Pattern Of Lymphokines Research Articles

New proteoliposome vaccine formulation from N. meningitidis serogroup B, without aluminum hydroxide, retains its antimeningococcal protectogenic potential as well as Th-1 adjuvant capacity

Proteoliposomes purified from the Outer Membrane of Neisseria meningitidis B, have been successfully used as core for adjuvants and vaccine formulations. We have tried to increase their structural definition and to conserve their efficacy and stability avoiding the addition of the aluminum hydroxide to the final formulation. Liposomal particle systems were prepared from components of defined molecular structure, such as a Neisseria meningitidis B protein complex, extracted and purified without forming vesicle structures. Liposomes were prepared from a mixture of dioleoyl phosphatidyl serine and cholesterol, using the classical dehydration-rehydration method. Transmission Electron Microscopy (TEM) was used to characterize the liposomes. BALB/c mice were used for animal testing procedures. Analysis of specific IgG response, serum bactericidal activity as well as DTH reaction was carried out. Isolation and purification of mRNA and real-time PCR, was performed to determine the dominating Th lymphokine pattern. The new antimeningococcal formulation without aluminum hydroxide prepared with components of defined molecular structure assembled itself into Neoproteoliposomes (NPL) ranging from 50 to 70 nm in diameter. The extraction and purification of selected membrane proteins to provide the antigen for this new formulation (PD-Tp), as well as the NPL-formulation favors a Th1 response pattern, suggested by the higher percentages of DTH, increased expression of proinflamatory lymphokine mRNAs when administered by intramuscular and intranasal routes. It stimulates a systemic bactericidal antibody response against Neisseria meningitidis B and immunologic memory similar to the Cuban VA-MENGOC-BC® vaccine, even at lower dosages and is less reactogenic at the injection site in comparison with the formulation with aluminum hydroxide. This new adjuvant formulation could be applicable to the development of new and improved vaccines against meningococcal disease, and eventually as modulators of the immune response against other diseases.

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

Tumour necrosis factor alpha (TNF-α) is a major inducer for inflammation and bone loss. Here, we investigated whether interleukin (IL)-17 plays a role in TNF-α-mediated inflammation and bone resorption. Human TNF-α transgenic (hTNFtg) mice were treated with a neutralizing anti-IL-17A antibody and assessed for inflammation, cartilage and bone damage. T-cell transcription factors and lymphokine patterns were measured in the LNs. IL-17A inhibition in the absence of IL-1 was also evaluated by treating hTNFtg/IL-1(-/-) mice with an IL-17A neutralizing antibody. IL-17A neutralization had only minor effects on TNF-α-induced inflammation but effectively reduced local and systemic bone loss by blocking osteoclast differentiation in vivo. Effects were based on a shift to bone-protective T-cell responses such as enhanced Th2 differentiation, IL-4 and IL-12 expression and Treg cell numbers. Whereas inflammation in hTNFtg/IL-1(-/-) mice was highly sensitive to IL-17A blockade, no shift in the T-cell lineages and no additional benefit on bone mass were observed in response to IL-17A neutralization. We thus conclude that IL-17A is a key mediator of TNF-α-induced bone loss by closely interacting with IL-1 in blocking bone protective T-cell responses.

The role of a heat shock protein from V. cholerae 0139 in the gut immune response

An immunodominant heat shock protein (Hsp 24) was purified from Vibrio cholerae O139 at 42 degrees C and used as an immunomodulator for studying the gut immune response. T cell clone and T cell line specific for the Hsp 24 were generated from the lymphocytes of lamina propria and intra-epithelial lymphocytes of mice orally infected with V. cholerae O139, respectively. The T cell clone was TCR alphabeta(+), CD4(+) and appeared to play an important role in the functioning of gut B-lymphocytes. The T cell line had heterogenous population of CD8+ and CD4+ cells, most of which were found to be TCR alphabeta(+) and a minor population was TCR gammadelta(+). The lymphokine profile of T cell line showed IFN-gamma to be the most abundant lymphokine followed by IL-2 and IL-4. The possible involvement of alternative pathway of activation for T cell clone was also addressed in this study. The splenocytes showed an up-regulation of their CD2 receptor expression on stimulation with the Hsp-24. The pattern of lymphokines released by splenocytes stimulated with the Hsp-24 showed no particular cell type to be responsible for mounting immune response. Thus, there is involvement of both, mucosal and peripheral arm of the immune system.

