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Ryo Abe

Publications and source records attributed to Ryo Abe.

At least 37 records · Page 2Linked to original sources
PubMed2005

Effect of inflammation on costimulation blockade-resistant allograft rejection.

Previously, we reported that allogeneic skin grafts were rapidly rejected by CD28 and CD40 ligand double deficient mice mediated by CD8+ T cells. These results indicated that some elements in addition to CD28- and CD40-mediated costimulation provide stimulatory signals for the activation of donor-specific CD8+ T cells. In this report, we investigated the role of inflammation associated with transplantation on costimulation-independent priming of CD8+ T cell during graft rejection. B6 RAG1 KO mice were transplanted with BALB/c-skin and adoptively transferred with syngeneic CD8+ T cells the same day or 50 days after transplantation. When blockade of CD28- and CD40-mediated costimulation failed to prevent acute rejection of freshly transplanted skin grafts, it efficiently delayed rejection of well-healed skin grafts. These results showed that factors associated with transplantation have essential roles in inducing costimulation blockade-resistant allograft rejection. Costimulation blockade failed to prevent acute graft-infiltration of NK cells and increasing expression of intragraft IL-12 and IL-15. These factors may trigger the graft-infiltration and priming of CD8+ T cells to induce costimulation blockade-resistant allograft rejection.

Animals↗
PubMed2005

Effect of nutritional conditions on changes in leukocyte populations in Japanese black calves.

To clarify the effect of nutritive conditions on changes in immune cells in Japanese Black (JB) calves during the growth period, leukocyte populations were analyzed in ten healthy JB calves managed in one herd. The calves were divided into two groups: five calves in Group 1 were given insufficient nutrition, and the other five calves in Group 2 received adequate nutrition. The levels of serum total cholesterol and glucose were significantly lower in Group 1 than in Group 2 at 1 month. The numbers of CD3+, CD4+ and CD8+ cells tended to be lower in Group 1 than in Group 2 at months 1 and 2, and the difference in CD4+ was significant at month 2. The number of MHC class-II(+high) cells was significantly lower in Group 1 than in Group 2 at months 1 and 2. These results suggest that adequate nutrition might stimulate an increase in immune cells in calves during the growth period.

Animal Nutritional Physiological Phenomena↗
PubMed2005

[Regulation of immune response by T cell co-signaling. ].

The activation of naive T cells requires two signals from the antigen presenting cells (APC). Firstly, an antigen specific signal which is triggered by the binding of the T cell receptor (TCR) to the peptide-MHC complex, and secondly, antigen nonspecific signals initiated through a set of co-signalling receptors. Co-signalling molecules are cell-surface glycoproteins that play essential roles for the communication of a T cell with virtually all other host cells by modulating and fine-tuning TCR signals. On the basis of their functional outcome, co-signalling molecules can be divided into co-stimulators and co-inhibitors, which promote or suppress T-cell activation, respectively. By expression at the appropriate time and location, co-signalling molecules positively and negatively control the priming, growth, differentiation and functional maturation of a T-cell response. In this article, I overview property of co-signaling molecules in the CD28- and TNFR family and discuss their potential functional relationships with each other. In addition, role of these co-signalling molecules in various diseases, such as autoimmune diseases, graft rejection, allergy, inflammatory bowel disease, and cancer, and the therapeutic potential of targeting these molecules to enhance or curtail an ongoing immune response in these diseases are discussed.

Antigen-Presenting Cells↗
PubMed2004

Cutting edge: CD28-mediated transcriptional and posttranscriptional regulation of IL-2 expression are controlled through different signaling pathways.

Despite the clear functional importance of CD28 costimulation, the signaling pathways transduced through CD28 have remained controversial. PI3K was identified early as a candidate for CD28 signaling, but conflicting data during the past decade has left the role of PI3K unresolved. In this report, we have resolved this controversy. We show that mutation of the PI3K interaction site in the cytosolic tail of CD28 site disrupts the ability of CD28 to recruit protein kinase C-theta; to the central supramolecular activation cluster (c-SMAC) region of the immunological synapse, promote NF-kappaB nuclear translocation, and enhance IL-2 gene transcription. In contrast, mutation of the PI3K interaction site had no effect on the ability of CD28 to enhance IL-2 mRNA stability. These results suggest that two distinct pathways mediate CD28-induced up-regulation of IL-2 expression, a PI3K-dependent pathway that may function through the immunological synapse to enhance IL-2 transcription and a PI3K-independent pathway that induces IL-2 mRNA stability.

