The role of IL-4 in the staphylococcal enterotoxin B-triggered immune response: increased susceptibility to shock and deletion of CD8Vbeta8+ T cells in IL-4 knockout mice

Administration of superantigens in vivo triggers responding T cells into clonal expansion and subsequent activation of the programmed cell death pathway, as well as into anergy. We examined the possibility that Th1 cytokines are involved in rescue from superantigen-induced programmed cell death and prevention of anergy by studying the Staphylococcus aureus enterotoxin B (SEB) immune response in mice in which the IL-4 gene was deleted (IL-4-/-). In these mice, Th1 cell activation triggers increased IFN-gamma and reduced IL-5 production as compared to IL-4+/+ mice. The primary anti-SEB antibody response in IL-4-/- mice is thus dominated by immunoglobulins of the IgG2a isotype, whereas the IgG1 isotype prevails in IL-4+/+ mice. Our results also show that, in contrast to expectations, IL4-/- mice are more susceptible to SEB plus low-dose D-galactosamine-induced shock and that this response is TNF-alpha-dependent. In vivo treatment induces partial deletion and anergy of remaining SEB-reactive T cells. During the SEB-induced response, CD4Vbeta8+ T cells are deleted in IL-4-/- mice, but not in IL-4+/+ mice, suggesting a function for IL-4 in CD8+ T cell rescue from apoptosis. We show that IL-4 efficiently protects CD8+ T cells from in vitro starvation-induced apoptosis, and conclude that IL-4 has an important role in Th1 immune response regulation.     

Mechanism of antitumor activity of a single-chain interleukin-12 IgG3 antibody fusion protein (mscIL-12.her2.IgG3).

We have constructed an antibody interleukin-12 (IL-12) fusion protein (mscIL-12.her2.IgG3) that demonstrates significant antitumor activity against the murine carcinoma CT26-expressing human HER2/neu. We now report that this antitumor activity is dose dependent and comparable to or better than recombinant murine IL-12 (rMuIL-12) using subcutaneous and metastatic models of disease. The antitumor activity of mscIL-12.her2.IgG3 is reduced in Rag2 knockout mice, suggesting that T cells play a role in tumor rejection. In SCID-beige mice, the antitumor activity is further reduced, suggesting that natural killer (NK) cells or macrophages or both are also important. The isotype of the antibody response to HER2/neu is consistent with a switch from a Th2 to a Th1 immune response and the infiltration of mononuclear cell in tumors from mice treated with mscIL-12.her2.IgG3. Immunohistochemistry reveals that mscIL-12.her2.IgG3 is antiangiogenic. Thus, the mechanism of the antitumor activity exhibited by mscIL-12.her2.IgG3 is highly complex and involves a combination of T and NK cell activity, a switch to a Th1 immune response, and antiantiogenic activity. This is the first study comparing the in vivo antitumor activity of an antibody-IL-12 fusion protein and free IL-12. Our results suggest that antibody-IL-12 fusion proteins may be useful for the treatment of human cancer.     

T-helper 1 dominated responses to erythrocyte Band 3 in NZB mice.

Band 3, the red blood cell (RBC) anion channel protein, is the target autoantigen for the pathogenic RBC autoantibodies and T-helper (Th) cells in New Zealand Black (NZB) mice with autoimmune haemolytic anaemia (AIHA). To determine the subpopulation of these Th cells, they were stimulated with Band 3 and the profile of the cytokines elaborated by the responding cells was measured. NZB T cells stimulated with Band 3 produced high levels of the Th1 cytokine, interferon-gamma (IFN-gamma), but little or no interleukin-4 (IL-4), IL-5 or IL-10. Similar patterns were produced by NZB T cells responding to a spectrin preparation from the RBC membrane skeleton, or to mycobacterial heat-shock protein (hsp) 65 following immunization of mice with hsp 65 in incomplete adjuvant. By contrast, T cells from CBA mice similarly immunized with hsp 65 produced high levels of IL-4 and IL-5 in response to hsp 65. Examination of the isotype of the RBC-bound immunoglobulins in NZB mice revealed that immunoglobulin G2a (IgG2a) autoantibodies were the first to be detected in most mice and that later in the disease, IgG3 autoantibodies were often prominent. It is concluded that, contrary to expectation, the development of RBC autoantibodies in NZB mice is associated with Th1 cytokine-dominated responses.     