Experimental approaches to evaluate respiratory allergy in animal models

Asthma is defined as a chronic disease of the entire lung and asthma attacks may either be immediate, delayed or dual in onset. Allergic asthma is a complex chronic inflammatory disease of the airways and its etiology is multifactorial. It involves the recruitment and activation of many inflammatory and structural cells, all of which release mediators that result in typical pathological changes of asthma. A wealth of clinical and experimental data suggests that allergic asthma is due to an aberrant lung immune response mediated through T-helper type 2 (Th2) cells and associated cytokine-signaling pathways. The pathology of asthma is associated with reversible narrowing of airways, associated with prominent features that involve structural changes in the airway walls and extracellular matrix remodeling including abnormalities of bronchial smooth muscle, eosinophilic inflammation of the bronchial wall, hyperplasia and hypertrophy of mucous glands. The primary objective of respiratory allergy tests is to determine whether a low-molecular-weight chemical (hapten) or high-molecular-weight compound (antigen) exhibits sensitizing properties to the respiratory tract. This may range from reactions occurring in the nose (allergic rhinitis), in the bronchial airways (i.e., allergic bronchitis, asthma) or alveoli (e.g., hypersensitivity pneumonitis). Current assays utilize several phases, viz. an induction phase, which includes multiple exposures to the test compound (sensitization) via the respiratory tract (e.g., by intranasal or intratracheal instillations), by inhalation exposures or by dermal contact, and a single or multiple challenge or elicitation phase. The challenge can either be with the chemical (hapten), the homologous protein conjugate of the hapten or the antigen. The choice depends both on the irritant potency and the physical form (vapor, aerosol) of the hapten. The appropriate selection of concentrations (dosages) both for the induction and elicitation of respiratory allergy appears to be paramount for the outcome of test. Endpoints to characterize positive response range from the induction of immunoglobulins, cytokine or lymphokine patterns in serum (or the lung) to (patho-)physiological reactions typifying asthma. None of the currently applied animal models duplicate all features of human asthma. Accordingly, the specific pros and cons of the selected animal model, including protocol variables, animal species and strain selected, must be interpreted cautiously in order to arrive at a meaningful extrapolation for humans.

T‐cell responses in atopic eczema

T‐cell responses in atopic eczema

In vitro induction of CD25+ CD4+ regulatory T cells by the neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH).

Recently, we have found that the neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) not only suppresses IFN-gamma production, but also induces TGF-beta1 production by activated effector T cells. These alpha-MSH- treated effector T cells function as regulatory T cells in that they suppress IFN-gamma production and hypersensitivity mediated by other effector T cells. Experimental autoimmune uveoretinitis (EAU) was suppressed in its severity and incidence in mice that were injected with primed T cells activated in vitro by APC and antigen in the presence of alpha-MSH. Moreover, it appeared that alpha-MSH had converted a population of effector T cells polarized to mediate hypersensitivity into a population of T cells that now mediated immunoregulation. To characterize these alpha-MSH- treated T cells, primed T cells were TCR-stimulated in the presence of alpha-MSH in vitro and their lymphokine profile was examined. Such effector T cells displayed enhanced levels of TGF-beta1 production and no IFN-gamma or IL-10, with IL-4 levels remaining unchanged in comparison with inactivated T cells. In addition, if soluble TGF-beta receptor II was added to cocultures of alpha-MSH-treated T cells and activated Th1 cells, the alpha-MSH-treated T cells could not suppress IFN-gamma production by the Th1 cells. These results suggest that alpha-MSH induces T cells with a regulatory lymphokine pattern, and that through their production of TGF-beta1 these cells suppress other effector T cells. Examination of the alpha-MSH-treated T cells showed that alpha-MSH did not alter the phosphorylation of CD3 molecules following TCR engagement. Primed T cells express the melanocortin 5 receptor (MC5r), a receptor that is linked to an intracellular signalling pathway shared by other cytokine receptors. Blocking the receptor with antibody prevented alpha-MSH from suppressing IFN-gamma production by the activated regulatory T cells, suggesting that alpha-MSH immunoregulation is through the MC5r on primed T cells. Surface staining and cell sorting of the alpha-MSH- treated primed T cells showed that the regulatory T cells are CD25+ CD4+ T cells. From these results we find that alpha-MSH can mediate the induction of CD25+ CD4+ regulatory T cells. These regulatory T cells require specific antigen for activation, but through non-specific TGF-beta1-mediated mechanisms they can suppress other effector T cells.

