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1.
Cell Immunol ; 393-394: 104779, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37935074

RESUMEN

Inflammatory bowel diseases are associated with dysregulated inflammatory immune responses in the gastrointestinal tract. We found that deficiencies of both IL-4 receptor alpha chain (IL-4Rα) and IL-10 in BALB/c mice (IL-4Rα × IL-10 KO mice) highly induced spontaneous rectal prolapse and diarrhea. These mice also exhibited severe colitis in their cecum and colon and marked elevation of serum proinflammatory cytokines including TNFα and IFNγ. These pathologies were transmittable with their cecal contents containing Helicobacter spp. Their mesenteric LN cells produced TNFα and IFNγ in response to soluble H. hepaticus antigens and high titers of H. hepaticus-specific serum IgG were also detected. These results suggested the important function of IL-4Rα signaling in controlling the intestinal inflammation and the susceptibility to intestinal microbes including H. hepaticus. Therefore, these IL-4Rα × IL-10 KO mice potentially provide the significant murine model for clarifying the causes and control of spontaneous colitis and intestinal inflammation.


Asunto(s)
Colitis , Interleucina-10 , Receptores de Interleucina-4 , Animales , Ratones , Colitis/genética , Helicobacter hepaticus/fisiología , Inflamación/patología , Interleucina-10/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-4/genética , Factor de Necrosis Tumoral alfa
2.
Nat Rev Immunol ; 2(11): 845-58, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12415308

RESUMEN

Established models of T-helper-2-cell dominance in BALB/c mice infected with Leishmania major -- involving the early production of interleukin-4 by a small subset of Leishmania-specific CD4+ T cells -- have been refined by accumulating evidence that this response is not sufficient and, under some circumstances, not required to promote susceptibility. In addition, more recent studies in L. major-resistant mice have revealed complexities in the mechanisms responsible for acquired immunity, which necessitate the redesign of vaccines against Leishmania and other pathogens that require sustained cell-mediated immune responses.


Asunto(s)
Leishmania major/inmunología , Leishmaniasis Cutánea/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Susceptibilidad a Enfermedades/inmunología , Humanos , Interleucina-12/fisiología , Interleucina-4/fisiología , Ratones , Ratones Endogámicos BALB C , Vacunas Antiprotozoos/inmunología , Células TH1/inmunología , Células Th2/inmunología
3.
BMC Immunol ; 13: 6, 2012 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-22292924

RESUMEN

BACKGROUND: The IL-4 receptor α (IL-4Rα) chain has a broad expression pattern and participates in IL-4 and IL-13 signaling, allowing it to influence several pathological components of allergic lung inflammation. We previously reported that IL-4Rα expression on both bone marrow-derived and non-bone marrow-derived cells contributed to the severity of allergic lung inflammation. There was a correlation between the number of macrophages expressing the IL-4Rα, CD11b, and IA(d), and the degree of eosinophilia in ovalbumin challenged mice. The engagement of the IL-4Rα by IL-4 or IL-13 is able to stimulate the alternative activation of macrophages (AAM). The presence of AAM has been correlated with inflammatory responses to parasites and allergens. Therefore, we hypothesized that IL-4Rα⁺ AAM play an active role in allergic lung inflammation. To directly determine the role of AAM in allergic lung inflammation, M-CSF-dependent macrophages (BMM) were prepared from the bone-marrow of IL-4Rα positive and negative mice and transferred to IL-4RαxRAG2(-/-) mice. Wild type TH2 cells were provided exogenously. RESULTS: Mice receiving IL-4Rα(+/+) BMM showed a marked increase in the recruitment of eosinophils to the lung after challenge with ovalbumin as compared to mice receiving IL-4Rα(-/-) BMM. As expected, the eosinophilic inflammation was dependent on the presence of TH2 cells. Furthermore, we observed an increase in cells expressing F4/80 and Mac3, and the AAM marker YM1/2 in the lungs of mice receiving IL-4Rα(+/+) BMM. The BAL fluid from these mice contained elevated levels of eotaxin-1, RANTES, and CCL2. CONCLUSIONS: These results demonstrate that transfer of IL-4Rα + macrophages is sufficient to enhance TH2-driven, allergic inflammation. They further show that stimulation of macrophages through IL-4Rα leads to their alternative activation and positive contribution to the TH2-driven allergic inflammatory response in the lung. Since an increase in AAM and their products has been observed in patients with asthma exacerbations, these results suggest that AAM may be targeted to alleviate exacerbations.


