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PubMed1995

Anti-CD3-induced anergy in cloned human Th0, Th1, and Th2 cells.

In the mouse, activation of T cells by T cell receptor (TCR) crosslinking with anti-CD3 antibodies in the absence of a costimulatory signal induces Th1 but not Th2 cell anergy. Furthermore, anti-CD3 induces anergy of Th1- but not Th2-type lymphokine secretion in Th0 cells. This study was designed to determine whether this is also the case in man. Human rye grass allergen Lol p I-specific cloned CD4+ T helper cells of subtypes Th0, Th1, and Th2 were treated with immobilized anti-CD3. The cells were rested for 4 days and then activated under optimal conditions with antigen and antigen-presenting cells (APCs). Cell proliferation and IL-2, IFN-gamma, and IL-4 secretion was determined to test for the anergic state. The initial anti-CD3 treatment induced cell proliferation, IL-2, IFN-gamma, and/or IL-4 secretion by T cells of all three subsets which was followed by an anergic state in Th0, Th1, and Th2 cells as shown by a 51 to > 94% decrease in cell proliferation and IFN-gamma and/or IL-4 secretion after subsequent APC and Lol p I activation. Addition of IL-2 or IL-4 during anti-CD3 treatment of the cells did not prevent unresponsiveness. However, the addition of IL-2 but not IL-4 during APC and Lol p I stimulation partially reversed the anergic state. These data demonstrate that, contrary to the mouse, cloned T cells of all three human T helper cell subtypes are anergized by anti-CD3 TCR activation in the absence of costimulatory signals. The fact that human Th2 cells can be anergized may be important for the development of new treatments in Th2-mediated allergic disorders.

Allergens↗
PubMed2001

Differentiation of resting human peripheral blood gamma delta T cells toward Th1- or Th2-phenotype.

Depending on the microenvironment, murine gamma delta T cells differentiate into either Th1 (IFN-gamma-producing) or Th2 (IL-4-producing) cells. It is unclear, however, whether circulating human peripheral blood gamma delta T cells can be driven into Th1 or Th2 cells by modulation of the priming cytokine milieu. In this study, peripheral blood gamma delta T cells were stimulated by phosphoantigen (isopentenyl pyrophosphate) or Daudi lymphoma cells in the presence of Th1-priming (rIL-12, anti-IL-4 Ab) or Th2-priming (rIL-4, anti-IL-12 Ab) conditions. Single-cell analysis of cytokine secretion (IFN-gamma and IL-4) was performed by flow cytometry after 18 h and after restimulation of expanded gamma delta T cells. The early activation of resting gamma delta T cells was characterized by the induction of IFN-gamma. Priming under Th1 conditions induced a Th1 profile characterized by increased secretion of IFN-gamma and TNF-alpha, while Th2 conditions caused increased production of IL-4 (Th2 profile) by the gamma delta T cells. These results indicate that the major subset of human gamma delta T cells can be polarized into either Th1 or Th2 cytokine pattern depending on the cytokine milieu in which contact with antigen occurs.

Antibodies, Monoclonal↗
PubMed1997

Candida infection following severe trauma exacerbates Th2 cytokines and increases mortality.

Following trauma, there is an increase of Th2 cytokines (IL-4, IL-6, and IL-10) and a decrease in Th1 cytokines (IFN-gamma and IL-2) that may account for impaired cellular immunity. However, the functional significance of a dominant Th2 pattern to the host remains unclear. The aim of this study was to evaluate whether Candida albicans (CA) sepsis in the setting of a Th2 response to trauma leads to increased mortality and to examine the mediators involved. Female BALB/c mice were randomized (12 per group) to receive no injury (C); trauma, consisting of a combined femur fracture and 40% total blood loss (T); no injury plus CA infection (C+CA); and CA infection 1 week following trauma (T+CA). Survival was then followed for 3 weeks. In a separate study, mice were treated as above (5 per group) and sacrificed. Harvested splenocytes were evaluated for concanavalin A-stimulated cytokine production and liver and kidney homogenates were plated to evaluate CA growth per organ and examined histologically. Candida infection at 1 week following trauma resulted in significantly increased mortality compared to infected controls. Furthermore, the Th2 dominant cytokine pattern was significantly augmented in the presence of CA infection in both C+CA and T+CA groups. Additional analysis showed significant growth of CA in liver and kidney homogenates from T+CA compared to C+CA mice. These results suggest that injured and infected mice demonstrate augmentation of Th2 dominant responses above that of injury or infection alone, as well as a decreased ability to clear Candida which may partially explain the increase in mortality observed. Therapies designed to neutralize Th2 cytokines or augment Th1 cytokines may prove beneficial in the setting of sepsis following trauma.