The low efficiency of dendritic cells and macrophages from mice susceptible to Paracoccidioides brasiliensis in inducing a Th1 response.

In the present study we evaluated T cell proliferation and Th lymphokine patterns in response to gp43 from Paracoccidioides brasiliensis presented by isolated dendritic cells from susceptible and resistant mice. T cell proliferation assays showed that dendritic cells from susceptible mice were less efficient than those from resistant mice. The pattern of T cell lymphokines stimulated by dendritic cells was always Th1, although the levels of IL-2 and IFN-gamma were lower in T cell cultures from susceptible mice. To determine whether different antigen-presenting cells such as macrophages and dendritic cells stimulated different concentrations of Th1 lymphokines, the production of IFN-gamma and IL-2 was measured. It was observed that dendritic cells were more efficient than macrophages in stimulating lymphoproliferation in resistant mice. However, no significant difference was observed for IFN-gamma or IL-2 production. When cells from susceptible mice were used, macrophages were more efficient in stimulating lymphoproliferation than dendritic cells, but no difference was observed in the production of Th1 cytokine. Taken together, these results suggest the lower efficiency of dendritic cells and macrophages from B10.A mice in stimulating T cells that secrete Th1 lymphokines in vitro, an effect that may be involved in the progression of the disease in vivo.

Exercise and Recovery Responses of Lymphokines to Heavy Resistance Exercise

To examine the effect of dynamic resistance exercise on the response patterns of lymphokines, 10 strength-trained men (21.7 ± 0.6 y) performed 2 resistance exercise protocols, high force (HF) and high power (HP), of equal total work (HF = 33.0 ± 2.5 kJ; HP = 33.3 ± 2.7 kJ) in a randomized order separated by 1 week. Resting blood samples were obtained preexercise and 0 (R-0), 15 (R-15), and 240 (R-240) minutes postexercise. Plasma lactate significantly (p <0.05) increased from baseline for both protocols; however, concentrations were higher in response to the HF protocol. Plasma interleukin-2 (IL-2) concentrations were significantly decreased from baseline at R-15 following the HF protocol. Plasma interfer-on-gamma (IFN-γ) concentrations decreased at R-0 following the HP protocol and returned to preexercise levels by R-15. Although the suppression of these 2 lymphokines was transient, the results indicate that the acute stress of high force and high resistance workouts induce differential IFN-γ and IL-2 responses.

Exercise and Recovery Responses of Lymphokines to Heavy Resistance Exercise

To examine the effect of dynamic resistance exercise on the response patterns of lymphokines, 10 strength-trained men (21.7 +- 0.6 y) performed 2 resistance exercise protocols, high force (HF) and high power (HP), of equal total work (HF 5 33.0 +- 2.5 kJ; HP 5 33.3 +- 2.7 kJ) in a randomized order separated by 1 week. Resting blood samples were obtained preexercise and 0 (R-0), 15 (R-15), and 240 (R-240) minutes postexercise. Plasma lactate significantly (p < 0.05) increased from baseline for both protocols; however, concentrations were higher in response to the HF protocol. Plasma interleukin- 2 (IL-2) concentrations were significantly decreased from baseline at R-15 following the HF protocol. Plasma interferon- gamma (IFN-g) concentrations decreased at R-0 following the HP protocol and returned to preexercise levels by R-15. Although the suppression of these 2 lymphokines was transient, the results indicate that the acute stress of high force and high resistance workouts induce differential IFN-g and IL-2 responses.

LYMPHOKINES IN BLEOMYCIN-INDUCED LUNG INJURY IN BLEOMYCIN-SENSITIVE C57BL/6 AND-RESISTANT BALB/c MICE

To study the pattern of lymphokines in bleomycin-induced lung injury, T cells were isolated from lung interstitial tissue (LIL), peribronchial lymphatic tissue (PBLT), and bronchoalveolar lavage (BAL) fluid of bleomycin-"sensitive" C57Bl/6 and bleomycin-''resistant'' BALB/c mice at 3, 6, and 14 days following intratracheal instillation of bleomycin or saline. After 48 hours in culture, conditioned media were collected and assayed with specific enzyme-linked immunosorbent assay (ELISA) for interferon (IFN)-, interleukin (IL)-2, IL-4 and IL-5. In bleomycin-treated C57B1/6 mice, IFN- production was increased up to 20-fold at 3 and 6 days in LIL, and at 3 days in PBLT lymphocytes. IL-4 production was slightly decreased in LIL and PBLT lymphocytes at 14 days. IL-2 and IL-5 were not changed by bleomycin. In BALB/c mice, IFN- production was increased 5-fold at 14 days, and IL-2 production at 6 days, in LIL but not PBLT. IL-4 and IL-5 were not significantly changed. The increase in IFN- may play a role in the pathogenesis of bleomycin-induced lung injury. Differences in the cytokine pattern between the strains of mice may contribute to the variable strain susceptibility in bleomycin-induced lung injury.

