Th2-type Inflammatory Responses Research Articles

Biological Responses to Diesel Exhaust Particles (DEPs) Depend on the Physicochemical Properties of the DEPs

Diesel exhaust particles (DEPs) are the main components of ambient particulate materials, including polyaromatic hydrocarbons (PAHs), n-PAHs, heavy metals, and gaseous materials. Many epidemiological, clinical, and toxicological studies have shown that ambient particles, including DEPs, are associated with respiratory disorders, such as asthma, allergic rhinitis, and lung cancer. However, the relationship between the biological response to DEPs and their chemical composition remains unclear. In this study, we investigated the physicochemical properties of DEPs before toxicological studies, and then administered a single intratracheal instillation of DEPs to mice. The mice were then killed 1, 7, 14 and 28 days after DEP exposure to observe the biological responses induced by DEPs over time. Our findings suggest that DEPs engulfed into cells induced a Th2-type inflammatory response followed by DNA damage, whereas DEPs not engulfed into cells induced a Th1-type inflammatory response. Further, the physicochemical properties, including surface charge, particle size, and chemical composition, of DEPs play a crucial role in determining the biological responses to DEPs. Consequently, we suggest that the biological response to DEPs depend on cell-particle interaction and the physicochemical properties of the particles.

Thymic stromal lymphopoietin mediates breast cancer progression and metastasis (48.9)

Abstract Breast cancer escape and metastasis is an active process that requires inflammation and participation of immune cells. We have previously reported that this is a primary tumor-controlled process which activates lungs to produce CCL17 and CCL22 to facilitate lung metastasis together with the recruitment of CCR4+ regulatory T cells (Tregs). To understand the mechanism of this process, we performed expression array analysis in both metastatic and non-metastatic cancer cells and found that metastatic cells produced thymic stromal lymphopoietin (TSLP), an IL-7-like type 1 inflammatory cytokine that is often associated with the induction of Th2-type allergic responses in the lungs. Moreover, TSLP was also abundantly expressed in variety of human solid tumors, including breast, lung, colon and ovarian cancers. To gain further insights into the role of TSLP in cancer progression, we have blocked TSLP expression in cancer cells and found that TSLP is required for efficient breast cancer escape and metastasis. Moreover, utilizing adoptive transfer studies in TSLPR deficient mice, we demonstrated that by targeting CD4+ T cells to induce Th2-type inflammatory responses, cancer-produced TSLP promoted cancer escape. Taken together, our data indicate that TSLP is an important factor that needs to be controlled to effectively combat with cancer escape.

IL-4 Plays a Pivotal Role in Regulating the Development of Th2 and Th17 Responses in the Airways

RATIONALE: IL-33 is produced by tissue cells, such as airway epithelial cells and endothelial cells, and has been implicated in the development of Th2-type inflammatory responses in mucosal organs. However, the roles for IL-4 in the development of IL-33-mediated airway immunity are unknown. METHODS: Naïve 4get, BALB/cJ (WT) and IL-4 knockout (IL-4 KO) mice were exposed intranasally to a model antigen, endotoxin-free ovalbumin (OVA), with or without IL-33. In vitro splenocyte recall responses to OVA and intracellular expression of cytokines, as well as in vivo airway responses to intranasal challenge with OVA, were studied. RESULTS: Four days after exposure to OVA plus IL-33, naïve 4get mice showed IL-4 expression by CD4+ T cells. After 2 weeks, this response was followed by robust development of OVA antigen-specific, Th2-type CD4+ T cells. Intranasal OVA challenge of WT mice, previously exposed to OVA plus IL-33, provoked airway Th2 cytokine production and eosinophilia. In contrast, intranasal OVA challenge of IL-4 KO mice, previously exposed to OVA plus IL-33, partially impaired the development of OVA-specific Th2-type CD4+ T cells, but enhanced the development of Th17-type CD4+ T cells. These mice also developed airway neutrophilia accompanied by increased airway production of IL-12p40, IL-17 and keratinocyte-derived chemokine. CONCLUSIONS: IL-33 may serve as a potent airway mucosal adjuvant to induce adaptive T cell responses to inhaled antigens. When airways are exposed to IL-33, IL-4 may play a pivotal role to direct to the development of either Th2- or Th17-type CD4+ T cells.

