Th1/Th2 differentiation and cross-regulation

The T helper (Th) phenotypes, Th1/Th2, are acquired upon interaction of a naive T helper cell and an antigen presenting cell (APC). Naive T helper cells may differentiate into either phenotype, and the actual outcome is determined by the density and avidity of the antigenic determinants presented by the APC, and the APCs inherent costimulatory properties. Until recently it was thought that differentiation is further affected by cytokines. However, Murphy et al. (1996, J. Exp. Med. 183, 901) have demonstrated that the experimental results, formerly interpreted as Th1/Th2 differentiation, in effect comprise an observation of two consecutive processes. (i) An interaction between naive T cells and APC creates a mixture of mature cells irreversibly committed to Th1 or Th2 phenotype. (ii) Subsequent addition of regulatory cytokines, promotes expansion of one phenotype while suppressing the other. The consequent shift in the per culture production of marker cytokines mimics the appearance of a cellular phenotype switch. We present and analyse a mathematical model that extrapolates these experimental facts into systemic behavior during an immune response. Despite the fact that differentiation produces cells of Th1 and Th2 phenotypes with the same receptor specificity, our results indicate that competition for antigenic stimulation, mediated by the APCs, combines with cytokine mediated cross-suppression between phenotypes to yield a response that is eventually dominated by T helper cells that are uniform in both receptor specificity (clonotype) and in cytokine secretion phenotype.     

Th1 and th2 responses, HIV-1 coreceptors, and HIV-1 infection.

The Th1/Th2 model provides an interesting paradigm for understanding several pathophysiological processes and possibly for developing new immunotherapeutical strategies. In HIV-1 infection the interaction between the type of HIV-1 strain and the pathway of the ongoing T-cell effector response, despite its complexity, may represent one of the crucial mechanisms in determining the outcome of virus infection. While the possibility of an HIV-1-driven Th1 to Th2 switch of the immune response is still debated, evidence is accumulating to suggest that cytokines produced during an immune response can contribute to promote a selective pressure toward the evolution of HIV-1 viral strains with different tropism. This article summarizes the results of our recent studies in which the expression of CCR5 and CXCR4 HIV-1 co-receptors, as well as the activity of R5- or X4- tropic strains of HIV-1 in different in vitro models of Th1/Th2 polarization was analyzed.     

In vitro Th1 cytokine-independent Th2 suppressive effects of bifidobacteria

A comparison between 17 strains of lactic acid bacteria and 15 strains of bifidobacteria indicated that bifidobacteria induced significantly lower levels of interleukin-12 (IL-12) in murine splenic cells. The present study aims to evaluate the effect and mechanism of Bifidobacterium longum BB536, a probiotic strain, in suppressing antigen-induced Th2 immune response in vitro. BB536 suppressed immunoglobulin (Ig) E and IL-4 production by ovalbumin-sensitized splenic cells, but induction of Th1-inducing cytokine production, such as IL-12 and gamma interferon (IFN-gamma) tended to be lower compared with lactic acid bacteria. Neutralization with antibodies to IL-12, IFN-gamma, IL-10 and transforming growth factor beta indicated negative involvement of Th1-inducing cytokines and regulatory cytokines in the suppression of Th2 immune response by BB536, especially when treated at higher doses of BB536 (>10 microg cells/ml). Furthermore, BB536 induced the maturation of immature bone marrow-derived dendritic cells (BM-DCs), and suppressed antigen-induced IL-4 production mediated by BM-DCs. These results suggested that BB536 suppressed Th2 immune responses, partially independent of Th1-inducing cytokines and independent of regulatory cytokines, mediated by antigen-presenting cells such as dendritic cells.     

The pattern and level of cytokines secreted by Th1 and Th2 lymphocytes of syphilitic patients correlate to the progression of the disease