Asunto(s)
Traslado Adoptivo , Eosinófilos/patología , Hipersensibilidad/complicaciones , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Macrófagos/trasplante , Neumonía/complicaciones , Neumonía/patología , Animales , Trasplante de Médula Ósea , Líquido del Lavado Bronquioalveolar , Pollos , Modelos Animales de Enfermedad , Eosinófilos/metabolismo , Humanos , Hipersensibilidad/patología , Pulmón/inmunología , Pulmón/patología , Activación de Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Ovalbúmina/inmunología , Fenotipo , Coloración y Etiquetado , Células Th2/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
4.
J Exp Med ; 198(11): 1741-52, 2003 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-14657224

RESUMEN

Our previous work demonstrated that cytotoxic T lymphocyte (CTL)-mediated tumor immunosurveillance of the 15-12RM tumor could be suppressed by a CD1d-restricted lymphocyte, most likely a natural killer (NK) T cell, which produces interleukin (IL)-13. Here we present evidence for the effector elements in this suppressive pathway. T cell-reconstituted recombination activating gene (RAG)2 knockout (KO) and RAG2/IL-4 receptor alpha double KO mice showed that inhibition of immunosurveillance requires IL-13 responsiveness by a non-T non-B cell. Such nonlymphoid splenocytes from tumor-bearing mice produced more transforming growth factor (TGF)-beta, a potent inhibitor of CTL, ex vivo than such cells from naive mice, and this TGF-beta production was dependent on the presence in vivo of both IL-13 and CD1d-restricted T cells. Ex vivo TGF-beta production was also abrogated by depleting either CD11b+ or Gr-1+ cells from the nonlymphoid cells of tumor-bearing mice. Further, blocking TGF-beta or depleting Gr-1+ cells in vivo prevented the tumor recurrence, implying that TGF-beta made by a CD11b+ Gr-1+ myeloid cell, in an IL-13 and CD1d-restricted T cell-dependent mechanism, is necessary for down-regulation of tumor immunosurveillance. Identification of this stepwise regulation of immunosurveillance, involving CD1-restricted T cells, IL-13, myeloid cells, and TGF-beta, explains previous observations on myeloid suppressor cells or TGF-beta and provides insights for targeted approaches for cancer immunotherapy, including synergistic blockade of TGF-beta and IL-13.


Asunto(s)
Antígenos CD1/inmunología , Células de la Médula Ósea/inmunología , Neoplasias Experimentales/inmunología , Linfocitos T Citotóxicos/inmunología , Factor de Crecimiento Transformador beta/biosíntesis , Animales , Antígenos CD1d , División Celular/inmunología , Femenino , Citometría de Flujo , Inmunofenotipificación , Interleucina-13/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neoplasias Experimentales/patología , Recurrencia , Células Tumorales Cultivadas
5.
Front Microbiol ; 2: 154, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21811487

RESUMEN

Genetically modified B cells are excellent tolerogenic antigen-presenting cells (APCs) in multiple models of autoimmunity. However, the mechanisms of action are still not completely understood. In our models, we generate antigen-specific tolerogenic B cells by transducing naïve or primed B cells with an antigen-immunoglobulin G (peptide-IgG) construct. In order to be transduced, B cells require activation with mitogens such as LPS. We and others have found that LPS stimulation of B cells upregulates the production of IL-10, a key cytokine for maintaining immune tolerance. In the current study, we defined the role of B-cell produced IL-10 in tolerance induction by using IL-10 deficient B cells as donor APCs. We found that peptide-IgG transduced IL-10 KO B cells have the same effects as wt B cells in tolerance induction in an experimental autoimmune encephalomyelitis model. Moreover, we demonstrated that the tolerogenic effect of peptide-IgG B cells was completely abrogated in anti-IL-10 receptor antibody treated recipients. Taken together, our results suggest that tolerance induced by peptide-IgG B-cell gene therapy requires IL-10 from the host but not donor B cells. These data shed important insights into the mechanisms of tolerance induction mediated by B-cell gene therapy.