IL-31 Receptor (IL-31RA) Knockout Mice Exhibit Elevated Responsiveness to Oncostatin M

IL-31 signals through the heterodimeric receptor IL-31RA and oncostatin M receptor (OSMR), and has been linked with the development of atopic dermatitis, a Th2 cytokine-associated disease in humans. However, recent studies of IL-31RA knockout (KO) mice have suggested that IL-31 signaling may be required to negatively regulate Th2 type responses rather than exacerbate them. Because those studies were performed on genetically modified mice, we examined whether neutralizing IL-31 with a specific mAb would give similar results to IL-31RA KO mice in two Th2 cytokine-associated immune models. We report no difference in lymphocyte Th2-type cytokine production after Ag immunization between IL-31RA KO mice, mice treated with the IL-31 mAb, or control animals. Second, we tested whether the absence of the IL-31RA subunit in IL-31RA KO mice may allow for increased pairing of the OSMR subunit with another cytokine receptor, gp130, resulting in overrepresentation of the heterodimeric receptor for OSM and increased responsiveness to OSM protein. We found that intranasal OSM challenge of IL-31RA KO mice resulted in increased IL-6 and vascular endothelial growth factor production in the lung compared with wild-type littermate control animals. Moreover, PBS-challenged IL-31RA KO mice already had increased levels of vascular endothelial growth factor, which were further increased by OSM challenge. These data imply that IL-31RA-deficient mice produce increased levels of OSM-inducible cytokines during airway sensitization and challenge, which may be the driving force behind the apparent exacerbation of Th2-type inflammatory responses previously observed in these mice.

The Transcriptional Repressor BCL6 Controls the Suppressive Function of Regulatory T cells and Inhibits Th2 Cytokine Expression by Regulatory T cells (49.10)

Abstract Regulatory T cells (Tregs) expressing the transcription factor FOXP3 represent a distinct lineage of T helper cells indispensable for the maintenance of immune homeostasis and the inhibition of autoimmunity. The transcriptional repressor protein BCL6 critically regulates the immune response. BCL6-deficient mice develop severe and spontaneous inflammation early in life that is frequently lethal. BCL6 is a potent inhibitor of Th2 cell differentiation and is required for differentiation into the follicular helper lineage. However, the role of BCL6 in other T cell subsets is less clear, and little is known about the role of BCL6 in Treg cells despite the fact that BCL6 is an inhibitor of inflammation. We have found that BCL6 is an important regulator of Treg gene expression and function. BCL6-deficient Tregs are hyper-proliferative, are prone towards Th2 cytokine expression and do not suppress inflammation in vivo. Our data indicate that BCL6 is a key inhibitor of Th2 cytokine expression in Treg cells, and that lack of BCL6 activity in Treg cells can lead to abnormal Th2-type inflammatory responses.

Thymic stromal lymphopoietin induces tight junction protein claudin-7 via NF-κB in dendritic cells