The results of our previous work indicated that cell-mediated immune response, of importance in protection against Treponema pallidum, is distinctly inhibited at certain periods of syphilitic infection. Considering that cytokines, produced by Th1 lymphocytes, take part in this response and that their secretion may be regulated by cytokines of Th2 lymphocytes, we examined if, and in which stages of syphilis, such a regulation may exist. In this study we have examined the ability of cells to produce IL-2, IFN and TNF (Th1 or Th1 like cytokines) as well as IL-6 and IL-10 (Th2 or Th2 like cytokines). It was found that cells of syphilitic patients were able to produce IL-2, IFN, TNF, IL-10 and weakly IL-6 already in primary seronegative syphilis. At the same stage of syphilis, but seropositive, ability of Th1 lymphocytes to produce cytokines reached the highest values, whereas the cells producing IL-10 lost this ability. The cells producing IL-6 and MIF had the highest ability in secondary early syphilis. In this stage of syphilis again slightly increased the ability of cells to secrete IL-10, which reached the highest value in early latent syphilis. The growing ability to produce IL-6 and IL-10 was accompanied with a diminished production of IL-2, IFN and TNF nearly in all stages of syphilis. Only MIF, in contrast to other cytokines, was produced in late syphilis without distinct changes. The greatest suppression of Th1 lymphocytes to produce cytokines and cells to secretion of MIF was found in early latent syphilis when the level of IL-10 in cell culture supernates was the highest. High ability of Th2 lymphocytes to cytokines secretion in late syphilis and low ability of Th1 ones, which are very important for cell-mediated immune response, may be the reason for facilitating T. pallidum multiplication and development of latent stages of disease despite presence of immunologically competent cells.     

沙门菌- 斑马鱼感染模型用于Th1/Th2 免疫应答的研究

目的:通过构建斑马鱼成鱼感染模型,研究鼠伤寒沙门菌感染对机体Th1/Th2免疫应答的影响。方法:用不同剂量细菌口饲感染8月龄的斑马鱼成鱼,绘制3周生存率曲线。观察各剂量下对成鱼的感染情况,并用实时荧光定量聚合酶链式反应检测肝脏Th1、Th2型细胞相关基因和细胞因子的mRNA转录水平,计算Th2/Th1相对表达量比值。结果:用105 CFU感染2周斑马鱼全部存活,第15天开始出现死亡,且在3周后死亡率达到50%;感染后3周解剖发现,肝脏、脾脏和肠道有明显红肿和糜烂;肝脏Th1、Th2型细胞相关基因和细胞因子mRNA转录水平明显向Th2偏移。结论:用105 CFU鼠伤寒沙门菌口饲感染斑马鱼成鱼构建的模型,能反映机体感染和免疫功能变化,可用于研究体内Th1/Th2免疫应答,为进一步研究鼠伤寒沙门菌感染与免疫机制提供了很好的实验工具。     

Experimental autoimmune myasthenia gravis may occur in the context of a polarized Th1- or Th2-type immune response in rats.

Experimental autoimmune myasthenia gravis (EAMG) is a T cell-dependent, Ab-mediated autoimmune disease induced in rats by a single immunization with acetylcholine receptor (AChR). Although polarized Th1 responses have been shown to be crucial for the development of mouse EAMG, the role of Th cell subsets in rat EAMG is not well established. In the present work we show that while the incidence and severity of EAMG are similar in Lewis (LEW) and Brown-Norway (BN) rats, strong differences are revealed in the immune response generated. Ag-specific lymph node cells from LEW rats produced higher amounts of IL-2 and IFN-gamma than BN lymph node cells, but expressed less IL-4 mRNA. IgG1 and IgG2b anti-AChR isotype predominated in BN and LEW rats, respectively, confirming the dichotomy of the immune response observed between the two strains. Furthermore, although IL-12 administration or IFN-gamma neutralization strongly influenced the Th1/Th2 balance in BN rats, it did not affect the disease outcome. These data demonstrate that a Th1-dominated immune response is not necessarily associated with disease severity in EAMG, not only in rats with disparate MHC haplotype but also in the same rat strain, and suggest that in a situation where complement-fixing Ab can be generated as a consequence of either Th1- or Th2-mediated T cell help, deviation of the immune response will not be an adequate strategy to prevent this Ab-mediated autoimmune disease.     

Role of Th1 and Th2 cytokines in BCG-induced IFN-gamma production: cytokine promotion and simulation of BCG effect