T helper subset involvement in two high antibody responder lines of mice (Biozzi mice): HI (susceptible) and HII (resistant) to collagen-induced arthritis

CD4⁺ T helper cells play a critical role in the chronicity of collagen-induced arthritis (CIA) in mice. The present results focus on the involvement of Th1 and Th2 subsets at the initial stage of the experimental disease in two lines of mice selected for high antibody production: HI that is susceptible, and HII that is resistant to CIA. Both lines are known to be H-2^q, display an identical full set of V-β genes, and mount similar antibody responses to both heterologous and autologous CII. The kinetic analysis of local T cell and anti-bovine CII antibody responses was followed by Elispot assays, the production of interferon-γ (IFN-γ) and IgG2a being considered indicative of a Th1 profile, and interleukin-5 (IL-5) as well as IgG1-IgE, of a Th2 profile. The number of IL-5 Elispots is constantly higher in susceptible than in resistant mice. The IFN-γ production is rather low in HI compared to HII, and besides, preferential help is observed for the Th2-dependent IgG1-IgE isotype-producing B cells in HI, while a switch-over toward IgG2a anti-CII isotype is found in HII. These results suggest that a Th1 preeminence at the onset of the anti-CII response is decisive in the resistance to CIA.     

Non-major histocompatibility complex control of antibody isotype and Th1 versus Th2 cytokines during experimental infection of mice with Mycobacterium avium

Infection of different strains of mice with Mycobacterium avium has revealed genetic control of the immunoglobulin isotype induced and of the balance between Th1 and Th2 cytokines. Female BALB/c or C57BL/10 mice were infected intranasally with 10(5) M. avium organisms. The antibody response was measured over 18 weeks by enzyme-linked immunosorbent assay and Western blotting, while numbers of cytokine-producing cells were assessed at 12 to 15 weeks by ELISPOT assay. Upon infection, C57BL/10 mice produced a clear Th1 response with strong gamma interferon (IFN-gamma) production, no interleukin-4 (IL-4), and almost entirely immunoglobulin G2a (IgG2a) antibody. In contrast, BALB/c mice developed T cells producing IL-4, as well as those producing IFN-gamma, while the antibody response was a mixture of IgG1 and IgG2a. Antibodies from BALB/c mice were also able to recognize a greater range of antigens than were C56BL/10 mice. B10D2 mice, which carry the BALB/c major histocompatibility complex haplotype on a C57BL/10 background, followed the C57BL/10 cytokine pattern. Mice infected with Listeria monocytogenes did not show a similar response dichotomy.     

Complex pattern of Th1 and Th2 activation with a preferential increase of autoreactive Th1 cells in BALB/c mice with proteoglycan (aggrecan)-induced arthritis

The central role of CD4+ T cells and the balance between T helper (Th) subpopulations in the pathogenesis of autoimmune diseases have been extensively studied. Proteoglycan (aggrecan)-induced arthritis (PGIA) is a murine model for rheumatoid arthritis (RA), which is characterized by a Th1 dominance at the onset of the disease. In addition to CD4+ T cells, antigen-presenting B cells and autoantibodies seem to play an important role in the development and regulation of PGIA. To identify proteoglycan-specific CD4+ T cell subsets and Th1- and Th2-supported antibody isotypes during the progression of PGIA, spleen cells of proteoglycan-immunized BALB/c mice were harvested at different times of immunization, and at different stages of the disease, and their cytokine production and antigen-specific antibody isotype profiles were determined by enzyme-linked immunospot (ELISPOT) assays. Both Th1 and Th2 cytokine-producing cells, with the predominance of IL-4/IL-5-secreting cells, were detected during the prearthritic stage, and a shift toward a Th1 dominance was observed at the time of onset of arthritis. Tissue homogenates of acutely inflamed joints contained significantly higher levels of interferon-gamma than IL-4. The prearthritic period and both the acute and chronic phases of joint inflammation were characterized by IgG1 dominance in the sera and this correlated with the number of IgG1-secreting B cells in the spleen. However, the ratio of autoreactive IgG1/IgG2a-secreting cells decreased in arthritic animals. These results indicate the activation and possible regulatory roles of both Th1 and Th2 subsets in the autoimmune process, with the necessity of a relative increase of autoreactive Th1 cells for the induction of joint inflammation.     