Epithelial-derived thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine that triggers dendritic cell (DC)-mediated Th2-type inflammatory responses. The activated DCs can penetrate the epithelium to directly take up antigen without compromising the barrier function. Although it is reported that DCs express tight junction molecules and can establish tight junction-like structures with adjacent epithelial cells to preserve the epithelial barrier, the regulation of expression of tight junction molecules in DCs remains unknown. In the present study, to investigate the mechanical regulation of expression of tight junction molecules in DCs, XS52 DCs that was a long-term DC line established from the epidermis of a newborn BALB/c mouse, were treated with TSLP or toll-like receptor (TLR) ligands. In XS52 cells, tight junction molecules claudin-1, -3, -4, -6, -7, -8, and occludin were detected. mRNA expression of TSLP receptor and all these tight junction molecules was significantly increased in activated XS52 cells after treatment with TSLP. In addition, expression of claudin-7 protein was increased in dose- and time-dependent manner. In XS52 cells, which express TLR2, TLR3, TLR4, and TLR7, but not TLR9, expression of claudin-7 protein was also increased after treatment with ligands of TLR2, TLR4 or TLR7/8, Pam3Cys-Ser-(Lys)4, LPS, or CL097. The NF-kappaB inhibitor IMD-0354 prevented upregulation of claudin-7 after treatment with TSLP or TLR ligands. These findings indicate that TSLP induces expression of tight junction protein claudin-7 in DCs via NF-kappaB as well as via TLRs and may control tight junctions of DCs to preserve the epithelial barrier during allergic inflammation.

Thymic stromal lymphopoietin enhances tight-junction barrier function of human nasal epithelial cells

Epithelial-derived thymic stromal lymphopoietin (TSLP) triggers dendritic cell (DC)-mediated Th2-type inflammatory responses and is a master switch for allergic inflammatory diseases. In the present study, the expression and induction of TSLP and the effects of TSLP on the tight-junctional barrier of human nasal epithelial cells (HNECs) have been investigated in order to elucidate the role of TSLP in allergic rhinitis. We have found high expression of TSLP in the epithelium from patients with allergic rhinitis with recruitment and infiltration of DCs. In vitro, TSLP is significantly produced in HNECs after treatment with a toll-like receptor 2 (TLR2) ligand, Pam(3)Cys-Ser-(Lys)(4), and a mixture of interleukin-1beta and tumor necrosis factor-alpha. Treatment with TSLP rapidly enhances the barrier function of cultured HNECs, together with an increase of tight-junction proteins claudin-1, -4, -7, and occludin. The nasal-epithelial-derived TSLP thus not only activates DCs but also preserves the epithelial barrier via the upregulation of tight-junction proteins, thereby regulating antigen sensitization during the early stage of allergic rhinitis.

Lung vascular endothelial growth factor expression induces local myeloid dendritic cell activation

We previously demonstrated that vascular endothelial growth factor (VEGF) expression in the murine lung increases local CD11c+MHCII+ DC number and activation. In this study, employing a multicolor flow cytometry, we report increases in both myeloid (mDC) and plasmacytoid (pDC) DC in the lungs of VEGF transgenic (tg) compared to WT mice. Lung pDC from VEGF tg mice exhibited higher levels of activation with increased expression of MHCII and costimulatory molecules. As VEGF tg mice display an asthma-like phenotype and lung mDC play a critical role in asthmatic setting, studies were undertaken to further characterize murine lung mDC. Evaluations of sorted mDC from VEGF tg lungs demonstrated a selective upregulation of cathepsin K, MMP-8, -9, -12, and -14, and chemokine receptors as compared to those obtained from WT control mice. They also had increased VEGFR2 but downregulated VEGFR1 expression. Analysis of chemokine and regulatory cytokine expression in these cells showed an upregulation of macrophage chemotactic protein-3 (MCP-3), thymus-expressed chemokine (TECK), secondary lymphoid organ chemokine (SLC), macrophage-derived chemokine (MDC), IL-1beta, IL-6, IL-12 and IL-13. The antigen (Ag) OVA-FITC uptake by lung DC and the migration of Ag-loaded DC to local lymph nodes were significantly increased in VEGF tg mice compared to WT mice. Thus, VEGF may predispose the lung to inflammation and/or repair by activating local DC. It regulates lung mDC expression of innate immunity effector molecules. The data presented here demonstrate how lung VEGF expression functionally affects local mDC for the transition from the innate response to a Th2-type inflammatory response.