Induction of a T-helper-type 1 (Th1) immune response is indispensable for successful treatment of superficial bladder cancer with BCG. In this study possible involvement of various cytokines in BCG action as well as their potential roles in enhancing and mimicking BCG effect were explored. In immunocompetent cell cultures, IFN-gamma, a major Th1 cytokine, appears to be a late responsive cytokine to BCG stimulation. Its induction requires involvement of various endogenously produced Th1 and Th2 cytokines. Functional abolishment of any one of these cytokines (IL-2, IL-6, IL-12, IL-18, GMCSF, TNF-alpha, or IFN-alpha, except IL-10) by neutralizing antibodies leads to reduced IFN-gamma production (19-82% inhibition in mouse and 44-77% inhibition in human systems, respectively). In mice cytokines IL-2, IL-12, IL-18, and GMCSF are observed to synergize with BCG for IFN-gamma production, whereas in human cytokines IL-2, IL-12, TNF-alpha, and IFN-alpha exhibit similar synergistic effects. Rational combinations of these Th1-stimulating cytokines (IL-12 plus IL-18 in mice and IL-2 plus IL-12 in humans, respectively) dramatically up-regulate IFN-gamma production that is incomparably superior to BCG for induction of this cytokine. These results suggest that combined Th1-stimulating cytokines and combinations of BCG plus selected Th1-stimulating cytokines are rational candidates for further study in the treatment of bladder cancer patients.     

Influence of Th1/Th2 Cytokines and Nitric Oxide in Murine Systemic Infection Induced by Sporothrix schenckii

In an attempt to elucidate the effects of Sporothrix schenckii infection on the immune response, our laboratory has developed a murine model of disseminated sporotrichosis. Helper T cells can be further subdivided into Th1 and Th2 phenotypes. The differentiation of two subsets of T lymphocytes is driven by IL-12 and IL-4 cytokines, respectively. Th1 cells produce IFN-γ that activate macrophages and promote cell-mediated immunity. In addition, we found low levels of iNOS and NO production in the initial (1st and 2nd weeks) and final (9th and 10th weeks) periods of the infection, in contrast with the period of week 4 to 7 of elevated values. The determination of IFN-γ and IL-12 are in agreement with NO/iNOS detection, showing the presence of cellular immune response throughout the infectious process. However, the production of IL-4 shows an increase in levels after the 5th and 6th weeks suggesting a participation of Th2 response in this period as well. Regarding these results, the study demonstrated that in experimental sporotrichosis infection the cellular immune response participated throughout the period analyzed as a nitric oxide dependent mechanism. In contrast, the presence of Th2 response began in the 5th week, suggesting the participation of humoral immune response in advanced stages of sporotrichosis.     

Comparison of Th1 and Th2 responses in non-healing and healing patients with cutaneous leishmaniasis

Background:

Cutaneous leishmaniasis is an endemic disease in many regions of Iran, including the city of Mashhad. In recent years, some cases have not responded to Glucantime, the usual treatment for this disease. The cellular immune response caused by T-helper type 1 (Th1) cells has an important role in protection against leishmaniasis, and activation of the T-helper type 2 (Th2) response causes progression of the disease. By analyzing these responses we hope to find a more effective treatment than that currently in use for leishmaniasis patients.

Methods:

The cellular immune responses in 60 cases of non-healing and healing cutaneous leishmaniasis, and individuals in a control group, were analyzed by measuring cytokines released by peripheral blood mononuclear cells (PBMCs) when stimulated with Leishmania major antigens by Enzyme Linked Immuno Sorbent Assay (ELISA).

Results:

Subjects from the healing group secreted more interleukin-12 (IL-12) and interferon gamma (IFN-γ) (p<0.05) and less interleukins -4, -5, -10 (IL-4, IL-5, and IL-10) (p<0.005) and -18 (IL-18) (p=0.003) than the non-healing group.

Conclusions:

The results demonstrate that secretion of cytokines that activate Th2 response including IL-4, IL-5 and IL-10 in non-healing subjects was higher than healing subjects and secretion of cytokines that activate Th1 response including IL-12 and IFN-γ in healing subjects was higher relative to the non-healing subjects. In this study it has been shown that the level of IL-18 progresses disease in non-healing patients when the level of IL-12 gets decreased. Key Words: Cytokines, Cutaneous leishmaniasis, Glucantime     

A Th1-recognized peptide P277, when tandemly repeated, enhances a Th2 immune response toward effective vaccines against autoimmune diabetes in nonobese diabetic mice

Subunit immunogens containing tandemly repeated copies of T and B cell epitopes have been shown to be more immunogenic than the respective immunogen containing only a single copy of the sequence. To investigate whether the increased copies of the Th2-activated peptide sequence will enhance the Th2-like immune response, we compared the cytokine secreted in mice that inoculated with two immunogens containing one or six tandemly repeated copies of a Th2-activated peptide sequence P277. Immunization of mice with a 6xP277 fusion protein elicited much higher levels of Th2-type cytokines and lower Th1-type cytokines than with a fusion protein with one P277 peptide. The data of tandemly repeated peptide P277 potentiate the anti-inflammatory in NOD mice, most likely associated with a Th1 to Th2 cytokine shift specific for the autoimmune T cells, which suggested that application of multiple tandem repeats of a Th2-activated epitope is an efficient method to enhance the anti-inflammatory immune response by shifting the immune response from Th1-like to Th2-like. The subunit immunogens containing tandemly repeated copies of peptide P277 might be effective vaccines against autoimmune diabetes in NOD mice.     