Active Transport, Cell Nucleus↗
PubMed2004

Up-regulation of IL-4 production by the activated cAMP/cAMP-dependent protein kinase (protein kinase A) pathway in CD3/CD28-stimulated naive T cells.

The signal transduction of the cAMP/cAMP-dependent protein kinase [protein kinase A (PKA)] pathway through multiple receptors is critical for many processes in all cell types. In T cells, the engagement of both the TCR-CD3 complex and the CD28 co-stimulatory molecule also induces cAMP, and subsequently activates PKA. It is believed that elevation of cAMP levels in T cells is inhibitory of IL-2 production and T cell proliferation. However, the function and detailed signal transduction mechanisms of the cAMP/PKA pathway in naive T(h) cells are less well understood. In this study, we show that calcitonin gene-related peptide (CGRP) down-regulates IL-2 and IFN-gamma production and up-regulates IL-4 production to promote T(h)2 differentiation by moderate activation of the cAMP/PKA pathway via the CGRP receptor in the presence of a CD3/CD28 co-stimulation signal. The IL-4 production and transcriptional activation of T(h)2 cytokine mRNAs were also reproduced by the addition of a cAMP analogue, dibutyryl-cAMP, in CD3/CD28-stimulated naive T(h) cells. More interestingly, cAMP/PKA activation in naive T(h) cells stimulated with anti-CD3 plus anti-CD28 mAb is essential for inducing IL-4 production and promoting T(h)2 differentiation; in addition, NF-AT is a downstream effector of the cAMP/PKA signaling pathway. These findings indicate that the cAMP/PKA pathway transduces the critical activation signal to T(h)2 polarization by a CD3/CD28 co-stimulation signal and a PKA activating reagent.

Animals↗
PubMed2004

Effects of double blockade of CD28 and inducible-costimulator signaling on anti-glomerular basement membrane glomerulonephritis.

Inducible costimulator (ICOS) is the third member of the CD28 superfamily, expressed on antigen-primed T-cells, enhancing Th2 differentiation. Anti-glomerular basement membrane (anti-GBM) glomerulonephritis results from multiple effects generated by both Th1 and Th2 cells. To evaluate the contribution of these T-cells to the progression of anti-GBM glomerulonephritis, we investigated the effect of double blockade of CD28 and ICOS signaling. Anti-GBM glomerulonephritis was induced in C57BL/6 mice, a Th1-prone strain. CD28 signaling was inhibited with the use of fusion proteins of cytolytic T-lymphocyte-associated antigen-4 (CTLA4 immunoglobulin) and ICOS signaling by the monoclonal antibody (mAb) for ICOS. Blood and urine samples were collected 5 and 14 days after induction of anti-GBM glomerulonephritis. Mice were killed to facilitate histopathologic analyses at the same time. Anti-GBM glomerulonephritis was prevented from functionally deteriorating (eg, proteinuria or increasing serum creatinine) by CTLA4 immunoglobulin or anti-activation-inducible lymphocyte immunomodulatory molecule (AILIM) mAb as an anti-ICOS mAb. Nevertheless, double or single blockade of ICOS signaling showed a weaker inhibitory effect than single blockade of CD28 signaling in terms of the serum immunoglobulin level and histopathologic change. There is no synergistic effect between CTLA4 immunoglobulin and anti-AILIM mAb when simultaneously administered in experimental anti-GBM glomerulonephritis. Double blockade of both CD28 signaling and ICOS signaling is effective for preventing functional deterioration in this model. However, CD28 single blockade is more effective than double blockade both serologically and histopathologically.

Abatacept↗
PubMed2004

Economic slump and suicide method: preliminary study in Kobe.

During the recent half decade, Japan's suicide rate at approximately 25 deaths per 100 000 people has been one of the highest rates in the world. From the perspective of suicide prevention by restricting access to suicidal means, the aim of the present study was to examine what kind of suicidal method increased during prolonged economic slump. During 21 years (1981-2001), for all suicide victims (5161 cases) the gender, age, and suicide methods were investigated. The yearly full unemployment rate was also used as a representative socioeconomic factor during the same periods in Japan using government statistics, and the relationship between methods of suicide and full unemployment rate was investigated. Pearson's correlation suggested that there was a significant correlation only for hanging rate (r = 0.736, P < 0.001), but not for the percentages of other methods of suicide. This finding that unemployed persons may have a susceptibility towards certain suicide methods could help in the prevention of suicides. Mental health in Japan should be given more attention, especially for the working population, and social programs offering help should be considered widely.