Allergen‐induced in vitro expression of IL‐18, SLAM and GATA‐3 mRNA in PBMC during sublingual immunotherapy

Signalling lymphocytic activation molecule (SLAM) and interleukin (IL)-18 induce interferon (IFN)-gamma production from Th1 cells. The allergen-induced SLAM and IL-18 mRNA expressions are increased during subcutaneous immunotherapy (SCIT), but nothing is known about their role during sublingual immunotherapy (SLIT). Transcription factor GATA-3 is associated with Th2 cells but its role in SCIT and SLIT is yet unexplored. This study was undertaken to analyse the allergen induced in vitro mRNA expression of IL-18, SLAM and GATA-3 in peripheral blood mononuclear cells (PBMC) of children with allergic rhinitis (AR) during SLIT. Ten patients with AR undergoing pollen SLIT with a weekly dose of 200,000 SQ-U, 10 with 24,000 SQ-U of mixture of Betula verrucosa, Corylus avellana and Alnus glutinosa and 10 with placebo were included. Peripheral blood mononuclear cell were stimulated with birch extract prior to, after 1 and 2 years of the treatment. The mRNA expression was assessed using kinetic real-time RT-PCR (TaqMan); Applied Biosystems, Foster City, CA, USA). The expression of IL-18 mRNA was increased in the high-dose group in comparison to the placebo group after 1 year of therapy (P = 0.028) and had an inverse correlation with the late phase skin reaction after the second study year (r = -0.41, P = 0.041). SLAM mRNA expression increased in the high-dose group from baseline to 1 year (P = 0.028) and correlated with IL-10 (r = 0.96, P < 0.0001) and transforming growth factor-beta (r = 0.80, P = 0.0037) mRNA expression. No significant changes were seen in GATA-3 mRNA expression. During SLIT, IL-18 and SLAM are upregulated, suggesting that the Th2 type inflammatory response is downregulated during SLIT by increased Th1 type response.

A possible role for TSLP in inflammatory arthritis

Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine that triggers dendritic cell-mediated Th2-type inflammatory responses and is considered as a master switch for allergic inflammation. In this study, we found increased levels of TSLP and, also TNF-α as previously reported, in synovial fluid specimens derived from patients with rheumatoid arthritis (RA) when compared with those from patients with osteoarthritis (OA). In addition, TNF-α up-regulated TSLP expression in RA- and OA-derived synovial fibroblasts, which was inhibited by IFN-γ. Furthermore, anti-TSLP neutralizing antibody ameliorated a TNF-α-dependent experimental arthritis induced by anti-type II collagen antibody in mice. Collectively, these results suggest that TSLP, as a downstream molecule of TNF-α, may be involved in the pathophysiology of inflammatory arthritis. TSLP might thus play a role not only in allergic diseases but also in inflammatory arthritis such as RA.

Boosting Interleukin-10 Production: Therapeutic Effects and Mechanisms

More than forty cytokines have been extensively researched on the molecular structure, cell signaling and transduction pathway. With respect to cytokine-regulating therapy in immunological imbalance however, the reported results are conflicting because of the pleiotropic functions and the intricate interactions of the cytokine network. In this review, we outline the observations on interleukin-10 (IL-10) upregulatory therapy. Despite varying opinions on its therapeutic effects for different disorders, IL-10 has been considered a potential anti-inflammatory cytokine. Numerous studies support the view that IL-10 shows a strong suppressive effect on Th1 lymphocytes, antigen presenting cells and the production of inflammatory mediators. It is also noticeable that recent research has revealed the relationship between IL-10 induced antigen specific regulatory CD4+ T cells and antigen specific immune tolerance. This specific regulation was mediated in part through IL-10 secretion, because anti-IL-10 treatment reverted the inhibitory effect of regulatory T cell clones. In different models, these cells were shown to inhibit both Th1 and Th2-type inflammatory responses through the secretion of IL-10. With the presence of IL-10, regulatory T cells may induce peripheral immune tolerance. Exogenous administration, transgenic expression and endogenous stimulative agents of IL-10 have been used for a variety of inflammatory diseases, autoimmune diseases and allograft rejection in patients and experimental models. A therapeutic intervention with drug inducing endogenous IL-10 may be more practical than an exogenous administration of IL-10 with transient effect. Although further investigation on gene regulation of IL-10 is necessary, increasing studies have been reported concerning the attempt to develop the agents, which could promote endogenous IL-10 production for the treatment of immunological disorders and inflammatory diseases. With some unclear mechanisms, these agents have strongly upregulated IL-10 production in vitro or in vivo. Reported IL-10 upregulatory agents have shown promising prospects for remission of autoimmune diseases and inflammatory diseases and have even induced antigen specific immune tolerance. It is interesting that the IL-10 upregulatory effect of several traditional immunosuppressive drugs has been detected, e.g. glucocorticoid, which is considered "not more as an immunosuppressive drug but an immune modulating agent". Approximately twenty IL-10 upregulatory agents as instances are described in the present review. In addition, their therapeutic effects in various diseases are discussed.