6.
J Immunol ; 179(4): 2435-44, 2007 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-17675505

RESUMEN

BALB/c IL-4Ralpha(-/-) mice, despite the absence of IL-4/IL-13 signaling and potent Th2 responses, remain highly susceptible to Leishmania major substain LV39 due exclusively to residual levels of IL-10. To address the contribution of CD4(+)CD25(+) T regulatory (Treg) cells to IL-10-mediated susceptibility, we depleted CD4(+)CD25(+) cells in vivo and reconstituted IL-4Ralpha x RAG2 recipients with purified CD4(+)CD25(-) T cells. Although anti-CD25 mAb treatment significantly decreased parasite numbers in IL-4Ralpha(-/-) mice, treatment with anti-IL-10R mAb virtually eliminated L. major parasites in both footpad and dermal infection sites. In addition, IL-4Ralpha x RAG2 mice reconstituted with CD4(+) cells depleted of CD25(+) Treg cells remained highly susceptible to infection. Analysis of L. major-infected BALB/c and IL-4Ralpha(-/-) inflammatory sites revealed that the majority of IL-10 was secreted by the CD4(+)Foxp3(-) population, with a fraction of IL-10 coming from CD4(+)Foxp3(+) Treg cells. All T cell IFN-gamma production was also derived from the CD4(+)Foxp3(-) population. Nevertheless, the IL-4Ralpha(-/-)-infected ear dermis, but not draining lymph nodes, consistently displayed 1.5- to 2-fold greater percentages of CD4(+)CD25(+) and CD4(+)Foxp3(+) Treg cells compared with the BALB/c-infected dermis. Thus, CD4(+)Foxp3(-) T cells are a major source of IL-10 that disrupts IFN-gamma activity in L. major-susceptible BALB/c mice. However, the increase in CD4(+)Foxp3(+) T cells within the IL-4Ralpha(-/-) dermis implies a possible IL-10-independent role for Treg cells within the infection site, and may indicate a novel immune escape mechanism used by L. major parasites in the absence of IL-4/IL-13 signaling.


Asunto(s)
Factores de Transcripción Forkhead/inmunología , Interleucina-10/inmunología , Leishmania major/inmunología , Leishmaniasis Cutánea/inmunología , Receptores de Superficie Celular/deficiencia , Linfocitos T Reguladores/inmunología , Células Th2/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Dermis/inmunología , Dermis/parasitología , Dermis/patología , Oído/parasitología , Oído/patología , Factores de Transcripción Forkhead/genética , Predisposición Genética a la Enfermedad/genética , Inflamación/genética , Inflamación/inmunología , Inflamación/parasitología , Inflamación/patología , Interferón gamma/inmunología , Interleucina-10/antagonistas & inhibidores , Interleucina-13/inmunología , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/parasitología , Ganglios Linfáticos/patología , Depleción Linfocítica , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptores de Superficie Celular/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T Reguladores/patología
7.
Eur J Immunol ; 32(5): 1428-33, 2002 05.
Artículo en Inglés | MEDLINE | ID: mdl-11981831

RESUMEN

Naive CD4(+) T cell populations rapidly produce small amounts of IL-4 in response to T cell receptor-mediated stimulation and may undergo Th2 differentiation without exogenous IL-4. Whether this is due to autocrine IL-4-stimulation or the production of IL-4 by an infrequent naive cell has not been determined. Here we show that single CD4(+) T cells from RAG2-/- T cells receptor transgenic mice primed with their cognate antigen give rise to IL-4-producing cells at a similar frequency whether primed with or without added IL-4, but not if anti-IL-4 is added to the culture. Thus, each founder cell or one or more of its early daughters can produce sufficient IL-4 to drive Th2 differentiation. This indicates that autocrine IL-4 production by naive CD4 T cells can drive the appearance of Th2 cells.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Interleucina-4/metabolismo , Células Th2/inmunología , Animales , Antígenos/administración & dosificación , Linfocitos T CD4-Positivos/citología , Diferenciación Celular , Células Clonales , Proteínas de Unión al ADN/genética , Interleucina-4/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Modelos Inmunológicos , Ovalbúmina/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Interleucina-4/genética , Células Th2/citología
8.
J Immunol ; 170(10): 5152-8, 2003 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-12734362