Acute Disease↗
PubMed1998

Differential effects of lead and cAMP on development and activities of Th1- and Th2-lymphocytes.

Lead (Pb) is known to have detrimental effects on the central nervous, hematopoietic, renal, and immune systems. Herein, it is demonstrated that Pb can skew T cell reactivities by preferentially enhancing the development of Th2 cells and inhibiting the development of Th1 cells. When naive splenic CD4+ T cells from DO11.10 ovalbumin-specific transgenic (OVA-tg) mice or OVA-tg/RAG2-/- mice were developed in vitro in the presence of Pb, preferential skewing toward Th2 cells was evident. The Pb-driven skewing toward Th2 was blocked significantly in the presence of exogenous IL-12 or anti-IL-4 mAbs. Although Pb and dibutyryl cAMP (dbcAMP) appear to have similar effects on the development and reactivity of Th1 cells, unlike Pb, dbcAMP did not enhance Th2 development/activity. Further evidence of Pb's differential T cell effects was observed, in that regardless of the activation stimuli (Ag/APC; anti-CD3; PMA + ionomycin), the addition of PbCl2 consistently resulted in significant inhibition of IFN gamma production by a Th1 clone and in increased IL-4 production by a Th2 clone. In vitro addition of IL-12 overcame Pb's inhibition of Th1 cells. Th1 cells treated with a phosphodiesterase inhibitor had significantly elevated [cAMP]i levels following anti-CD3 activation in the presence of Pb, suggesting that Pb may inhibit Th1 development by enhancing adenylate cyclase activity and elevating the [cAMP]i level. Similar to Pb, a low concentration (10 microM) of dbcAMP inhibited IFN gamma production by Th1, which was prevented by IL-12; however, inhibition of protein kinase A activity by KT5720 did not reverse these effects. These results indicate that the environmental toxicant Pb can modify immune reactivities by significantly altering the differentiation of precursor or naive Th cells as well as by directly inhibiting Th1 cells and stimulating Th2 cells.

Animals↗
PubMed2003

Incomplete Th2 skewing of cytokines in plasma of patients with squamous cell carcinoma of the head and neck.

Levels of cytokines, and in particular those that reflect Th1 or Th2 bias, were measured in the plasma of patients with head and neck squamous cell carcinomas (HNSCC). Compared with plasma cytokine levels of age-matched controls, cytokine levels in HNSCC patients suggested a shift to a Th2 bias as levels of the Th2 cytokines interleukin-4 (IL-4), IL-6, and IL-10 were increased, and levels of the Th1 cytokine interferon-gamma (IFN-gamma) were decreased. However, levels of the Th1 cytokines IL-2 and granulocyte macrophage-colony-stimulating factor (GM-CSF) were increased, which is not consistent with full Th2 skewing. Assessment of cytokine levels in patients with malignancies other than HNSCC demonstrated many similarities to HNSCC patients, but HNSCC patients exhibited a more pronounced increase in GM-CSF levels and a decline in IFN-gamma levels. For most cytokines there was no association between the shifts in cytokine levels in HNSCC patients and either the extent of tumor burden or extent of metastasis. However, patients with large HNSCC tended to be the population that demonstrated increased levels of IL-4 and IL-6. These results suggest skewing toward a Th2 bias in HNSCC patients, with the Th2 shift being incomplete and indicative of the presence, rather than the extent, of malignant disease.

Aged↗
PubMed2006

The mast cell mediator PGD2 suppresses IL-12 release by dendritic cells leading to Th2 polarized immune responses in vivo.