Circadian organization of the immune response: A role for melatonin

Virtually all immunological variables investigated to date in animals and humans display biological periodicity. Circadian rhythmicity is revealed in circulating cells, lymphocyte metabolism and transformability, circulating hormones and other substances that may exert various actions on different targets of the immune system, cytokines, receptors, and adhesion molecules. Immune cells have recently started to be examined for the presence of clock genes (hPer1, hPer2, hPer3, hDecl) that were found to be expressed in a circadian manner in human peripheral blood mononuclear cells. Melatonin acts as an arm of the circadian clock, giving a time-related signal to the immune system. This review discusses the physiological basis of this effect. Melatonin has a general immunoenhancing effect in many species, including humans. This depends on the ability of melatonin to enhance the production of cytokines as well as on its reported anti-oxidant and anti-apoptotic action. Melatonin acts on specific membrane receptors expressed on immunocompetent cells with MT2 receptors playing apparently the major role. Immune cells also possess a reasonably well-characterized nuclear melatonin receptor. Melatonin may favor a T helper (Th) type 1 response. Physiologically, nocturnal melatonin concentration correlates with the rhythmicity of Th-1 / Th-2 ratio. The possible undesirable implications of the immunoenhancing effects of melatonin in patients with autoimmune disorders is discussed.     

Immune responses to Trichinella spiralis and T. pseudospiralis in mice.

A comparison was made of the immunological responses of inbred NIH mice to the intestinal stage of infection with two species of the genus Trichinella, T. spiralis and T. pseudospiralis, which are known to have distinct parasitological and pathological relationships with their hosts. The parameters studied, namely antigen-specific IgG1 and IgG2a antibody responses, mucosal mastocytosis, and levels of the cytokines interferon-gamma (IFN-gamma) and interleukin-5 (IL-5) produced by concanavalin A-pulsed mesenteric node lymphocytes in vitro, were chosen to provide information about the relative activities of the Th1 and Th2 T-helper (Th) lymphocyte subsets. In this high-responder host the time-course of infections was similar, although initial levels of establishment were considerably higher for T. pseudospiralis. Both species elicited mucosal mastocytosis. Distinct differences were seen in the IgG isotype responses. Trichinella spiralis-infected mice produced a predominantly IgG2a response, whereas T. pseudospiralis elicited an IgG1 response. Cytokine release showed infection dose-related suppression of IFN-gamma and enhancement of IL-5. These effects were most marked in T. pseudospiralis-infected mice, i.e. there was an earlier shut-off of IFN-gamma and an earlier switch to IL-5. These data suggest that the two species of Trichinella show a time-related differential activity of Th subsets during the early stages of infection. The possibility that this may reflect antigenic differences between these closely related species or result from parasite-induced immunological-endocrinological changes is discussed.     

