Biomedical subjects

T Hiroi

Publications and source records attributed to T Hiroi.

At least 55 records · Page 3Linked to original sources

PubMed1998

High mucosal levels of tumor necrosis factor alpha messenger RNA in AIDS-associated cytomegalovirus-induced esophagitis.

BACKGROUND & AIMS: To evaluate the role of tumor necrosis factor alpha (TNF-alpha), a key inflammatory cytokine, in cytomegalovirus-associated gastrointestinal disease, we quantitated the level of TNF-alpha messenger RNA (mRNA) in esophageal mucosa from patients with cytomegalovirus-associated esophagitis and acquired immunodeficiency syndrome. METHODS: Four patients underwent endoscopic biopsy of their cytomegalovirus-associated esophageal ulcers before and after ganciclovir therapy. The level of TNF-alpha mRNA in coded esophageal specimens was assessed by in situ hybridization, reverse-transcription polymerase chain reaction, and quantitative polymerase chain reaction. RESULTS: Esophageal mucosa from 3 patients whose ulcers healed or markedly improved contained before therapy numerous macrophages expressing TNF-alpha mRNA and high tissue levels of TNF-alpha mRNA that decreased substantially or were not detectable after therapy. In contrast, esophageal specimens from the single patient whose ulcer worsened after therapy contained many mucosal macrophages expressing TNF-alpha mRNA before as well as after therapy, and the high number of molecules of TNF-alpha mRNA present in the tissue before therapy increased further after treatment. CONCLUSIONS: Increased macrophage production and high tissue levels of TNF-alpha mRNA are associated with cytomegalovirus-associated esophageal ulcers and probably contribute to the inflammatory response associated with cytomegalovirus-induced gastrointestinal disease.

AIDS-Related Opportunistic Infections↗

PubMed1998

Induction of Th2 cytokine expression for p27-specific IgA B cell responses after targeted lymph node immunization with simian immunodeficiency virus antigens in rhesus macaques.

To determine if there is an association between the isotype of simian immunodeficiency virus (SIV)-specific B cell responses and the profile of Th1 and Th2 cytokine expression, rhesus macaques were immunized with SIV antigens via the iliac lymph nodes, using a targeted lymph node (TLN) immunization procedure. When CD4+ T cells purified from antigen-stimulated peripheral blood mononuclear cells were analyzed, the levels of Th2 cytokine production were gradually increased after the second and third immunizations. However, interferon-gamma production did not change. Analysis of SIV-specific B cell responses revealed that the main isotype was IgG after the second and third immunizations. In addition, a peak of SIV-specific IgA B cell responses was noted following the third immunization. These findings suggest that the induction of Th2 type responses in TLN-immunized rhesus macaques reflects the sequence of initial induction of SIV-specific IgG-producing cells followed by IgA-secreting cells.

Animals↗

PubMed1998

High frequency oscillatory ventilation attenuates the activation of alveolar macrophages and neutrophils in lung injury.

BACKGROUND: Recent investigations have shown that leukocyte activation is involved in the pathogenesis of ventilator-associated lung injury. This study was designed to investigate whether the inflammatory responses and deterioration of oxygenation in ventilator-associated lung injury are attenuated by high-frequency oscillatory ventilation (HFO). We analyzed the effects of HFO compared with conventional mechanical ventilation (CMV) on the activation of pulmonary macrophages and neutrophils in 10 female rabbits. RESULTS: After surfactant depletion, the rabbits were ventilated by CMV or HFO at the same mean airway pressure. Surfactant-depletion followed by 4 h mechanical ventilation hindered pulmonary oxygenation in both groups. Impairment of oxygenation was less severe in the HFO group than in the CMV group. In the HFO group the infiltration of granulocytes into alveolar spaces occurred more readily than in the CMV group. Compared with CMV, HFO resulted in greater attenuation of beta2-integrin expression, not only on granulocytes, but also on macrophages. CONCLUSIONS: In the surfactant-depleted lung, the activation of leukocytes was attenuated by HFO. Reduced inflammatory response correlated with decreased impairment of oxygenation. HFO may reduce lung injury via the attenuation of pulmonary inflammation.

Journal Article↗

PubMed1998

Arginine enhances induction of T helper 1 and T helper 2 cytokine synthesis by Peyer's patch alpha beta T cells and antigen-specific mucosal immune response.