Dendritic cells (DC) and mast cells (MC) are colocalized in superficial organs such as the skin. Both cell types recognize and respond to pathogens. DC capture and transport antigens to the draining lymph node for CD4+ T cell priming and T helper 1 (Th1) or Th2 polarization. As MC are mainly associated with Th2 responses, DC-MC interactions may favor Th2 priming by DC. Here, we show the role of different MC mediators on IL-12 and IL-10 production by DC. While histamine, leukotriene C4, heparin and chondroitin sulfate A had little and unspecific effects on the cytokine production, prostaglandin D2 (PGD2) downregulated IL-10, IL-12p70 and p40. After subcutaneous (s.c.) injection of ovalbumin (OVA)-loaded, lipopolysaccharide (LPS)-matured DC into Th1-prone C57BL/6 mice, the levels of IFN-gamma produced by Th1 cells were decreased while IL-4 production remained low. When TNF-matured DC were pretreated with PGD2, loaded with the endotoxin-free antigen KLH and injected s.c. into Th2-prone BALB/c mice, we found a dose- and time-dependent upregulation of IL-4 and downregulation of IFN-gamma by T cells. Together, MC-derived PGD2 instructs DC to polarize CD4+ T cells towards Th2 responses. As a consequence, such a DC-MC cooperation may contribute to the maintenance of Th2 responses in allergic patients.

Animals↗
PubMed2004

Essential role of dendritic cell CD80/CD86 costimulation in the induction, but not reactivation, of TH2 effector responses in a mouse model of asthma.

BACKGROUND: Airway dendritic cells (DCs) are crucial for the generation of TH2 cells from naive T cells during sensitization and for reactivation of primed TH2 cells on allergen challenge in mouse models of asthma. It is unknown whether CD80/CD86 costimulation is necessary during both phases of the response because primed T cells rely less on costimulatory molecules compared with naive T cells. OBJECTIVE: We sought to study the contribution of CD80/CD86 costimulatory molecules on DCs during sensitization or challenge in a mouse model of asthma. METHODS: Naive BALB/c mice received an intratracheal injection of ovalbumin (OVA)-pulsed DCs obtained from the bone marrow of wild-type (WT) or CD80/CD86-/- mice and were subsequently challenged with OVA aerosol to address the role of costimulation during sensitization. OVA-sensitized mice received OVA-pulsed WT or CD80/CD86-/- DCs without OVA aerosol to address the role of costimulation during challenge. RESULTS: WT DCs induced the proliferation and effector TH2 differentiation of naive OVA-specific T cells, whereas CD80/CD86-/- DCs induced only proliferation. Not surprisingly, WT DCs but not CD80/CD86-/- DCs induced sensitization to OVA in naive mice. In contrast, in OVA-sensitized mice intratracheal injection of CD80/CD86-/- OVA-pulsed DCs led to eosinophilic airway inflammation, goblet cell hyperplasia, and effector TH2 cytokine production that was not different from that seen after injection with WT OVA-DCs, even when the inducible costimulator ICOS was blocked or cytotoxic T lymphocyte-associated antigen 4 immunoglobulin was given. CONCLUSION: CD80/CD86 costimulation on DCs is only necessary during priming of naive T cells into TH2 cells but not during restimulation of previously primed TH2 cells in the challenge phase.

Animals↗
PubMed2006

Altered neuroantigen-specific cytokine secretion in a Th2 environment reduces experimental autoimmune encephalomyelitis.

Activation of Th2 cells suppresses clinical experimental autoimmune encephalitis (EAE), demyelination and expression of genes associated with Th1-mediated inflammation. Despite both reduced central nervous system inflammation and IFN-gamma induced MHC class II expression by microglia, the composition of CNS infiltrates in Th2-protected mice were similar to mice with EAE. Analysis of the CNS infiltrating cells by flow cytometry suggests that protection did not correlate with abrogation of CD4+ T cell recruitment, preferential recruitment of donor Th2 cells or an increased frequency of CD25+ CD4+ T cells. By contrast, protection correlated with an increased frequency of neuroantigen-specific Th2 cells infiltrating the CNS. These data suggest that a peripheral Th2 cytokine environment influences both potential antigen presenting cells as well as recruitment and/or retention of neuroAg-specific Th2 CD4+ T cells.

Adoptive Transfer↗
PubMed2005

Targeting memory Th2 cells for the treatment of allergic asthma.

Th2 memory cells play an important role in the pathogenesis of allergic asthma. Evidence from patients and experimental models indicates that memory Th2 cells reside in the lungs during disease remission and, upon allergen exposure, become activated effectors involved in disease exacerbation. The inhibition of memory Th2 cells or their effector functions in allergic asthma influence disease progression, suggesting their importance as therapeutic targets. They are allergen specific and can potentially be suppressed or eliminated using this specificity. They have distinct activation, differentiation, cell surface phenotype, migration capacity, and effector functions that can be targeted singularly or in combination. Furthermore, memory Th2 cells residing in the lungs can be treated locally. Capitalizing on these unique attributes is important for drug development for allergic asthma. The aim of this review is to present an overview of therapeutic strategies targeting Th2 memory cells in allergic asthma, emphasizing Th2 generation, differentiation, activation, migration, effector function, and survival.