<Emphasis Type="Italic">Brucella abortus</Emphasis> phosphoglyceromutase and dihydrodipicolinate reductase induce Th1 and Th2-related immune responses

Brucellae are intracellular bacterial pathogens that cause Brucellosis, bringing great economic burdens to developing countries. The pathogenic mechanisms of Brucella are still poorly understood. Earlier immune response plays an important role in the Brucella infection. Phosphoglyceromutase (PGM) and dihydrodipicolinate reductase (DapB) were cloned, expressed, purified, and their immunocompetence was analyzed. Cytokines were detected by murine macrophages (RAW 264.7) and splenocytes that stimulated with the two recombinant proteins. The immune responses were analyzed by ELISA from mice with the two recombinant proteins immunized. TNF-α, IL-6 and IL-8 were produced in stimulated RAW 264.7 cells and splenocytes. Th1-type cytokines, IFN-γ and IL-2, induced in RAW 264.7 cells and splenocytes were higher then Th2-type cytokines, IL-4 and IL-5. Th2-related immune response was induced in splenocytes obtained 35 days after mice immunized with the two proteins. The production of IgG1 was higher than IgG2a in immunized mice. Taken together, our results demonstrated that the two proteins could induce Th1 and Th2-type immune responses in vivo and in vitro.     

Adenoviral-mediated overexpression of monocyte chemoattractant protein-1 differentially alters the development of Th1 and Th2 type responses in vivo

The expression of chemokines during an immune response may participate in determining the intensity and type of the developing immune response. In the present study, we have examined the effect of overexpressing monocyte chemoattractant protein (MCP)-1 at the site of immunization during different stages of Th1- and Th2-type granulomatous responses. The overexpression of MCP-1 by MCP-1 adenovirus during the sensitization phase of the purified protein derivative Th1-type model significantly reduced the elicitation of the granulomatous response. In contrast, the overexpression of MCP-1 during the sensitization phase of the schistosome egg Ag Th2 response led to an enhanced granulomatous reaction. When cytokines were examined upon restimulation of splenocytes ex vivo, an altered cytokine profile was observed, as compared with control mice. IFN-gamma and IL-12 were significantly reduced in the purified protein derivative Th1-type response, whereas IL-10 and IL-13 were up-regulated in the schistosome egg Ag Th2-type response. The regulation of the immune response was further examined by using the MCP-1 adenovirus at later time points during the elicitation phase. When MCP-1 was overexpressed during the elicitation phase of the responses, neither the Th1-type nor the Th2-type granuloma was altered. Likewise, the cytokine profiles after restimulation of splenocytes ex vivo were unchanged. Thus, the function of MCP-1 may depend on the stage and type of immune response.     

Paradoxical roles of IFN-gamma in models of Th1-mediated autoimmunity

T-cell responses to antigens are classified on the basis of the cytokines they produce as either Th1 (IFN-gamma, IL-2) or Th2 (IL-4, IL-10), with these Th types being indicative of either cell-mediated or antibody-mediated responses, respectively. Using this classification, T-cell responses in MHC-class-II-restricted autoimmune diseases appear to be predominantly of the Th1 type, based on the presence of high levels of IFN-gamma. This simplistic classification has recently been challenged, however, as disease incidence and severity are frequently elevated in animals that have a deficient IFN-gamma response. The recent data discussed here indicate that the cytokine circuits involved in the regulation of cell-mediated and humoral immune responses during the development of autoimmune arthritis are more complex than originally proposed; perhaps our characterization of autoimmune responses as strictly Th1 or Th2 is overly simplistic, especially as it pertains to the role of IFN-gamma.     

