animals↗
PubMed1994

Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells.

We have described a murine model of IBD that was induced in C.B-17 scid mice by transfer of the CD45RBhi subpopulation of CD4+ T cells from normal BALB/c mice and could be prevented by cotransfer of the CD45RBlo CD4+ T cell subset. Here we have dissected the mechanism of pathogenesis of IBD in this model and used this information for rational immunotherapy of the disease. CD4+ cells from diseased mice displayed a highly polarized Th1 pattern of cytokine synthesis upon polyclonal stimulation in vitro. The administration of anti-IFN gamma MAb to mice soon after T cell transfer prevented development of colitis for up to 12 weeks. Continual neutralization of TNF with anti-TNF MAbs reduced the incidence of severe disease; however, neutralization of TNF during only the first 3-4 weeks had no effect. Severe colitis was completely abrogated in mice treated systemically with rIL-10, but not with rIL-4.

Animals↗
PubMed1994

Particulate Aspergillus fumigatus antigens elicit a TH2 response in BALB/c mice.

BACKGROUND: In order to understand the immunoregulation in allergic aspergillosis, a murine model was developed by exposing animals to particulate and soluble antigens of Aspergillus fumigatus. METHODS: BALB/c mice were exposed to soluble Aspergillus antigen intranasally. Animals showing moderate levels of IgE were subsequently exposed to soluble antigen or antigen conjugated to polystyrene beads intranasally. The IgE and IgG1 in the sera and the eosinophils in the blood and lungs were studied. The spleen and lung mononuclear cells were stimulated with both concanavalin A and antigen and evaluated for production of interleukin (IL)-4, IL-5, IL-10, and interferon-gamma. RESULTS: Animals exposed to particulate antigens showed more elevated serum IgE levels and increased numbers of eosinophils in the blood and lungs than those exposed to soluble antigen. Lung cell cultures from animals exposed to particulate antigens when stimulated with Aspergillus produced IL-4 and IL-5, indicating a TH2 type of response. Animals exposed to soluble antigens showed a weaker TH2 response, as evidence by low IgE levels in sera, fewer eosinophils in the blood, and low levels of cytokine production from lung and spleen cells. CONCLUSION: The results indicate that the physical nature of the antigen may have a major role in determining the type of immune response of the host.

Administration, Inhalation↗
PubMed1994

Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus.

The loss of T helper cell (TH) function in asymptomatic HIV type 1-infected individuals occurs before the decline in CD4+ T cells. At least part of the loss in TH function results from changes in immunoregulatory cytokine profiles. To investigate the role of IL-10 in such dysregulation, we tested whether: (a) expression of IL-10-specific mRNA would be upregulated in PBMC from asymptomatic, HIV-infected (HIV+) individuals; (b) PBMC from these same individuals would produce increased levels of IL-10 when stimulated in vitro with phytohemagglutinin; and (c) defective antigen-specific TH function could be restored by anti-IL-10 antibody. We observed that IL-10-specific mRNA was marginally upregulated, and increased levels of IL-10 were produced by PBMC from HIV+ individuals compared with PBMC from uninfected individuals. Those individuals whose TH function was more severely compromised produced higher levels of IL-10. Additionally, defective antigen-specific TH function in vitro could be reversed by anti-IL-10 antibody, including the response to HIV envelope synthetic peptides. Furthermore, the antigen-specific TH responses of HIV-uninfected PBMC could be reduced with IL-10, a process reversed by anti-IL-10. These results confirm that the early loss of TH function in HIV+ individuals is due at least in part to cytokine-induced immune dysregulation, and support the hypothesis of a switch from a predominant type 1 state to a predominant type 2 condition in HIV infection.

Antigens, CD↗
PubMed1994

Cell-mediated immunity to schistosomes. Evaluation of mechanisms operating against lung-stage parasites which might be exploited in a vaccine.

This report describes parallel studies examining T cell and cytokine responses to Schistosoma mansoni in mice and man. The prevalence of IFNg production amongst murine (C57BL/6) T cell lines and clones, plus good DTH reactivity by IFNg-secreting clones, highlights the predominance of the Th1 response in the pulmonary immunity characteristics of the murine irradiated vaccine model. In human studies, effects of anti-cytokine antibodies on the proliferation of PBMC from human patients to various soluble schistosome antigen preparations have been examined. Data suggest that both Th1 (against early antigens) and Th2 (against late antigens) responses are present. A role for IL-10 is highlighted in chronic intestinal, but not acute or chronic hepatosplenic patients, as a downregulator of responses which are associated with morbidity and are against late stage antigens.