Animals↗
PubMed1997

Corticosteroid modulation of human, antigen-specific Th1 and Th2 responses.

Corticosteroids are potent antiinflammatory agents that modulate human T-lymphocyte responses. Controversy remains as to their possible differential effects on Th1 and Th2 subsets. This study explores the kinetics and efficacy of these agents in human, antigen-driven peripheral blood mononuclear cells (PBMCs) and in nontransformed, antigen-specific Th1 and Th2 clones. Ragweed- and tetanus toxoid-driven proliferative responses of PBMCs from dually sensitized individuals were downregulated equally by dexamethasone (inhibitory concentration of 50% [IC(50)] = 3 x 10(-9) and 2 x 10(-9) mol/L, respectively). The addition of dexamethasone as late as 36 hours after ragweed stimulation still resulted in more than 75% inhibition of the proliferative response, whereas the efficacy of dexamethasone was less than 50% when added 24 hours after tetanus toxoid stimulation. Antigen-induced gene expression for proinflammatory cytokines (IL-4, IL-5, IL-13, and interferon-gamma) from PBMCs was also downregulated by dexamethasone. Proliferation of antigen-specific Th1 and Th2 clones was inhibited by several corticosteroids (hydrocortisone < budesonide < dexamethasone; IC(50) = 10(-6) to 10(-8) mol/L), but no significant differences between Th1 and Th2 clones were evident. IC(50) values in the clones were 10-fold greater than in PBMCs. Gene expression and protein secretion for IL-4, IL-13, and interferon-gamma were downregulated in a concentration-dependent manner by each of the corticosteroids in Th1 and Th2 clones. These data suggest that Th1 and Th2 responses are equally affected by corticosteroids.

Adrenal Cortex Hormones↗
PubMed1999

Receptors and cytokines involved in allergic TH2 cell responses.

Cytokines produced by allergen-specific TH2 cells play a central role in the induction and maintenance of allergic responses. Therefore antagonizing TH2 differentiation and TH2 effector functions will provide an effective way to intervene in allergic diseases. This article discusses that antagonizing the effects of IL-4 and IL-13 by IL-4Ralpha antagonists inhibits human TH2 development and IgE synthesis. In addition, it is shown that the activation of allergen-specific TH2 cells with an agonistic anti-CDw150 mAb redirects the cytokine production profile of these TH2 cells to a TH0 phenotype.

Animals↗
PubMed2001

Th2 cells support intrinsic anti-inflammatory properties of the brain.

In experimental autoimmune encephalomyelitis (EAE), Th1 cells are responsible for disease induction while Th2 cells can be protective. To address the mechanisms of this differential behavior, we utilized organotypic murine entorhinal-hippocampal slice cultures to analyze interactions between myelin basic protein-specific Th1 and Th2 cells with microglial cells. While both Th1 and Th2 cells induced CD40 expression, only Th1 cells induced intercellular adhesion molecule-1 (ICAM-1) expression on microglia. Moreover, Th2 cells prevented or even reversed Th1-induced ICAM-1 upregulation. Evidently, Th2 cells could diminish Th1-induced inflammatory reactions and actively support the resting state of microglia, which could be one mechanism of Th2-mediated remission of neuroinflammation during EAE.

Animals↗
PubMed2000

Bone marrow cells promote TH2 polarization and inhibit virus-specific CTL generation.

This laboratory recently reported that human bone marrow cells (BMC) inhibit the generation of virus-specific CTL in culture. The culture supernatants contained increased levels of prostaglandin E(2) (PGE(2)) (shown to favor TH2 cell development) and also inhibited EBV-CTL effector cell development. In this study, we obtained PBL from Epstein-Barr virus (EBV) IgG antibody positive kidney transplant recipients (R) and their living-related donors (LRD) one year after renal transplantation. EBV-specific CTL were then generated in vitro by stimulating PBL with autologous EBV-transformed B cells (EBV-B) in the presence or absence of autologous BMC. The addition of BMC to the EBV-CTL generation cultures increased the intracellular expression in CD3+ cells of IL-4,-5,-6,-10, and -13. These CD3+ cells also expressed increased levels of the TH2 associated receptor CCR3. Inhibition was even observed by preparing EBV-CTL generating cultures in trans-wells that separated the autologous BMC from the PBL + EBV-B. It was then observed that CD3+ cells obtained after 7 days of culture in the presence of autologous BMC could be used as inhibitors of EBV-CTL generation. Protein Kinase A (PKA), a cAMP kinase that is involved in the upregulation of TH2 cytokine activity, was increased in EBV-CTL cultures by the presence of BMC. Additionally, IL-4-mediated signal transduction and activation of transcription (STAT-6) phosphorylation was slightly increased. These results show that the BMC inhibition is mediated by soluble factors (cytokines) and that cell-cell contact in this autologous system is not required, so that BMC (at least partially, via cytokine production) promote TH2 polarization in culture. Moreover, TH2 cells induced by culturing with autologous BMC directly inhibit EBV-CTL generation, and TH2 associated PKA, CCR3, and STAT-6 phosphorylation are enhanced by BMC.