Adolescent↗
PubMed2004

TNF-alpha is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice.

IL-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice spontaneously develop autoimmune arthritis. We demonstrate here that T cells are required for the induction of arthritis; T cell-deficient IL-1Ra(-/-) mice did not develop arthritis, and transfer of IL-1Ra(-/-) T cells induced arthritis in nu/nu mice. Development of arthritis was also markedly suppressed by TNF-alpha deficiency. We found that TNF-alpha induced OX40 expression on T cells and blocking the interaction between either CD40 and its ligand or OX40 and its ligand suppressed development of arthritis. These findings suggest that IL-1 receptor antagonist deficiency in T cells disrupts homeostasis of the immune system and that TNF-alpha plays an important role in activating T cells through induction of OX40.

Animals↗
PubMed2003

Involvement of ICOS-B7RP-1 costimulatory pathway in the regulation of immune responses to Leishmania major and Nippostrongylus brasiliensis infections.

The ICOS-B7RP-1-mediated T cell costimulatory pathway has been implicated crucial for T cell activation and differentiation. In this study, we investigated the role of this costimulation in the regulation of immune responses to parasitic infections by using blocking antibody against B7RP-1 as well as ICOS-deficient mice. The administration of anti-B7RP-1 monoclonal antibody (mAb) significantly suppressed the footpad swelling in susceptible BALB/c mice upon Leishmania major infection. The observation was consistent not only with the significant suppression of IL-4, IL-5 and IL-10 secretion from lymph node cells, which were derived from L. major-infected mice, but also with the significant reduction of total serum IgE and IgG(1) in anti-B7RP-1 mAb-treated BALB/c mice. Infection of ICOS-deficient mice with L. major also suggested the impaired Th2 immune responses in the absence of this costimulation. The immunological function of ICOS-B7RP-1 costimulatory pathway in infection was further confirmed by infecting anti-B7RP-1 mAb-treated wild type or ICOS-deficient mice with Nippostrongylus brasiliensis. The characteristic elevation of total serum IgE and eosinophilia upon N. brasiliensis infection was suppressed by blocking this costimulation. Moreover, the protection to N. brasiliensis adult worms was suppressed in anti-B7RP-1 mAb-treated wild type or ICOS-deficient mice. These results suggest the crucial role of this costimulatory pathway in the regulation of Th2-biased T cell differentiation and in host immune responses against L. major and N. brasiliensis infections.

Animals↗
PubMed2003

PI3-kinase and MAP-kinase signaling cascades in AILIM/ICOS- and CD28-costimulated T-cells have distinct functions between cell proliferation and IL-10 production.

Both AILIM/ICOS and CD28 provide positive costimulatory signals for T-cell activation, resulting in proliferation and cytokine production. In this study, we attempted to clarify the key signaling molecules in T-cell proliferation, and also IL-2 and IL-10 production, during T-cell activation by CD3 induced by costimulation with either AILIM/ICOS or CD28. We examined the role of both the PI3-kinase/Akt pathway and MAP kinase family members such as ERK1/2, JNK, and p38 kinase in this process. PI3-kinase and Erk1/2 were shown to potentially regulate primary T-cell activation and subsequent proliferation via both AILIM/ICOS- or CD28-mediated costimulation and the Erk signaling cascade was essential for this proliferation induction and also for IL-2 production. The JAK inhibitor, AG490, inhibited this induction. Our studies indicate that IL-2 is necessary for induction of T-cell proliferation and that the quantities of IL-2 produced by AILIM/ICOS ligation are also sufficient for T-cells to proliferate. In contrast, inhibition of Akt and p38, that are phosphorylated by both AILIM/ICOS and CD28-ligation, could downregulate IL-10 production but not T-cell proliferation. These data raise the interesting possibility that the signaling cascades between T-cell proliferation and IL-10 production are regulated by different molecules in AILIM/ICOS- and CD28-costimulated T-cells.

Antigens, CD↗
PubMed2003

Mechanism of allorecognition and skin graft rejection in CD28 and CD40 ligand double-deficient mice.