Virus-Specific Lymphokine Production Differs Quantitatively but Not Qualitatively in Acute and Chronic Hepatitis B Infection

Cytokines that are secreted as a response to viral antigen not only have direct antiviral properties but also crucially influence immune reactions determining the outcome of infection. As an advantageous alternative to the study of cytokines present in the supernatants of antigen-specific T cell clones and lines, we have used ELISPOT assays to determine the number of interferon-γ (IFN-γ)- and IL4-producing cells generated by peripheral blood mononuclear cells from patients with acute hepatitis B (AHB) and chronic hepatitis B (CHB) infection in response to HBcAg in a short-term culture (48 h). In response to HBcAg IFN-γ was predominantly produced. In contrast to the results obtained in acute hepatitis B, the typical lymphokine pattern in CHB was characterized by a weak or absent antigen-specific IFN-γ production. A predominance of IL-4-producing cells was not observed in either AHB or CHB. A significant number of IFN-γ-producing cells was usually detectable during phases of viral elimination and the quality of the lymphokine response seemed to be epitope independent. Comparison of the results obtained in proliferation assays and ELISPOT assays clearly shows that lymphokine production upon stimulation with viral protein is totally independent of T cell proliferation and more sensitively reflects antiviral reactivity.

Immune reconstitution following allogeneic peripheral blood stem cell transplants.

Growth factor-mobilized peripheral blood stem cells (PBSCs) engraft rapidly in myeloablated recipients compared to conventional BM, but this procedure also mobilizes mature lymphocytes and monocytes which can impact immune reconstitution and GVHD. Hence, we serially evaluated immune reconstitution and cytokine expression in PBSCT recipients in the first year. Engraftment of neutrophils and monocytes stabilized early but NK cells, B cells and CD4+ T cell numbers were significantly (P < 0.05) low with persistently reversed CD4:CD8 ratios. NK function remained low throughout the first year. The quantitative decrease in CD4+ T cells resulted in significantly decreased proliferation in response to mitogens and alloHLA antigens. Yet, a qualitative analysis of T cell function measured by Ca++ influx after T cell activation with antiCD3 as well as T-dependent polyclonal Ig secretion by mitogen-stimulated B cells was preserved even early post transplant. TNF alpha mRNA was detected in almost all recipients in the first year. IL-10 mRNA was detected in 77%, IL-2 in 22% and IFN gamma in 44% of recipients in the first 6 months. Only 30% expressed IL-10 in the second 6 months post transplant while expression of IL-2 and IFN gamma was detected in 38% and 46% respectively. Thirty-seven percent of PBSCT recipients developed grades II-IV acute GVHD but 72% went on to develop chronic extensive GVHD at a median of 120 days. Sixty-two percent developed CMV viremia and 5.4% developed overt CMV disease in the first year post PBSCT. Lymphocyte engraftment is quantitatively delayed but CD4 functions are preserved while NK numbers and function are compromised post PBSCT. IL-10 expression decreases after the first 6 months post transplant while TNF alpha is continually expressed. The balance between quantitative lymphocyte reconstitution and qualitative lymphocyte functions as well as changes in lymphokine patterns may influence infection and GVHD and thus the clinical outcome post PBSCT.

Antigen-Antibody Complex as Therapeutic Vaccine for Viral Hepatitis B

In a previous study, hepatitis B surface antigen (HBsAg) complexed to human anti-HBs immunoglobulins (HBIG) in excess of HBsAg was used as therapeutic vaccine to treat chronic hepatitis B patients and promising results were obtained. To study the mechanisms of this approach, mice were immunized with HBsAg or IC (immunogenic complex, i.e. HBsAg complexed with mouse polyclonal anti-HBs). Studies indicate that IC induced enhanced immune responses by increasing uptake of HBsAg through Fc receptors on antigen presenting cells and modulated HBsAg processing and presentation. This modulation led to stimulation of T cell responses, and increased production of IL-2 and IFN-γ. Assay for antibody subclasses showed that higher ratio of IgG 2a was observed in the IC immunized group, which correlated with the production of lymphokine pattern. When alum was used as the adjuvant, though antibody response was enhanced, production of cytokines decreased. When DNA from a recombinant plasmid was added to IC as an adjuvant, the liter of anti-HBs was significantly higher than those in mice immunized only with the DNA or the IC. Since DNA immunization can induce both cellular and humoral immune responses, combined immunization using IC and DNA might serve as another type of therapeutic vaccine for viral hepatitis B.