Bone Marrow Cells↗
PubMed2000

Both immunisation with a formalin-inactivated respiratory syncytial virus (RSV) vaccine and a mock antigen vaccine induce severe lung pathology and a Th2 cytokine profile in RSV-challenged mice.

Respiratory syncytial virus (RSV) is the most important cause of bronchiolitis and pneumonia in infants and young children. Immunopathology may play a role in RSV-induced disease and a severe RSV infection may also be associated with an increased risk of developing asthma. Vaccination with formalin-inactivated RSV (FI-RSV) prior to infection resulted both in human and in the mouse model in extensive lung pathology. In the mouse model, it has been shown that this aggravation of disease was associated with a shift in the balance between Th1 and Th2 cytokines towards a Th2-type response. The aim of the present study was to characterise the immunological and inflammatory responses in BALB/c mice upon RSV infection with or without prior vaccination with aluminium-adjuvanted FI-RSV or control antigens (FI-Mock). As previously reported by others, we also observed that a primary RSV infection in BALB/c mice resulted in a predominant Th1-type cytokine response, which was associated with slight bronchiolitis and alveolitis. FI-RSV vaccination prior to RSV challenge prevented virus replication and was associated with an aggravation of pulmonary histopathology and a shift towards a Th2-type response. Vaccination with FI-Mock did not prevent RSV replication in the lung but resulted in an even more pronounced Th2 response after infection while these mice were not sensitised to specific viral antigens. Thus, viral replication in a Th2 responding animal (induced by aluminium-adjuvanted mock vaccine) appears to boost the Th2 response upon RSV infection.

Animals↗
PubMed2002

Peripheral blood stem cell harvests from G-CSF-stimulated donors contain a skewed Th2 CD4 phenotype and a predominance of type 2 dendritic cells.

OBJECTIVE: To assess the numbers and function of dendritic cell (DC) subsets and T helper cells in bone marrow (BM) and peripheral blood stem cell (PBSC) harvests. PATIENTS AND METHODS: DC subsets in stem cell grafts were analyzed using three-color flow cytometry. Intracellular cytokine staining and the staining of IL-12Rbeta2 were used for determining the proportion of Th1-, Th2-, and IL-12-producing DC in the grafts. The ability of DC1 and DC2 to induce T-cell proliferation and cytokine secretion were studied using thymidine incorporation and ELISA techniques. RESULTS: PBSC recipients received a significantly higher number of DC2 than BM recipients and a lower proportion of IL-12-producing DC. Purified DC1 from both BM and PBSC grafts were capable of inducing proliferation of allogeneic T cells and also induced a predominant Th1 response when cultured with CD4(+)/CD45RA(+) cells. In contrast, DC2 induced a predominant Th2 cytokine response. PBSC grafts contained a higher number of both Th1 and Th2 cells compared to BM grafts; however, as a consequence of the increased number of Th2 cells the ratio of Th1:Th2 cells in PBSC grafts was 1.1:1 compared to 9.8:1 in BM. Furthermore, following in vitro activation of T cells, PBSC grafts contained a lower proportion of IL-12Rbeta2(+) T cells. CONCLUSION: G-CSF does not have a direct effect on DC function but acts to increase the numbers of DC2 in the blood of PBSC donors. This is associated with a higher proportion of Th2 cells present in PBSC grafts and T cells in PBSC grafts were less likely to develop a Th1 response following in vitro activation.

Animals↗
PubMed1997

Do holes in the T-cell repertoire have a center-surround regulatory structure? A rationale for the bifurcation of the Th1 and Th2 pathways of differentiation.