Adjuvants and the promotion of Th1-type cytokines in tumour immunotherapy

Immunotherapy includes both active and passive mechanisms that have the potential to treat many tumour types. Whereas monoclonal antibodies may kill cells by merely binding to them, 'cancer vaccines' involve the induction of an active immune response. The activation of tumour antigen-specific T-helper and cytotoxic T lymphocytes or non-specific macrophages and natural killer (NK) cells using immunotherapeutic approaches may lead to the subsequent destruction of tumour tissue. Administration of a tumour antigen alone is often not sufficient to stimulate an appropriate immune response. However, incorporating an immunological adjuvant into a vaccine regime often improves anti-tumour immunity. There are various types of adjuvants used in immunotherapy, ranging from microbial, chemical, and cellular components to proteins and cytokines. Previous reports have demonstrated that the induction of Th1-promoting cytokines, using specific adjuvants, can enhance anti-tumour immunity and can reduce or even prevent tumour growth. There is also increasing evidence that many adjuvants induce Th1-type cytokines, which correlates with the induction anti-tumour immunity. Th1-type responses which comprise cell-mediated immunity are characterised by the secretion of interferon-gamma by T cells, which is induced by antigen-presenting cell (APC)-derived IL-12. This review describes immunoadjuvants that are currently undergoing preclinical investigation, and emerging clinical data revealing that adjuvants which induce Th1-type responses can improve the efficacy of cancer vaccines. Therefore, the use of Th1-inducing adjuvants may provide an essential strategy for the future success of immunotherapy.     

Skewed Th1/Th2 immune response to Sarcoptes scabiei

Scabies is a contagious skin disease of humans and many other species of mammals. Previous studies suggested that the balance between the Th1 and Th2 immune responses may influence the outcome of a scabies infestation in a sensitized host. Therefore, in this study, we examined the T-helper cell cytokine profiles of splenocytes and lymph node cells in BALB/c mice that were immunized with scabies extract (primary response), infested with scabies mites (primary response), or immunized and then infested (secondary response). Lymphocyte cytokine expression was analyzed by flow cytometry after staining for intracellular cytokines. Immunization with scabies extract induced production of interferon-gamma (IFNgamma) (Th1 response) by both spleen and lymph node cells. Mice that were infested with scabies increased production of interleukin-4 by lymph node cells and of IFNgamma by splenocytes. Mice that were first immunized and then infested with mites increased production of IFNgamma by both spleen and lymph node cells. However, this increased level of IFNgamma was only about half of that induced by immunization alone. These results suggest that live scabies mites produced something that inhibited IFNgamma production in the lymph nodes of scabies-immunized mice. Our data also indicate that lymphocytes in the spleen and lymph nodes can present different cytokine response profiles.     

Effects of glucan treatment on the Th1/Th2 balance in patients with allergic rhinitis: a double-blind placebo-controlled study

BACKGROUND: Allergic rhinitis (AR) is a disease characterized by IgE-mediated, allergic inflammation of the nasal mucosa. T helper (Th) 2 cells play an important role in the development of IgE-mediated diseases such as AR, with local overproduction of Th2 cytokines (IL-4, IL-5 and IL-13) at the site of allergic inflammation. Th1 cytokines (IL-12 and IFN-gamma) are known to suppress this Th2 immune response, aiding the treatment of these diseases. Beta-1,3-1,6-glucan (Glucan) is an immunomodulator stimulating particularly the antitumor response. An efficient antitumor stimulation can be achieved through a Th1-mediated immune response. OBJECTIVE: The aim of this study was to investigate the effects of Glucan on the immunopathogenic processes in the microenvironment to determine if it reverses the Th2-mediated immune response in AR to Th1-mediated response. METHODS: 24 Olea europea mono-sensitized patients with AR were randomized into Glucan and placebo groups. The Glucan group consisted of 12 patients who received Glucan treatment for 12 weeks, while the placebo group of 12 patients received placebo during the same period. A nasal provocation test (NPT) with Olea europea was performed at the beginning and end of treatment, and nasal lavage followed the positive NPT. IL-4, IL-5, IFN-gamma and IL-12 levels and the eosinophil count (%) were measured in nasal lavage fluid (NLF) samples. Simultaneously, peripheral blood eosinophil % values were measured. RESULTS: After treatment, IL-4 and IL-5 levels in NLF from the Glucan group were found to have decreased significantly (p = 0.027, p = 0.04; respectively), while IL-12 levels were found to have significantly increased (p = 0.008). However, IFN-gamma levels had not changed. On the other hand, none of the cytokine levels had changed significantly in the placebo group following treatment. Moreover, the percentage of eosinophils in the NLF was found to have decreased significantly after treatment in the Glucan group (p = 0.01), while that of the placebo group did not change. Peripheral blood percentage eosinophil levels had not changed significantly in any group. CONCLUSION: Th2-originated IL-4 and IL-5 levels responsible for the allergic inflammatory response in the microenvironment of patients with AR, are decreased with Glucan while levels of Th1-originated IL-12 are increased. Moreover, eosinophils, which are important effector cells of the inflammatory response, are decreased in the microenvironment. As a result, Glucan may have a role as an adjunct to standard treatment in patients with AR.     