The effects of arginine on cell proliferation and subsequent T helper (Th) 1 and Th 2 cytokine synthesis by murine Peyer's patch (PP) Th cells in vitro and the influence of arginine on the induction of antigen-specific mucosal and systemic immune responses in vivo were examined. When the PP T cells were stimulated with the anti-alpha beta T cell receptor (TCR) antibody in the presence of different concentrations of arginine, a higher proliferative response was observed in the culture with an optimal concentration of arginine compared with that with a minimum amount of this amino acid. The concentration of cytokines in the supernatant, the number of cytokine-producing cells and the cytokine-specific mRNA expression of PP T cells were also increased in a dose-dependent fashion. Furthermore, when mice fed on an arginine-supplemented liquid diet were orally immunized with tetanus toxoid plus cholera toxin as a mucosal adjuvant, a higher level of antigen-specific fecal IgA was observed when compared with the response in mice fed on an arginine-free diet. Taken together, these results suggest that arginine enhanced antigen-specific mucosal immune response resulting from the supporting activation of cell proliferation and subsequent cytokine synthesis of PP Th cells.

Animal Feed↗

PubMed1997

Expression of four rat CYP2D isoforms in Saccharomyces cerevisiae and their catalytic specificity.

We cloned four cDNAs belonging to the CYP2D subfamily to express these enzymes in yeast cells and to compare their catalytic activities simultaneously. Three are believed to be alleles of CYP2D1, 2D2, and 2D3, respectively, based on high nucleotide sequence similarity, while CYP2D4 had both sequences of CYP2D4 and CYP2D18. Expression plasmids carrying CYP2D cDNAs were transformed into Saccharomyces cerevisiae. Typical P450 CO-difference spectra with absorbance maximum at 448 nm were recorded with microsomal preparations from the yeast cells expressing the four CYP2D forms. A catalytic study of these CYP2D forms was done with debrisoquine, bufuralol, and lidocaine. CYP2D2 had the highest debrisoquine 4-hydroxylation (2.2 nmol/min/nmol P450) activity, similar to that (2.2 nmol/min/nmol) of human CYP2D6 expressed in yeast cells. CYP2D3 had high lidocaine N-deethylation (43 nmol/min/nmol P450) activity, and both CYP2D3 and 2D2 exhibited high lidocaine 3-hydroxylation (2.4 and 1.6 nmol/min/nmol P450, respectively) activity. Bufuralol 1'-hydroxylation catalytic capabilities were comparable among the four isoforms. The activity of CYP2D1 was relatively low toward the three substrates (debrisoquine, 0.091; bufuralol, 1.5; lidocaine 3-hydroxylation, 0.019; lidocaine N-deethylation, 2.8 nmol/min/nmol P450). These findings indicate that debrisoquine, a typical substrate for CYP2D forms, was mainly metabolized by CYP2D2 but not CYP2D1 in rat liver and that the CYP2D forms have different substrate specificity.

Animals↗

PubMed1997

SP-22 is a thioredoxin-dependent peroxide reductase in mitochondria.

SP-22 is a mitochondrial antioxidant protein in bovine adrenal cortex. The protein is homologous to thioredoxin peroxidase and other antioxidant proteins. It protects radical-sensitive enzymes from oxidative damage by a radical-generating system (Fe2+/dithiothreitol) in the presence of a small amount of serum. In this study we purified a second mitochondrial protein with Mr 11,777, which cooperates with SP-22 to protect glutamine synthetase and other proteins from Fe2+/dithiothreitol-mediated damage. Without SP-22, the protein had no protecting activity. We determined amino acid and nucleotide sequences of the protein and its cDNA, respectively, and found that it was a protein of the thioredoxin family. The protein, designated as mt-Trx (mitochondrial thioredoxin), had a presequence composed of 59 amino acids that seemed to be a mitochondrial targeting signal. Mitochondrial extract prepared from adrenal cortex contained NADPH-dependent 5,5'dithiobis(2-nitrobenzoic acid) (Nbs2) reductase activity. The enzyme was thought to have thioredoxin reductase activity, since the Nbs2-reducing activity was stimulated by mt-Trx. We partially purified the Nbs2 reductase from bovine adrenocortical mitochondria. In the presence of the partially purified reductase, mt-Trx, and NADPH, SP-22 showed the activity to protect oxyhemoglobin against ascorbate-induced damage. Furthermore, with the three protein components (Nbs2 reductase, mt-Trx, and SP-22) NADPH was oxidized in the presence of hydrogen peroxide or tert-butyl hydroperoxide. The oxidation of NADPH was concomitant with the disappearance of an equimolar amount of hydrogen peroxide. Without any one of the protein components no hemoglobin-protecting and peroxide-dependent NADPH-oxidizing activities were observed. From these results we concluded that SP-22 is thioredoxin-dependent peroxide reductase or so-called thioredoxin peroxidase in mitochondria from the adrenal cortex.

Adrenal Cortex↗

PubMed1997

Specific binding of 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl propyl) piperazine (GBR-12935), an inhibitor of the dopamine transporter, to human CYP2D6.