Production of T Cell Clones

AbstractThis unit provides methods for the derivation of specific types of T cell clones: preparation and maintenance of alloreactive murine helper T (TH) lymphocyte and cytotoxic T lymphocyte (CTL) clones using the limiting dilution technique and derivation of TH clones reactive with soluble protein antigens including a method for the selection of either TH1 or TH2 lymphocyte subsets. These two subsets of TH cells exhibit helper function in different ways and can be distinguished by the patterns of lymphokines they synthesize. Support protocols describe preparation of different types of conditioned media that can be used to enhance the growth of desired clones.

A dominant mechanism coordinately suppresses the expression of Th2 lymphokines.

This study, we present evidence for a negatively acting control mechanism that coordinately suppresses the synthesis of the Th2 lymphokines IL-4, IL-5 and IL-6. This control mechanism operates in the murine thymoma cell line BW 5147. When cells of this line were fused to four independently established, well-defined Th2 cell clones, all resulting 74 lymphokine-secreting hybridomas secreted IL-2 which was not secreted by any of the parental Th2 cell clones. Most interestingly, however, none of the 74 hybridomas retained the capacity of the parental Th2 cells to express IL-4. Likewise, the secretion of IL-5 and IL-6 was also suppressed. Obviously, BW 5147 cells dominated the pattern of lymphokines produced, although the lymphokine pattern of Th2 cells was previously considered to be irreversibly fixed due to terminal differentiation of these cells. Suppression of IL-4 production was also observed at the mRNA level, as tested in Northern blot assays. Putative DNA target sequences for suppression of IL-4 gene transcription were not part of the proximal IL-4 promotor regions. Remote DNA control sequences may exist which coordinately regulate the proper, stage-specific expression of the Th2 lymphokines IL-4, IL-5 and IL-6.

Depletion of circulating allergen-specific T H2 T lymphocytes after allergen exposure in asthma

In allergic asthma, CD4+ T lymphocytes are a fundamental component of local chronic inflammation. Their cytokine profile is oriented toward a TH2 phenotype, characterized by production of IL-4, IL-5, IL-10, and IL-13. Egress of T cells from blood to airways after allergen challenge has been described. We have studied a cohort of six patients with asthma who had multiple allergies to investigate how exposure to allergen affects the proliferation of peripheral CD4+ T lymphocytes with different allergen specificities and lymphokine profiles. For each patient, CD4+ T-cell lines were generated by in vitro stimulation with sensitizing and with nonsensitizing allergens, and IL-4 and interferon-gamma production by these lines was assessed. Proliferation of peripheral blood CD4+ T lymphocytes in response to the same allergens was measured before and 24 hours after inhalation challenge with a sensitizing allergen. We found that each single sensitizing allergen can deplete peripheral blood of TH2-type CD4+ T lymphocytes specific for all sensitizing allergens, but not of TH1-type CD4+ T lymphocytes. Our results suggest the existence of mechanisms capable of sorting disease-associated antigen specificities together with defined lymphokine patterns into T lymphocytes that can migrate to target organs, in allergic asthma.

A 38-kDa antigen of Mycobacterium tuberculosis predominantly induces the secretion of interleukin-2, interferon-gamma and IgG2a antibodies.

In the present study, mice of 3 different haplotypes (H-2d, H-2k and H-2b) were sensitized subcutaneously with heat-killed H37Ra or 38-kDa antigen of Mycobacterium tuberculosis. Lymphocytes obtained from immunized animals were challenged in vitro with 38-kDa antigen in both cases. The dominant pattern of Th1-like lymphokines (IL-2 and IFN-gamma) and preferential production of 38-kDa specific IgG2a-type antibody were observed. It was noted that 38-kDa antigen was recognized permissively by all 3 strains of mice used in the present study. It was interesting to note that C3H/HeJ mice, which express BCG-resistant alleles showed a higher level of proliferative as well as cytokine response as compared to BALB/c and C57BL/6 mice, which bear BCG-susceptible alleles. These results suggest that not only in recall responses but also during the induction as well as expression phase of the immune response mediated by 38-kDa antigen of M. tuberculosis the Th1-like immune response predominates.