Mucosal homeostasis: role of interleukins, isotype-specific factors and contrasuppression in the IgA response

Oral ingestion of antigen elicits immune responses at mucosal sites where humoral immunity is largely due to antibodies of the IgA isotype. This is often accompanied by suppression of systemic responses to the same antigen, a state termed oral tolerance. This IgA response is regulated by interactions between T cell subsets found at IgA inductive tissues, i.e., the gut-associated lymphoreticular tissue (GALT) or Peyer's patches (PP). PP T helper (Th) cells support IgA responses, and interleukins 5 (IL-5) and IL-6 can augment secretion of this isotype. Subsets of Th cells may also express Fc receptors for IgA (Fc alpha R) and secrete Fc alpha R as an IgA-binding factor (IBF alpha). Membrane-derived Fc alpha R is a glycoprotein of 38,000 M.W. and this molecule induces selective increases in IgA secreting cells (as determined by the ELISPOT assay) in PP B cell cultures. Fc alpha R+ T cell lines have been shown to secrete IBF alpha as well as IL-5 both of which promote IgA synthesis. Recombinant IL-5 (rIL-5) and rIL-6 induce IgA synthesis mainly by PP B cell blasts, and principally act on surface IgA-positive (sIgA+) B cells for these responses. Another form of mucosal regulation is provided by T contrasuppressor (Tcs) cells, which abrogate oral tolerance when adoptively transferred to mice and restore systemic responsiveness to the antigen sheep erythrocyte (SRBC). Tcs cells from mice systemically primed with SRBC support IgM and IgG subclass responses, while Tcs cells from orally primed mice support IgM, IgG subclass and IgA anti-SRBC responses. These Tcs cells are CD3+, CD4-, 8- and are antigen-specific. These regulatory cells may use the gamma-delta (gamma-delta) form of T cell receptor for antigen recognition.     

Regulation of IgG1 and IgE Synthesis by Interleukin 4 in Mouse B Cells

Mouse interleukin 4 (IL-4) has been shown to act on B cells as an induction factor for Ig class switch. We studied the characteristics of IL-4-regulated Ig isotype production in lipopolysaccharide (LPS)-stimulated splenic B-cell cultures with emphasis on the comparison between the IgG1 and IgE responses. The results show that the kinetics for the appearance of IgG1 and IgE isotypes are similar, but that the dose of IL-4 required for the induction of an IgE response is 3-10 times higher than that for an IgG1 response. No requirement for T cells was found for the induction of either isotype. Pre-incubation of cells for 24 h with IL-4 alone was sufficient to induce an IgG1 response when cells were recultured with LPS from days 1 to 6. However, the simultaneous presence of both IL-4 and LPS for at least 24 h was required for a detectable IgE response. For an optimal IgE response, IL-4 needed to be present for more than 72 h in LPS-activated cultures. The possible reasons for the different regulation of IgG1 and IgE responses are discussed.     

Immunoglobulin isotype regulation by antigen-presenting cells in vivo

The isotype and magnitude of the B cell response clearly depends on the in vivo activation of T helper (Th) cells which secrete different lymphokines. Since Th are activated by the presentation of the antigen on specialized cells, we wished to test whether the nature of the antigen-presenting cells (APC) influences the isotypic profile of the humoral response. Data are presented showing that antigen-pulsed dendritic cells (DC) and peritoneal macrophages induce the synthesis of specific antibodies when injected in syngeneic animals. By contrast, a single injection of antigen-pulsed resting B cells does not prime the mice in vivo. Moreover, the injection of antigen-pulsed DC induces the synthesis of specific IgG2a and IgG1 antibodies, whereas peritoneal macrophages favor the production of IgG1 and IgE antibodies specific for the antigen. These data show that the isotype and the amplitude of the B cell response can be regulated by the nature of the APC, and indirectly suggest that Th cell differentiation is controlled at the level of antigen presentation.     