BACKGROUND: It has been shown that simultaneous blockade of CD28- and CD40-mediated costimulatory signals significantly prolongs allograft survival. Although these results led to an expectation of the establishment of specific immunotolerant therapy for organ transplantation, it became evident that these treatments rarely resulted in indefinite allograft survival. To uncover the mechanisms underlying these costimulation blockade-resistant allograft rejections, we studied the process of allogenic skin graft rejection in CD28 and CD40 ligand (L) double-deficient (double-knockout [dKO]) mice. METHODS: Skin grafts from BALB/c or BALB.B mice were transplanted to C57BL/6 background dKO mice. The frequency of CD4+ and CD8+ T cells responding to alloantigens presented by direct or indirect pathways were defined by the use of a cytostaining assay. RESULTS: BALB/c skin grafts were rapidly rejected by dKO mice. This CD28 and CD40L independent allograft rejection was inhibited by the depletion of CD8+ T cells. In vitro studies indicated that CD8+ T cells from BALB/c skin-grafted dKO mice responded to donor antigen presented only by the direct pathway. Unlike major histocompatibility complex (MHC)-mismatched donors, allogenic skin grafts from MHC-matched donors were accepted by dKO mice. CONCLUSION: In the absence of CD28 and CD40 costimulatory signals, CD8+ T cells recognize MHC antigens by the direct pathway, resulting in the rejection of skin grafts from MHC-mismatched donors. In contrast, MHC-matched and non-MHC-mismatched donor skin grafts indefinitely survive in dKO mice. These results indicated that donor-host MHC matching may still be critical to costimulation blockade therapy for organ transplantation.

Animals↗
PubMed2003

A role of suppressor of cytokine signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated interleukin 2 production.

Suppressor of cytokine signaling (SOCS)3 has been characterized as a negative feedback regulator in cytokine-mediated Janus kinase signal transducer and activator of transcription signaling. However, this study shows that T cells from transgenic mice expressing SOCS3 exhibit a significant reduction in interleukin (IL)-2 production induced by T cell receptor cross-linking when T cells are costimulated with CD28. Decreased protein expression in SOCS3(+/-) mice enhanced CD28-mediated IL-2 production, clearly indicating the correlation between expression level of SOCS3 and IL-2 production ability. The SOCS3 protein interacted with phosphorylated CD28 through its SH2 domain but not the kinase inhibitory region. In addition, a point mutation in the SOCS3 SH2 domain attenuated the inhibition of CD28 function in IL-2 promoter activation. Committed T helper (Th)2 cells exclusively expressed SOCS3 and production of Th2 cytokines, such as IL-4 and IL-5, was much less dependent on CD28 costimulation compared with interferon gamma and IL-2 production in Th1 cells. Consistent with this notion, the expression level of SOCS3 in early T cell activation influenced the ability of IL-2 production induced by CD28 costimulation. Therefore, the SOCS3 may play an alternative role in prohibiting excessive progression of CD28-mediated IL-2 production.

Animals↗
PubMed2003

A single amino acid alteration in cytoplasmic domain determines IL-2 promoter activation by ligation of CD28 but not inducible costimulator (ICOS).

The CD28 family molecules, CD28, and inducible costimulator (ICOS) all provide positive costimulatory signals. However, unlike CD28, ICOS does not costimulate IL-2 secretion. The YMNM motif that exists in the CD28 cytoplasmic domain is a known binding site for phosphatidylinositol 3-kinase (PI3-K) and Grb2. ICOS possesses the YMFM motif in the corresponding region of CD28 that binds PI3-K but not Grb2. We postulated that the reason that ICOS does not have the ability to induce IL-2 production is because it fails to recruit Grb2. To verify this hypothesis, we generated a mutant ICOS gene that contains the CD28 YMNM motif and measured IL-2 promoter activation after ICOS ligation. The results indicated that ICOS became competent to activate the IL-2 promoter by this single alteration. Further analysis demonstrated that Grb2 binding to ICOS was sufficient to activate the NFAT/AP-1 site in the IL-2 promoter and that the cytoplasmic domain of CD28 outside of the YMNM motif is required for activation of the CD28RE/AP-1 and NF-kappaB sites. Together, these observations lead us to believe that the difference of a single amino acid, which affects Grb2 binding ability, may define a functional difference between the CD28- and ICOS-mediated costimulatory signals.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Resistance of CD28-deficient mice to autologous phase of anti-glomerular basement membrane glomerulonephritis.