Acute Disease↗
PubMed1993

Modulation of murine macrophage function by IL-13.

Activated macrophages are important effector cells for immune response to many parasites and immune responses are strongly modulated in part by the effect of Th cell-derived cytokines on macrophages. Th1-derived cytokines such as IFN-gamma are strong stimulators of macrophage activation, while cytokines produced by Th2 cells, including IL-4 and IL-10, have been shown under some conditions to inhibit macrophage activities associated with inflammatory responses. IL-13, a recently described cytokine produced by Th2 cells, is also capable of down-modulating macrophage activity in a manner similar to that previously described for IL-4. Treatment of activated macrophages with IL-13 reduces the production of inflammatory monokines in response to IFN-gamma or LPS, both potent stimulators of these factors. In addition, IL-13 decreases the production of nitric oxide by activated macrophages. Nitric oxide has been implicated in both macrophage cytotoxicity and macrophage-associated immunosuppression. The suppression of nitric oxide by IL-13 leads to a decrease in parasiticidal activity by activated macrophages. However, our data indicate that IL-13 has pleiotropic effects, while the inflammatory potential of activated macrophages is significantly reduced, the potential of other macrophage subsets is unimpaired. These data indicate that IL-13 could be a potent modulator of immune responses in vivo, with effects that may embrace both macrophage suppressive and macrophage potentiating functions.

Animals↗
PubMed1993

Leishmania antigens presented by GM-CSF-derived macrophages protect susceptible mice against challenge with Leishmania major.

Leishmania major, a causative agent of leishmaniasis, in humans is also capable of infecting mice. Several strains of mice, including the BALB/c strain, are unable to mount appropriate T cell responses to the parasite and develop a fatal, disseminated infection. We present evidence that injection of granulocyte-macrophage-CSF derived bone marrow macrophages (GMM phi), previously incubated with L. major antigens, into BALB/c mice before infection, induced a Th1-dominated response and subsequent healing. Injection of BALB/c mice with GMM phi pulsed with irrelevant Ag, or other macrophages pulsed with L. major Ag, failed to protect against L. major challenge. Protection induced by L. major Ag-bearing GMM phi correlated with the induction of a Th1-like response with the production of high levels of IFN-gamma, delayed-type hypersensitivity reactivity and long-lived resistance to reinfection. GMM phi-T cell interaction, rather than parasite killing by GMM phi, appeared to be a crucial step and there was a strong correlation between ability to function as APC in vitro and induction of protective immunity in vivo. These data suggest that presentation of Ag by a population of L. major Ag-bearing GMM phi can activate Th1 cells in BALB/c mice, leading to a protective immune response to parasite invasion. This implies that the nature of the APC population which presents Ag may influence the response to that Ag in vivo.

Animals↗
PubMed1993

Reconstitution of C.B-17 scid mice with BALB/c T cells initiates a T helper type-1 response and renders them capable of healing Leishmania major infection.

C.B-17 scid mice, which were found to be very susceptible to infection with Leishmania major, were reconstituted with various doses of T cells, T plus B cells or unfractionated spleen cells from nonhealer BALB/c mice. All reconstitution protocols, except for the transfer of very high numbers of BALB/c spleen cells, led to a spontaneously healing infection and resistance to reinfection, rather than the lethal, nonhealing infection typical of BALB/c mice. These healing responses were associated with a strong T helper 1 (Th1)-like response characterized by delayed-type hypersensitivity (DTH) responsiveness, but no elevation of serum IgE, and by the production of high levels of interferon-gamma (IFN-gamma), but no interleukin-4 (IL-4) by lymph node and spleen cells after restimulation with antigen in vitro. The development of this Th1 response from BALB/c Th cells requires IFN-gamma during the initial infection period. Treatment of scid mice with a single injection of neutralizing anti-IFN-gamma antibody prior to infection and reconstitution prevented healing and permitted the development of a Th-2 like response as indicated by elevated serum IgE, but no DTH, and by the production of IL-4, but very little IFN-gamma, after antigen stimulation in vitro. As few as 10(4) transferred T cells led to a Th1-like response, suggesting that the IFN-gamma is of host rather than donor origin. The transfer of very high numbers (7.5 x 10(7)) of BALB/c spleen cells overcame the effects of the IFN-gamma and led to the nonhealing infection and cytokine pattern characteristic of BALB/c mice. The enrichment or depletion of B cells from the transferred T cells had no measurable effect upon the development of a healing response in reconstituted scid mice.