IFN-γ上调Th17/IL-17应答介导衣原体呼吸道感染免疫保护

目的 探讨IFN-γ在小鼠沙眼衣原体感染中对Th17/IL-17应答的调节作用.方法 利用沙眼衣原体鼠肺炎株小鼠呼吸道感染模型,用抗鼠IFN-γ单克隆抗体吸入中和肺组织IFN-γ,对照组给予同等剂量的独特型抗体IgG2a,于感染后7 d处死小鼠.免疫酶法检测小鼠肺组织衣原体生长;利用RT-PCR技术检测衣原体感染小鼠肺组织中Th17相关因子IL-17及其上游因子IL-23 mRNA的表达;细胞内细胞因子染色检测衣原体感染小鼠脾脏IL-17-CD4+T细胞的扩增.结果 与对照组相比,IFN-γ抗体中和小鼠有严重的疾病状态,包括明显的体重下降、肺组织更高的衣原体负荷和肺组织更严重的病理损伤;肺组织IL-17和IL-23 mRNA的表达水平显著降低;脾脏IL-17-CD4+T细胞百分率也显著降低.结论 小鼠衣原体感染中,IFN-γ通过上调Th17/IL-17应答起保护作用.

Abstract：

Objective To investigate the regulation of IFN-γ to Th17 response in Chlamydia muridarum (Cm) lung infection in mice. Methods A murine model of pneumonia induced by intranasal inoculation of Cm was used for this study. Anti-mouse IFN-γ McAbs were used to neutralize endogenous IFN-γfollowing Cm lung infection. Control group received the same dose of isotype antibody (IgG2a). Mice were sacrificed at day 7 postinfection. Chlamydial growth in the lung was assessed by immunoenzyme technique.IL-17 and IL-23 mRNA expression in the lung was assayed by RT-PCR and the proliferation of IL-17 + CD4 +T cells in the spleen was assayed by intracellular cytokine staining. Results IFN-γ-neutralized mice exhibited serious disease course, include greater body weight loss, higher organism growth and much more severe pathological changes in the lung compared with control mice. The mRNA expression of IL-17 and IL-23 in the lung and the proliferation of IL-17 + CD4 + T cells in the spleen significantly decreased in the IL-17- neutralized mice. Conclusion IFN-γ was protective in Cm lung infection through up-regulating the antigen specific Th17 responses.     

Genetically programmed biases in Th1 and Th2 immune responses modulate atherogenesis

Atherosclerotic lesions contain T lymphocytes, which orchestrate adaptive immunity and regulate many innate immune pathways. This study examined the influence of Th1 and Th2 helper cell subsets on atherogenesis in two ApoE(-/-) mouse strains, C57BL/6 and BALB/c, which display opposite T-cell subset polarizations. ApoE(-/-) BL/6 mice showed predominant Th1-like immune responses on polyclonal stimulation of splenic CD4(+) T cells and had IgG2a antibodies to oxidized low-density lipoprotein (a disease-related antigen) whereas ApoE(-/-) BALB/c mice displayed predominant Th2 responses by CD4(+) T cells and an IgG1 isotype response toward oxidized low-density lipoprotein. ApoE(-/-) BL/6 and BALB/c mice consumed a high-cholesterol diet for 10, 16, and 24 weeks with equivalent cholesterolemic responses. The Th1-slanted BL/6 mice developed significantly more atherosclerosis in the aortic root and abdominal aorta at all time points compared with BALB/c mice, supporting a proatherogenic role for Th1 response. Progression of atherosclerosis was associated with increased levels of interleukin (IL)-6 in mouse serum and CD4(+) T-cell culture supernatants and increased levels of the acute-phase protein, serum amyloid A (SAA). Both IL-6 and SAA levels rose significantly in ApoE(-/-) BL/6 mice compared with BALB/c mice. The circulating cytokine milieu (IL-6) and acute phase reactants such as SAA may reflect alterations in the Th1/Th2 balance. The results presented here illustrate how genetically determined modifiers of both immune and inflammatory responses can modulate atherogenesis independently of lipid levels.     