CD44, but not l‐selectin, is critically involved in leucocyte migration into the skin in a murine model of allergic dermatitis

CD44 and l-selectin (CD62L) are major adhesion receptors that mediate leucocyte recruitment at inflammatory sites and lymph nodes, by supporting cell rolling under blood flow. Both CD44 and CD62L have been implicated in inflammatory skin disorders, but their specific involvement in an immediate-type allergic reaction remains uncertain. We used mice deficient in CD44 or CED62L or both in order to determine whether one or both of these molecules were required for leucocyte extravasation in an atopic dermatitis-like allergic response. Wild-type (WT) mice and mice deficient in CD44, CD62L or both were immunized with ovalbumin (OVA). Inflammatory reaction in the ear was elicited once by means of intradermal injection of OVA. Effective sensitization of CD62L knockout (KO) mice required intraperitoneal antigen injection; however, OVA-specific T helper 2 (Th2)-type immune responses and IgE production in mice lacking CD44, CD62L or both were comparable to those in WT mice following intraperitoneal immunization. We employed intravital videomicroscopy to monitor the recruitment of fluorescence-labelled leucocytes to the ear tissue following challenge with OVA. The number of adherent leucocytes was significantly reduced in CD44 KO and CD44/CD62L double KO mice, indicating that CD44 was involved in firm adhesion, the committed step of leucocyte extravasation. Histology of the OVA-challenged ears showed a diminished leucocyte infiltration in the ears of CD44 KO and double KO mice. The results of our study demonstrate that CD44, but not CD62L, is required for leucocyte extravasation during a Th2-type inflammatory response.

Prostaglandin D2 reinforces Th2 type inflammatory responses of airways to low-dose antigen through bronchial expression of macrophage-derived chemokine.

PGD2, a lipid mediator released from mast cells, is known to participate in allergic reactions. However, the mechanism by which PGD2 contributes to such reactions remains unclear. We established a novel experimental model of asthma that permitted direct assessment of the role of PGD2 in airway inflammation. Antigen-sensitized mice were exposed to aerosolized prostaglandin D2 (PGD2) 1 d before challenge with low-dose aerosolized antigen. Not only the numbers of eosinophils, lymphocytes, and macrophages but also the levels of IL-4 and IL-5 in bronchoalveolar lavage fluid were higher in PGD2-pretreated mice than in control mice. The expression of macrophage-derived chemokine (MDC), a chemoattractant for Th2 cells, was greater in PGD2-pretreated mice than in control. Injection of anti-MDC antibody into PGD2-pretreated mice markedly inhibited inflammatory cell infiltration as well as Th2 cyto-kine production after antigen challenge. These results indicate that PGD2 accelerates Th2 type inflammation by induction of MDC. Our results suggest that this mechanism may play a key role in the development of human asthma and that MDC might be a target molecule for therapeutic intervention.