Animals↗
PubMed1993

Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo.

The lack of cell-mediated (TH1-like) immunity that is often associated with strong humoral immune responses is thought to be due in part to the inhibition of Th1 effector function by the Th2-derived cytokine interleukin-10 (IL-10). This hypothesis, however, is based entirely on results from in vitro studies, wherein IL-10 has been shown to inhibit Th1 cytokine synthesis. In this study we have compared the regulatory effects of both IL-4 and IL-10 on the development of a more complex Th1 effector function in vivo, the development of delayed-type hypersensitivity (DTH) to Leishmania major in mice immune to Leishmania. The results revealed two findings unexpected from in vitro studies with Th1 clones. First, optimal inhibition of the DTH response (up to 70%), assessed by footpad swelling and leukocytic infiltration, required the combination of IL-4 and IL-10, indicating that these two activities synergized to inhibit DTH reactivity. Second, IL-4 inhibited interferon-gamma (IFN-gamma) production by lymph node cells draining the site of antigen challenge as well as did IL-10. The combination of both cytokines was no more effective than either alone. The mechanism by which IL-4 and IL-10 acted to inhibit DTH responses did not appear to be through inhibition of IFN-gamma or tumor necrosis factor production as treatment with antibodies which neutralized these activities failed to inhibit DTH responses. Inhibition of the DTH with IL-4 and IL-10 is the most effective specific regulator of DTH responses reported and the only one capable of modulating tuberculin DTH. These data establish IL-4 and IL-10 as potent inhibitors of Th1 effector function in vivo and suggest their utility in controlling deleterious Th1-mediated inflammatory responses such as occur in some infectious and autoimmune diseases.

Animals↗
PubMed1993

Role of transforming growth factor-beta in the preferential induction of T helper cells of type 1 by staphylococcal enterotoxin B.

Stimulation of murine CD4+ T cells with staphylococcal enterotoxin B (SEB) results in the preferential development of T helper (Th) 1 cells [i.e. high interferon (IFN)-gamma and low interleukin (IL)-4, IL-5 and IL-10]; whereas in response to plate-bound anti-CD3 or anti-T cell receptor-alpha beta, Th1 as well as Th2 cells develop. In the present study, we examined the mechanism which is responsible for the selective Th1 development in the SEB system. The addition of IL-4 resulted in a strong development of Th2 cells showing that SEB stimulation can result in Th2 differentiation. Co-stimulation with anti-CD28 was insufficient in this regard. Lack of Th2 development in the SEB system was in part due to the inhibitory effect of endogenously produced transforming growth factor-beta (TGF-beta), because anti-TGF-beta allowed the development of Th2 cells. Similarly, TGF-beta inhibited Th2 development and stimulated Th1 development in the anti-CD3 system. This shift was only partially prevented by also including IL-4 in the cultures. The effects of TGF-beta could only partially be explained by stimulation of IFN-gamma or inhibition of IL-4 as intermediatory cytokines: (1) TGF-beta stimulated Th1 development even in the presence of anti-IL-4 and anti-IFN-gamma, and (2) a strong inhibitory effect of anti-TGF-beta on Th1 development was still observed when anti-IL-4 and IFN-gamma were simultaneously added to the cultures. It is concluded that SEB favors Th1 development by stimulation of TGF-beta production. Inhibition of Th2 development by TGF-beta is due, in part, to inhibition of IL-4 and stimulation of IFN-gamma, and, in part, to a direct effect of TGF-beta on the responding T cells.

Animals↗
PubMed1993

Endogenous retroviral superantigen presentation by B cells induces the development of type 1 CD4+ T helper lymphocytes.