BACKGROUND: The engagement of CD28 on T cells provides an essential costimulatory signal for T-cell activation and differentiation. Recent studies suggest that CTLA4Ig inhibits T-cell activation in vitro and in vivo, prevents acute and chronic allograft rejection, and induces tolerance in some experimental transplantation models. METHODS: The present study examined the role of the CD28 costimulatory pathway in the induction of experimental anti-glomerular basement membrane (GBM) glomerulonephritis (GN). An accelerated type of anti-GBM GN was induced in wild-type mice and CD28-deficient (KO) mice. After 7 and 14 days, functional parameters, such as serum creatinine, amount of proteinuria, and serum mouse IgG levels were assessed. Histological studies were performed simultaneously to examine glomerular changes by light microscopy and immunoglobulin deposition by immunofluorescence staining. Flow cytometric analysis was undertaken to assess I-A(b) antigen expression on spleen cells. RESULTS: Anti-GBM GN induction was almost completely prevented in CD28-KO mice. CD28-KO mice had impaired ability to evoke B-cell activation, and developed lower mouse anti-rabbit IgG antibody titers in their serum than wild-type C57BL/6 mice. Furthermore, glomerular deposition of mouse anti-rabbit IgG was not detectable in CD28-KO mice after immunization with anti-GBM antibody. CONCLUSIONS: This is the first demonstration that the CD28 costimulatory pathway plays a critical role in autologous antibody production in anti-GBM GN, and suggests that effective inhibition of CD28-dependent autologous antibody production could be useful in the treatment of antibody-dependent GN in humans.

Animals↗
PubMed2003

Development of Th1 and not Th2 immune responses in mice lacking IFN-regulatory factor-4.

IFN-regulatory factor (IRF)-4 is a member of the IRF family of transcription factors expressed in lymphocytes and macrophages. The previous studies using mice deficient in the IRF-4 gene showed profound defects in function of both B and T cells. To further investigate the role of IRF-4 in CD4(+) T cell function, IRF-4(-/-) mice were challenged with the intracellular pathogen Leishmania major. The mice were protected against L. major during the early phase of the infection and CD4(+) T cells of the infected mice produced IFN-gamma in response to L. major antigen. However, during the late phase of infection, lymphocyte numbers were dramatically reduced in the draining lymph nodes, resulting in the deterioration of the lesion, indicating that IRF-4 was required for sustained immune responses against L. major infection. The function of CD4(+) T cells was further investigated using TCR transgenic mice lacking the IRF-4 gene. CD4(+) T cells from IRF-4(-/-) mice produced IFN-gamma and expressed T-bet after culture under T(h)1-skewing conditions in vitro. However, T(h)2 cell development was not observed after culture under T(h)2-polarizing conditions. Proliferation of CD4(+) T cells to IL-4 was reduced in IRF-4(-/-) mice, suggesting the defects in the responsiveness to IL-4. Furthermore, stimulation of the IRF-4(-/-) CD4(+) T cells with IL-4-induced activation of signal transducer and activator of transcription 6, but not expression of growth factor independent-1. Thus, development of CD4(+) T cell subsets differentially depends on IRF-4; induction of T(h)1 response does not depend on IRF-4, while T(h)2 response depends entirely on IRF-4.

Animals↗
PubMed2003

Critical contribution of CD28-CD80/CD86 costimulatory pathway to protection from Trypanosoma cruzi infection.

The CD28-CD80/CD86-mediated T-cell costimulatory pathway has been variably implicated in infectious immunity. In this study, we investigated the role of this costimulatory pathway in resistance to Trypanosoma cruzi infection by using CD28-deficient mice and blocking antibodies against CD80 and CD86. CD28-deficient mice exhibited markedly exacerbated T. cruzi infection, as evidenced by unrelenting parasitemia and 100% mortality after infection with doses that are nonlethal in wild-type mice. The blockade of both CD80 and CD86 by administering specific monoclonal antibodies also exacerbated T. cruzi infection in wild-type mice. Splenocytes from T. cruzi-infected, CD28-deficient mice exhibited greatly impaired gamma interferon production in response to T. cruzi antigen stimulation in vitro compared to those from infected wild-type mice. The induction of T. cruzi antigen-specific CD8(+) T cells was also impaired in T. cruzi-infected, CD28-deficient mice. In addition to these defects in natural protection against T. cruzi infection, CD28-deficient mice were also defective in the induction of CD8(+)-T-cell-mediated protective immunity against T. cruzi infection by DNA vaccination. These results demonstrate, for the first time, a critical contribution of the CD28-CD80/CD86 costimulatory pathway not only to natural protection against primary T. cruzi infection but also to DNA vaccine-induced protective immunity to Chagas' disease.

Animals↗