The complex role of interleukin-10 in autoimmunity

Interleukin-10 (IL-10) is a cytokine that has been tested in different clinical trials based on its ability to down regulate T helper 1-type responses, namely IFN-γ secretion and activation of monocytes/macrophages. There is also evidence in different animal models, that IL-10 could be useful in controlling Th2-mediated inflammatory processes. However, IL-10 also displays immunostimulatory properties especially on B cells and activated CD8 +T cells. These seemingly divergent effects may explain the apparent lack of activity or adverse effects observed after IL-10 treatment in several animal models or clinical trials. Nevertheless, the ability of IL-10 to induce the differentiation of a subset of regulatory CD4 +T cells (Tr1) and the importance of IL-10 for the in vivo function of regulatory T cells tends to support the view of IL-10 as a crucial cytokine in the control of immune responses. In different in vivo models, these cells were shown to inhibit Th1 and Th2-type inflammatory responses through the secretion of IL-10. These Tr1 cells may thus be used in specific cellular therapy in order to deliver IL-10 precisely at the site of inflammation.

Idiopathic eosinophilic esophagitis is associated with a TH2-type allergic inflammatory response

Background: Idiopathic eosinophilic esophagitis (IEE) is a chronic-inflammatory disorder of the esophagus of unknown origin. The established cornerstone of diagnosis is a dense infiltration of the esophagus with eosinophils, but neither the precise pattern of inflammatory cell infiltration nor the mechanisms that likely contribute to induction and maintenance of the inflammatory response have been described. Objective: The intention of this study was to characterize the esophageal inflammatory infiltrate and the expression of cytokines in the esophagus in this disease. In addition, we searched for immunologic abnormalities of blood leukocytes to exclude major primary hyporeactive and hyperreactive conditions of the immune system. Methods: Infiltration of inflammatory cells in the esophagus, stomach, and duodenum was analyzed by immunohistochemistry through use of mAbs against lineage-associated molecules. Cytokine expression was measured by ELISA and immunohistochemical analysis. Lymphocyte subpopulations in blood were determined by means of flow cytometry. Results: High eosinophil infiltration into the esophageal squamous epithelium was observed in patients with IEE but not in control subjects. Interestingly, increased T-cell and mast cell numbers were also found within the epithelium in these patients. In contrast, the numbers of inflammatory cells were not increased in the stomach and duodenum in patients with IEE, suggesting a specific inflammatory process within the esophagus. Moreover, increased expression of IL-5 and TNF-α was observed in esophageal epithelial biopsy specimens. The distribution of lymphocyte subsets in the peripheral blood and their capacity to generate cytokines did not reflect the changes observed at the inflammatory site. Conclusions: IEE is a selective inflammatory response of the esophagus. T cells, IL-5, eosinophils, and IgE-mediated mechanisms appear to be involved, giving rise to the possibility that allergic reactions might play a role in the pathogenesis of the disease. (J Allergy Clin Immunol 2001;108:954-61.)

Expression of chemokine receptors by lung T cells from normal and asthmatic subjects.

The lung is an important tertiary lymphoid organ with constant trafficking of T cells through the lung in both health and disease. T cell migration is controlled by a combination of adhesion receptors and chemokines expressed on vascular endothelium and in the tissue, often in an organ-specific manner. This leads to selective accumulation of different T cell subsets, a process called lymphocyte homing. There is evidence for a distinct lung-homing pathway, but no specific lung-homing receptors have been described. We analyzed the chemokine receptor profile of lung T cells to determine the extent to which lung T cells shared homing pathways with other organs such as the gut and skin. In addition, we compared expression of receptors in normal and asthmatic individuals to determine whether different pathways were used in health and disease. We observed that lung T cells expressed a profile of chemokine and adhesion receptors distinct from that of gut- and skin-homing T cells although no chemokine receptor specific for the lung was found. In particular, lung T cells expressed CCR5 and CXCR3, but not CCR9 or cutaneous lymphocyte Ag, and only low levels of CCR4 and alpha(4)beta(7). No differences were observed between lung T cells from normal vs asthmatic subjects. This study provides added support for the concept of a lung-homing pathway separate from other mucosal organs such as the gut and suggests that the chemokine pathways that control T cell migration in normal homeostasis and Th2-type inflammatory responses are similar.