Th type 1-stimulating activity of lung macrophages inhibits Th2-mediated allergic airway inflammation by an IFN-gamma-dependent mechanism

In the mucosal immune system, resident dendritic cells are specialized for priming Th2-polarized immunity, whereas the Ag-presenting activity of macrophages has been linked with the development of Th1 phenotype. As an immune switch toward Th1 can protect against Th2-mediated allergic response, this study investigated the capacity of lung macrophages to stimulate Th1 responses during the secondary exposure to inhaled allergen, thereby suppressing Th2-mediated allergic airway inflammation in a murine model of allergic asthma. Following airway macrophage depletion in OVA-sensitized mice, lung T cells defaulted to a phenotype that produced less Th1 (IFN-gamma) and more Th2 (IL-4 and IL-5) cytokines, leading to more severe airway hyperreactivity and inflammation after intranasal Ag challenge. After OVA pulsing and adoptive transfer, lung macrophages selectively promoted a Th1 response in Ag-sensitized recipients and did not induce pulmonary eosinophilia. By contrast, OVA pulsing and adoptive transfer of a lung cell preparation, consisting of dendritic cells, B cells, and macrophages, promoted a Th2 response with an associated inflammatory response that was suppressed when macrophages were present and pretreated with IFN-gamma, but exacerbated when macrophages were depleted before IFN-gamma treatment. In addition, Th1-promoting activity of lung macrophages was not related to the autocrine production of IL-12p40. These results suggest that the Th1-promoting APC activity may be an inherent property of the lung macrophage population, and may play an important role, upon stimulation by IFN-gamma, in antagonizing an ongoing Th2 immunity and Th2-dependent allergic responses.     

Serum Th1 and Th2 profile cytokine level changes in patients with Graves' ophthalmopathy treated with corticosteroids.

The aim of this study was to estimate the influence of corticosteroids on Th1 and Th2 serum cytokine balance in patients with GO: IFNgamma, TNFalpha, IL-4 and IL-10. Further, we tested the hypothesis of an up-regulation of Th2 immune response during successful treatment with corticosteroids to explain their beneficial effect in Graves' ophthalmopathy. Serum cytokines were detected in three groups of subjects: 20 patients with Graves' disease without ophthalmopathy (Gd), 16 patients with clinical symptoms of ophthalmopathy (GO) (CAS over 3 points, last consultation record for GO less than a year old) and 16 healthy volunteers. Corticosteroid therapy consisted of intravenous infusions of methylprednisolone (MP) (2 series, 3 g each time) and subsequent treatment with oral prednisone (60 mg per day) in a tapering schedule. The serum samples were collected 24 hours before MP, 24 hours after MP, 14 days of treatment with prednisone and at the end of corticosteroid therapy. The levels of IFNgamma, TNFalpha, IL-4 and IL-10 in the serum were determined using ELISA. Statistical significance was estimated by the Mann-Whitney U-test. Our findings show a deviation to systemic Th2 profile cytokines in Graves' disease. In patients with GO, we found a significantly increased serum IL-10 concentration. In corticosteroid-responsive patients, the balance of serum cytokines IL-4/IFNgamma, IL-4/TNFalpha, IL-10/IFNgamma and IL-10/TNFalpha increased and remained upregulated until the end of the study. In non-responders, the balance of serum cytokines studied increased after methylprednisolone but declined markedly during continuation of the therapy with prednisone. In summary, our results show that efficient corticosteroid therapy may be related to its influence on Th2/Th1 profile cytokine balance. The upregulation of serum IL-4 and IL-10 during successful treatment with corticosteroids indicate the possibility of using these cytokines as predictors of the beneficial effect of corticosteroids in Graves' ophthalmopathy.