Deviation of the allergic IgE to an IgG response by gene immunotherapy

The Th1/Th2 type immune response to E. coli beta-galactosidase (beta-gal) was compared to that to gene vaccination with plasmid (p) DNA encoding beta-gal. BALB/c mice were immunized with beta-gal in alum or a pDNA construct consisting of a CMV-based promoter and the beta-gal gene (pCMV-LacZ). Beta-gal in alum induced IgG1 and IgE antibodies and the CD4+ T cells from these mice secreted interleukin 4 (IL-4) and IL-5 but no interferon-gamma (IFN-gamma) after in vitro antigen stimulation. In contrast, mice immunized with pCMV-LacZ formed predominantly IgG2a antibodies and their CD4+ T cells secreted IFN-gamma but no IL-4 and IL-5. These data indicate that beta-gal induced a Th2 and the pCMV-LacZ a Th1 response to beta-gal. The pDNA induced Th1 response dominated over the Th2 response. Mice primed with pCMV-LacZ failed to produce IgE antibodies after a booster injection of beta-gal in alum. Boosting of mice primed with beta-gal in alum with pCMV-LacZ resulted in a 75% decrease in the IgE antibody titer within 6 weeks and IgG2a antibody formation and CD4+ T cells that secreted IFN-gamma in amounts similar to T cells from pDNA primed mice. As shown by adoptive cell transfer, both CD4+ and CD8+ T cells from pDNA immunized mice inhibited an IgE response to beta-gal in alum in the recipient mice. pDNA immunization also inhibited the eosinophilic infiltration of the lung of ovalbumin (OVA) immunized mice after OVA inhalation challenge in an animal model of the late phase reaction. The mechanism of the pDNA induced Th1 immune response was shown to be the result of stimulation by distinct non-coding immunostimulatory DNA sequences (ISS) in the backbone of the pDNA. The ISS induced antigen presenting cells to secrete cytokines that cause naive T cells to differentiate into Th1 cells (e.g. IFN-alpha, IL-12). The data indicate that gene vaccination induces a Th1 immune response that is capable of down-regulating a preexisting Th2 response and IgE antibody formation. Thus, immunization with pDNA encoding for allergens may provide a novel type of immunotherapy for allergic diseases.     

Delineation of the role of platelet-activating factor in the immunoglobulin G2 antibody response

Localized aggressive periodontitis (LAgP) is a chronic inflammatory disease characterized by severe destruction of periodontal tissues surrounding the first molars and incisors. LAgP subjects produce large amounts of immunoglobulin G2 (IgG2) antibody against oral pathogens, and this response is inversely correlated with the severity of disease. We previously demonstrated that platelet-activating factor (PAF) is required for optimal IgG2 responses. The present investigation was designed to determine the mechanism of IgG2 induction by PAF. Exogenous PAF acetylhydrolase suppressed approximately 80% of pokeweed mitogen-stimulated IgG2 production, confirming that PAF is essential for optimal responses. PAF-activated leukocytes produced gamma interferon (IFN-gamma), a Th1 cytokine that has been associated with IgG2 responses in previous studies. The monocyte-derived cytokines interleukin-12 (IL-12) and IL-18 are upstream of IFN-gamma production, and IgG2 production was suppressed by neutralizing antibodies against these proteins. In addition, PAF induced monocyte-derived dendritic cells (DC) but not macrophages (MPhi) to secrete IL-12 and IL-18. This observation was interesting because monocyte differentiation in LAgP subjects is skewed to the DC phenotype. Although other investigators have implicated IFN-gamma in IgG2 production, its precise role in this response is controversial. Our studies suggest that IFN-gamma induces isotype switching to IgG2 but only in concert with the Th2 cytokine IL-4. Thus, it appears that the unique PAF metabolism of LAgP monocytes or DC promotes Th1 responses that are essential for optimal IgG2 antibody production. As IgG2 antibodies opsonize oral bacteria and promote their clearance and destruction, these alterations in PAF metabolism may be essential for limiting disease severity in LAgP patients.     