Regulatory strategies controlling the balance of Th1 versus Th2 T-helper cell responses have been a long-standing mystery with important consequences for immunological disease. A novel model is presented to explain the comparative differentiation of Th1 and Th2 T cells as part of a mechanism to ensure self-tolerance. This model is based on the assumption that thymic interactions of T cell antigen receptors with self major histocompatibility complex ligands may vary in efficacy. By this model, fully agonistic major histocompatibility complex ligands elicit apoptosis during thymic selection to generate 'holes' in the repertoire. Conversely, major histocompatibility complex ligands having some degree of partial efficacy (i.e. a mixed agonist/antagonist) may promote Th2 differentiation whereas fully antagonistic major histocompatibility complex ligands elicit Th0 differentiation. Differentiation of Th2 T cells may continue in the extrathymic tissues upon continued interactions with self major histocompatibility complex ligands having mixed agonist/ antagonist properties. By this mechanism, each 'hole' in the repertoire will develop an inhibitory surround comprised to Th2 T cell clones having partial reactivities to a particular self major histocompatibility complex ligand. During immune responses to self-mimicking foreign antigens, the more numerous Th2 T cells of the inhibitory surround would prevent clonal expansion and Th1 differentiation of any fully autoreactive T cell.

Animals↗
PubMed1998

Differences between IL-4R alpha-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses.

Allergens and infections with parasitic helminths preferentially induced Th2 immune responses associated with elevated levels of serum immunoglobulin E (IgE) and expansion of eosinophils and mast cells. Interleukin-4 (IL-4) is a key cytokine in the differentiation of naive CD4+ T cells into Th2 cells, which produce a panel of cytokines including IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 [1] and have been shown to trigger recovery from gastrointestinal nematodes [2]. Nonetheless, mice deficient for IL-4 have been shown to develop residual Th2 responses [3-5] and can expel the nematode Nippostrongylus brasiliensis [6], suggesting that there is a functional equivalent of IL-4 in these processes. IL-13 is a cytokine that shares some, but not all, biological activities with IL-4 [7,8]. There is now compelling evidence that IL-4 and IL-13 share receptor components, including IL-4R alpha and IL-13R alpha 1 [9]. In order to dissect the roles of IL-4 and IL-13 in the regulation of Th2 cells and in the response to nematode infections, we looked for differences between mice deficient for either the IL-4 gene or the IL-4R alpha gene. Unlike IL-4, IL-4R alpha was required for control of N. brasiliensis, and Th2 development during infection--as characterized by cytokine production, GATA-3 and surface CD30 expression--was more severely affected in IL-4R alpha-/- mice than in IL-4-/- mice. Injection of recombinant IL-13 induced worm expulsion in otherwise incompetent RAG2-/- mice. Our results suggest that IL-13 regulates Th2 responses to nematode infection and requires IL-4R alpha.

Animals↗
PubMed2000

T-cell subsets (Th1 versus Th2).

LEARNING OBJECTIVE: To understand the current status of knowledge in the basic field of polarized specific immune responses mediated by CD4+ T helper (Th) lymphocytes, based on their profile of cytokine production (type 1 or Th1 and type 2 or Th2). DATA SOURCES: Relevant articles and publications from the medical literature, especially review articles dealing with properties, mechanisms of polarization, transcription regulatory factors, and role in different human pathophysiological conditions of Th1 and Th2 cells. CONCLUSIONS: Th1 cells, which produce interferon (IFN)-gamma, interleukin (IL)-2 and tumor necrosis factor (TNF)-beta, evoke cell-mediated immunity and phagocyte-dependent inflammation. Th2 cells, which produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13, evoke strong antibody responses (including those of the IgE class) and eosinophil accumulation, but inhibit several functions of phagocytic cells (phagocyte-independent inflammation). Both environmental and genetic factors act in concert to determine the Th1 or Th2 polarization. Further, Th1-dominated responses are involved in the pathogenesis of organ-specific autoimmune disorders, Crohn's disease, sarcoidosis, acute kidney allograft rejection, and some unexplained recurrent abortions. In contrast, allergen-specific Th2 responses are responsible for atopic disorders in genetically susceptible individuals. Further, Th2-dominated responses play a pathogenic role in both progressive systemic sclerosis and cryptogenic fibrosing alveolitis, and favor a more rapid evolution of HIV infection towards the full-blown disease. Finally, the Th1/Th2 paradigm can provide the basis for the development of new types of vaccines against infectious agents and of novel strategies for the therapy of allergic and autoimmune disorders.

Cytokines↗