The endogenous retroviral superantigen, minor lymphocyte stimulating antigen (Mls 1a, encoded by Mtv-7), when presented by highly purified B cells induced the development of a highly polarized population of T helper (Th)1 cells from naive peripheral CD4+ T cells in vitro. Immobilized anti-V beta 6 antibodies similarly generated highly polarized, largely V beta 6+, Th 1 populations in vitro. In the presence of exogenous interleukin-4, both stimuli were capable of generating Th 2, rather than Th 1 populations. Mls 1a presentation by B cells in vivo led to the development of an equally polarized Th 1 population. Using monoclonal antibodies against interferon-gamma and transforming growth factor-beta, it was demonstrated that maximal Th 1 development with either stimulus in vitro was dependent on the endogenous production of these two cytokines. Thus, our results demonstrate that the retroviral encoded superantigen, Mls 1a, drives the development of Th 1 cells both in vitro and in vivo, and they suggest that B cell presentation does not, in itself, lead to the generation of Th 2 cells.

Animals↗
PubMed1993

Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo.

The lack of cell-mediated (Th1-like) immunity that is often associated with strong humoral immune responses is thought to be due in part to the inhibition of Th1 effector function by the Th2-derived cytokine interleukin-10 (IL-10). This hypothesis, however, is based entirely on results from in vitro studies, wherein IL-10 has been shown to inhibit Th1 cytokine synthesis. In this study we have compared the regulatory effects of both IL-4 and IL-10 on the development of a more complex Th1 effector function in vivo, the development of delayed-type hypersensitivity (DTH) to Leishmania major in mice immune to Leishmania. The results revealed two findings unexpected from in vitro studies with Th1 clones. First, optimal inhibition of the DTH response (up to 70%), assessed by footpad swelling and leukocytic infiltration, required the combination of IL-4 and IL-10, indicating that these two activities synergized to inhibit DTH reactivity. Second, IL-4 inhibited interferon-gamma (IFN-gamma) production by lymph node cells draining the site of antigen challenge as well as did IL-10. The combination of both cytokines was no more effective than either alone. The mechanism by which IL-4 and IL-10 acted to inhibit DTH responses did not appear to be through inhibition of IFN-gamma or tumor necrosis factor production as treatment with antibodies which neutralized these activities failed to inhibit DTH responses. Inhibition of the DTH with IL-4 and IL-10 is the most effective specific regulator of DTH responses reported and the only one capable of modulating tuberculin DTH. These data establish IL-4 and IL-10 as potent inhibitors of Th1 effector function in vivo and suggest their utility in controlling deleterious Th1-mediated inflammatory responses such as occur in some infectious and autoimmune diseases.

Animals↗
PubMed1993

Cytokine regulation of T-cell function: potential for therapeutic intervention.

CD4+ T cells, via the cytokines that they produce, play a pivotal role in the induction and regulation of cell-mediated and humoral immunity. Recently it has become clear that the CD4+ T-cell population is heterogeneous and that distinct CD4+ T-cell subsets, defined by their cytokine repertoire, regulate cell-mediated and humoral immune responses. Protective responses to pathogens are dependent on activation of the appropriate TH subset accompanied by its characteristic set of immune effector functions. Evidence to date suggests that the cytokines produced by the TH cells themselves are important regulators of TH subset activation and differentiation. Fiona Powrie and Robert Coffman discuss how manipulation of the levels of these cytokines can be used to alter the balance of TH-cell subsets and illustrate some clinical situations where this may be beneficial.

Animals↗
PubMed1993

Cytokine regulation of T-cell function: potential for therapeutic intervention.

CD4+ T cells, via the cytokines that they produce, play a pivotal role in the induction and regulation of cell-mediated and humoral immunity. Recently it has become clear that the CD4+ T-cell population is heterogeneous and that distinct CD4+ T-cell subsets, defined by their cytokine repertoire, regulate cell-mediated and humoral immune responses. Protective responses to pathogens are dependent on activation of the appropriate TH subset accompanied by its characteristic set of immune effector functions. Evidence to date suggests that the cytokines produced by the TH cells themselves are important regulators of TH subset activation and differentiation. Here, Fiona Powrie and Robert Coffman discuss how manipulation of the levels of these cytokines can be used to alter the balance of TH cell subsets and illustrate some clinical situations where this may be beneficial.

Animals↗