The role of co-stimulation in airway inflammation.

There is considerable evidence to support an important role for co-stimulatory molecules in regulating the proliferation and activation of T cells in the immune response. Of particular relevance is the interaction between CD28 on T cells and B7 expressed on the surface of antigen presenting cells (APCs). CTLA-4, another molecule present on activated T cells may downregulate T cell activity, but its role remains uncertain. CTLA4-Ig, a fusion protein consisting of the extracellular domain of CTLA4 and the Fc portion of human immunoglobulin G1 (IgG1), has been useful for studying the role of CD28/B7 interactions in immune responses. A number of studies have shown that CTLA4-Ig can switch off T cell activation. In an ovalbumin sensitive murine model of asthma, CTLA4-Ig treatment suppressed the response to inhaled allergen (increased airway hyperresponsiveness [AHR], IgE production, recruitment of eosinophils into the lungs, production of IL-4, IL-5, and IL-10 and increased IFNgamma production from CD3-TCR-activated T cells). Anti B7-2 treatment has similar effects suggesting that interaction of B7-2 with CD28 is important in the development of a Th-2 type inflammatory response in mice. Recent observations have been of relevance to human allergic disease. In vitro studies have shown that CTLA4-Ig or anti-B7-2 antibody can inhibit allergen-induced proliferation and cytokine production by peripheral blood mononuclear cells from atopic subjects. The role of co-stimulation has been studied in a human bronchial explant model of asthma. CTLA4-Ig fusion protein effectively blocked allergen-induced production of IL-5 and IL-13 in bronchial explants from atopic asthmatics. These studies confirm the requirement for interaction between co-stimulatory molecules in cytokine production and allergic inflammation, and point to the CD28-B7 pathway as being important to the allergen-induced inflammation in asthma. Studies of organ transplantation in primates suggest that CTLA4-Ig is extremely effective in preventing organ rejection. While phase 1 clinical trials have shown CTLA-4-Ig treatment of patients with psoriasis vulgaris to be well tolerated and to result in clinical improvement, its role in asthma management merits further investigation.

Antibodies to the IL-12 Receptor β2 Chain Mark Human Th1 But Not Th2 Cells In Vitro and In Vivo

AbstractGreat attention has been placed on the possibility of distinguishing Th1 from Th2 cells on the basis of differential expression of surface receptors. We have recently shown that the differential expression of the IL-12Rβ2 chain in Th1 and Th2 cells, as measured at the mRNA level, accounts for an important regulatory mechanism in the differentiation of the two cell subsets. In this study, we identify IL-12R expression at the protein level. We have generated an anti-IL-12Rβ2-specific mAb and analyzed IL-12Rβ2 expression on polarized Th cell populations generated in vitro and on T cells derived from patients with Th1- or Th2-mediated inflammatory conditions. Although IL-12Rβ2 was absent in freshly isolated PBMC and in cord blood cells, we were able to detect IL-12Rβ2 expression selectively in differentiated Th1 and T cytotoxic 1, but not Th2 or T cytotoxic 2 cells. In the presence of IL-12, cell surface expression of the IL-12Rβ2 subunit was readily detected on T cells after 24 h, reached the maximum at day 5, and declined thereafter. Most importantly, the anti-IL-12Rβ2 mAb recognizes lung T cells from patients with sarcoidosis, a disease characterized by a typical cell-mediated, Th1-type inflammatory response. In contrast, IL-12Rβ2 was absent in lung T cells from patients with allergic asthma, a disease characterized by a Th2-type inflammatory response. The mAb reported in this study should represent a powerful tool to investigate the role of Th1 and Th2 cells in inflammatory conditions and to monitor therapies aimed at altering the balance of Th cell subsets.