A novel phenotype for an activated macrophage: the type 2 activated macrophage

Activated macrophages were used as antigen presenting cells (APCs) to determine the extent to which these APCs could influence an adaptive immune response. We show that activated macrophages induced a strong polarized Th1-like T cell response that was predominated by IFN-gamma. However, when antigen was targeted to Fcgamma receptors on these macrophages, their phenotype changed, and they now induced a T cell response that was predominated by IL-4. The initial biasing by activated macrophages toward a Th1-like response was a result of activation of the innate immune response, as macrophages from MyD88(-/-) mice failed to produce Th1-inducing cytokines. The reversal of the Th1 biasing was a result of FcgammaR ligation, as macrophages lacking the FcR common gamma chain failed to reverse this biasing. To show that this biasing could occur in vivo, mice were injected with activated macrophages or activated macrophages whose FcgammaR had been ligated with an irrelevant immune complex. Mice injected with FcgammaR-ligated macrophages made more antibody than those receiving conventionally activated macrophages, and the antibody was predominantly of the IgG1 isotype. These studies demonstrate that FcgammaR ligation on activated macrophages can change the phenotype of these APCs to cells that preferentially drive a Th2-like response. We have termed these cells type 2 activated macrophages.     

CTLA4 (CD152) modulates the Th subset response and alters the course of experimental Leishmania major infection

Since both the nature and the amplitude of an antigen-specific T cell response are dependent on co-stimulatory signals, we have invesigated the role of CD28 / CD152-mediated T cell co-stimulation in the regulation of experimental cutaneous leishmaniasis. CD28-deficient mice and their wild-type littermates are equally susceptible to Leishmania major infection. Whole anti-CD152 antibody significantly exacerbates the disease while anti-CD152 Fab ameliorates the disease in genetically susceptible BALB / c mice but not in C57BL / 6, a resistant strain. The anti-CD152-induced exacerbation of the disease is accompanied by increased IL-4-secreting cell number, diminished parasite-specific delayed-type hypersensitivity (DTH) response and augmented anti-2,4,6-trinitrophenyl (TNP) IgG1 in response to TNP-leishmanial antigen crude soluble antigen (CSA), suggesting an exaggerated Th2 type of response. Anti-CD152 Fab-mediated amelioration of the disease is associated with increased IFN-γ-secreting cell number, increased parasite-specific DTH response and enhanced IgG2a isotype in response to TNP-CSA suggesting a Th1 type of response. Unlike TNP-CSA, TNP-keyhole limpet hemocyanin does not induce the change in Ig isotype, indicating that the immunomodulatory effect of anti-CD152 is antigen specific. Anti-CD152 antibody-induced early change in Th subsets suggests an important role for CD152 in determining the course of L. major infection, perhaps by alteration of Th subset differentiation.     

Pristane-induced arthritis in mice selected for maximal or minimal acute inflammatory reaction

The role of inflammatory and specific immune responses in pristane-induced arthritis (PIA) was investigated in mouse lines produced by bi-directional selective breedings for maximal (AIRmax) or minimal (AIRmin) acute inflammatory reaction, comparing the outcome of PIA and the humoral and cellular response to hsp65. Symptoms of arthritis were detected in 50 % AIRmax mice 120 days after pristane injection, reaching a maximal incidence of 65 %, whereas only 7 % of AIRmin mice developed arthritis within an observation period of 200 days. The production of IgG antibody against hsp65 was found to be similar on both lines, although the IgG1 isotype was predominant in AIRmax, and IgG2a in AIRmin line. In vitro T cell proliferation to hsp65 was similar in the two lines, however, ELISPOT assays carried out soon after pristane treatment, demonstrated higher numbers of IL-6-, TNF-alpha- and IL-4-secreting cells in the spleen of AIRmax than in AIRmin mice, while higher numbers of IFN-gamma-producing cells were found in AIRmin mice. These results suggest a major participation of acute inflammatory mechanisms in the susceptibility to PIA. The genetic background which determines high or low AIR favors a Th2-like response in susceptible AIRmax and Th1-like response in resistant AIRmin mice at the initial phase of arthritis induction.