RESUMEN

The roles of IL-10 and IL-4 receptor signaling were evaluated in a murine model of Leishmania major infection. In previous studies the L. major substrain LV39 caused progressive, nonhealing lesions in BALB/c mice deficient for IL-4R alpha-chain (IL-4R alpha), while substrain IR173 was highly controlled. To explore whether IL-10 is responsible for inducing susceptibility to LV39, wild-type and IL-4R alpha(-/-) mice were treated with anti-IL-10R mAb, and in a genetic approach, the IL-4R alpha(-/-) mice were crossed with BALB/c IL-10(-/-) mice. In contrast to the lack of resistance conferred by IL-4R alpha gene deletion, partial resistance to LV39 was conferred by IL-10 gene deletion or treatment of BALB/c mice with anti-IL-10R mAb. Lesion sizes and LV39 parasite numbers were further and dramatically reduced in both anti-IL-10R-treated IL-4R alpha(-/-) mice and IL-4R alpha x IL-10 double knockouts. Anti-IL-10R mAb treatment further suppressed parasite growth in IL-4R alpha(-/-) mice infected with L. major IR173. Production of IFN-gamma was only increased relative to wild-type or littermate controls in IL-4R alpha(-/-) mice with complementary defects in IL-10. Comparisons of IFN-gamma-treated infected macrophages in vitro indicated that LV39 required 25- to 500-fold greater concentrations of IFN-gamma than IR173-infected macrophages to achieve a similar efficiency of parasite killing. These studies suggest that regardless of parasite substrain, IL-10 is as important as IL-4/IL-13 in promoting susceptibility to L. major and even more so for those substrains that are relatively resistant to IFN-gamma mediated killing.


Asunto(s)
Predisposición Genética a la Enfermedad , Interleucina-10/fisiología , Leishmania major/inmunología , Leishmaniasis Cutánea/inmunología , Receptores de Interleucina-4/fisiología , Transducción de Señal/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Antígenos CD4/inmunología , Inmunidad Innata/genética , Inyecciones Intraperitoneales , Interleucina-10/deficiencia , Interleucina-10/genética , Leishmania major/crecimiento & desarrollo , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/prevención & control , Activación de Macrófagos/genética , Activación de Macrófagos/inmunología , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/parasitología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina/inmunología , Receptores de Interleucina-10 , Receptores de Interleucina-4/deficiencia , Receptores de Interleucina-4/genética , Transducción de Señal/genética , Especificidad de la Especie
9.
J Immunol ; 172(7): 4545-55, 2004 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-15034072

RESUMEN

Recent studies have suggested the IL-4Ralpha expressed on lung epithelium is necessary for TH2-mediated goblet cell differentiation and mucus hypersecretion in a murine model of allergic lung disease. However, the IL-4Ralpha is expressed on numerous cell types that could contribute to the overall pathology and severity of asthma. The relative role of the receptor on these cells has not yet been conclusively delineated. To dissect the contribution of IL-4Ralpha in the development of pulmonary allergic responses, we generated murine radiation bone marrow (BM) chimeras. BM from IL-4Ralpha(+) or IL-4Ralpha(-) mice was transferred into recipient mice that expressed or lacked IL-4Ralpha. In the absence of IL-4Ralpha in recipient mice, there was no goblet cell metaplasia or mucus hypersecretion in response to OVA, even in the presence of TH2 cells and substantial eosinophilic infiltration. More importantly, we found that expression of the IL-4Ralpha on a nonlymphoid, MHC class II(+), BM-derived cell type contributes to the severity of inflammation and mucus production. These results suggest that IL-4 and IL-13 contribute to the development of allergic inflammation by stimulating a complex interaction between IL-4Ralpha(+) cell types of both bone marrow and non-bone marrow origin.


Asunto(s)
Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Pulmón/inmunología , Pulmón/patología , Subunidades de Proteína/fisiología , Receptores de Interleucina-4/fisiología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/patología , Animales , Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/patología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Eosinofilia/inmunología , Eosinofilia/patología , Células Caliciformes/inmunología , Células Caliciformes/patología , Hiperplasia , Pulmón/metabolismo , Metaplasia , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Moco/metabolismo , Subunidades de Proteína/biosíntesis , Quimera por Radiación/inmunología , Receptores de Interleucina-4/biosíntesis , Índice de Severidad de la Enfermedad , Células Th2/inmunología , Células Th2/trasplante
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