Circulating allergen-reactive T cells from patients with atopic dermatitis and allergic contact dermatitis express the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen.

The cutaneous lymphocyte-associated antigen (CLA) is the major T cell ligand for the vascular adhesion molecule E-selectin, and it has been proposed to be involved in the selective targeting of memory T cells reactive with skin-associated Ag to cutaneous inflammatory sites. To further investigate the relation of CLA and cutaneous T cell responses, we analyzed the CLA phenotype of circulating memory T cells in patients with allergic contact dermatitis and atopic dermatitis (AD) alone vs in patients manifesting bronchopulmonary atopy (asthma with or without AD) and nonallergic individuals. Significant T cell proliferative responses to Ni, a contact allergen, and to the house dust mite (HDM), an allergen to which sensitization is often observed in AD and/or asthma, was noted only in allergic and atopic individuals, respectively. When the minor circulating CLA+CD3+CD45RO+ subset was separated from the major CLA-CD3+CD45RO+ subpopulation in Ni-sensitive subjects, the Ni-dependent memory T cell response was largely confined to the CLA+ subset. A similar restriction of the T cell proliferative response to the CLA+ memory subset was observed for HDM in patients with AD alone. In HDM-sensitive patients with asthma with or without AD, however, the CLA- subset exhibited a strong antigen-dependent proliferation, in contrast to patients with AD alone, whose CLA- subset proliferated very weakly to HDM. In asthma with or without AD, the HDM-dependent proliferation slightly predominated in the CLA- when compared to the CLA+ subset. The functional linkage between CLA expression and disease-associated T cell effector function in AD was also demonstrated by the finding that the circulating CLA+ T cell subset in AD patients, but not nonatopic controls, selectively showed both evidence of prior activation (human histocompatibility antigen-DR expression) and spontaneous production of interleukin 4 but not interferon-gamma. Taken together, these observations demonstrate the correlation of CLA expression on circulating memory T cells and disease-associated memory T cell responses in cutaneous hypersensitivity, and they suggest the existence of mechanisms capable of sorting particular T cell Ag specificities and lymphokine patterns into homing receptor-defined memory subsets.

Specific T-cell tolerance may reflect selective activation of lymphokine synthesis.

Selective T-cell unresponsiveness, as measured by interleukin 2 (IL-2) synthesis upon challenge with antigen, was induced in SJL mice by ovalbumin (OVA) in incomplete or complete Freund's adjuvant administered i.p. or s.c. Ten days later, the mice were given booster injections of 100 micrograms of OVA/complete Freund's adjuvant. On day 20, lymph node and spleen cells were challenged in vitro with serial dilutions of OVA. There was an antigen-specific dose-dependent down regulation of IL-2 production and T-cell proliferation in lymph node T cells. Concomitantly, 100 micrograms of OVA up regulated IL-4 and, to a lesser extent, interferon gamma (IFN-gamma) production, particularly by spleen T cells. Altogether, these data indicate that the drop of IL-2 production and T-cell proliferation, as well as the up regulation of IL-4 and IFN-gamma production, are complex manifestations of an evolving T-cell response. The maturation of the T-cell response leads to the production of different patterns of lymphokines, which may be significantly affected, as desired, by dosage, timing, and route of immunization, as well as by the choice of adjuvants.

T helper phenotype and genetic susceptibility in experimental Lyme disease.

Infection of inbred mice with Borrelia burgdorferi results in strain-specific variation in the severity of pathogen-induced arthritis: BALB/c mice develop only mild disease whereas C3H/HeJ mice develop severe arthritis. The immunologic basis for varying host susceptibility has yet to be defined. We modified experimental Lyme disease to facilitate measurement of antigen-specific cytokine production in resistant and susceptible mice. The analysis revealed highly polarized lymphokine patterns directly linked to differing disease outcomes. Among the inbred strains of mice challenged with B. burgdorferi, production of interleukin 4 (IL-4) correlated to resistance whereas production of interferon gamma (IFN-gamma) correlated to susceptibility. We also demonstrate that production of IL-4 or IFN-gamma regulates the severity of arthritis after infection. Neutralization of IL-4 in resistant BALB/c mice resulted in more severe arthritis whereas neutralization of IFN-gamma in susceptible C3H/HeJ mice attenuated the severity of disease. These results suggest a primary relationship between T helper cell phenotype and the genetic basis for susceptibility to experimental Lyme borreliosis.