The binding of [3H]1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl propyl) piperazine (GBR-12935), an antagonist of the dopamine transporter, to human P450s expressed in yeast cells was investigated. Among the ten forms of human P450 tested (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2D6, 2E1, and 3A4), [3H]GBR-12935 bound most strongly to CYP2D6. The calculated Kd of [3H]GBR-12935 binding to CYP2D6 was 42.2 nM, indicating that GBR-12935 has a high affinity for CYP2D6. The characteristics of [3H]GBR-12935 binding to CYP2D6 were investigated by competitive studies using several chemicals. The binding of [3H]GBR-12935 to CYP2D6 was not changed by dopamine, suggesting that these binding sites are not dopamine-sensitive binding sites. The binding of [3H]GBR-12935 to CYP2D6 was decreased partially by substrates or inhibitors of CYP2D isoforms (quinine, quinidine, propranolol, bufuralol, imipramine, and desipramine). By means of binding studies using several forms of expressed human P450, we demonstrated that the CYP2D isoform is one GBR-12935 binding site that is insensitive to dopamine.

Carrier Proteins↗

PubMed1997

Suppressive effects of tranilast on the expression of inducible cyclooxygenase (COX2) in interleukin-1beta-stimulated fibroblasts.

We investigated the effects of tranilast on inducible cyclooxygenase (COX2)-mediated prostaglandin E2 (PGE2) production and enzyme induction in interleukin-lbeta (IL-1beta)-stimulated cultured dermal fibroblasts. IL-1beta enhanced PGE2 production in cultured fibroblasts. Tranilast did not affect constitutive cyclooxygenase (COX1) or COX2 activity in non-stimulated or IL-lbeta-stimulated fibroblasts. However, the COX2 expression induced by IL-1beta was inhibited by tranilast. This result, that IL-1beta-induced COX2 expression was suppressed by tranilast, was confirmed by immunohistochemical analysis. Thus, it is possible for tranilast to regulate PGE2 production by inhibiting COX2 induction.

Anti-Allergic Agents↗

PubMed1997

Bacterial invasion induces interleukin-7 receptor expression in colonic epithelial cell line, T84.

The intestinal epithelial layer forms the interface between the external and the internal environments of a host. Since the interleukin-7 (IL-7) and IL-7 receptor (IL-7R) signaling pathway has been shown to play an important role in the mucosal immune system, we studied the expression of IL-7R in T84, a colonic epithelial cell line, after cells were infected with several types of enteropathogenic bacteria, including Salmonella typhimurium, enteropathogenic Escherichia coli and enteroinvasive Escherichia coli. Bacterial invasion induced IL-7R expression in T84 assessed by a semi-quantitative reverse transcription-polymerase chain reaction technique and flow cytometry. The inhibition of bacterial invasion by cytochalasin D, a specific inhibitor of actin polymerization, led to a reduction in the expression of IL-7R. These data indicate that bacterial invasion into intestinal epithelial cells is likely to be an essential process in the induction of IL-7R. The communication between the epithelium and mucosal lymphocytes which is mediated via IL-7 and IL-7R may be involved in the modulation of the mucosal inflammation which occurs in bacterial infection.

Antigens, CD↗

PubMed1997

Molecular and cellular mechanisms for periodontal diseases: role of Th1 and Th2 type cytokines in induction of mucosal inflammation.

An accumulation of elevated numbers of macrophages (M phi) and Ig producing cells is associated with localized and chronically inflamed gingiva of patients with adult periodontitis. When gingival lymphocytes were isolated from inflamed tissues and examined by flow cytometry, approximately 20-30% of lymphocytes were CD4+ T cells. For the analysis of Th1 and Th2 cytokine expression by these CD4+ T cells, RNA was extracted and reverse transcriptase polymerase chain reaction (RT-PCR) was performed by using specific 5' and 3' primers for IFN-gamma and IL-2 (Th1), IL-4, IL-5, IL-6, IL-10 and IL-13, (Th2) and beta-actin (housekeeping gene). Two distinct cytokine profiles were noted based on the expression of selected Th1 and Th2 cytokines. Thus, one pattern was represented by the expression of mRNA for IFN-gamma, IL-6, IL-10 and IL-13, while the other case consisted of mRNA for IFN-gamma, IL-6, and IL-13. Except for a few cases, messages for IL-2, IL-4 and IL-5 were not detected by cytokine-specific RT-PCR. The predominant expression of Th2 cytokines (e.g. IL-6, IL-10 and IL-13) may contribute to the induction of high B cell responses in local disease sites. On the other hand, lack of IL-4 may be responsible for the accumulation of M phi in diseased periodontium. We also investigated whether a relationship exists between IL-4 receptor (IL-4R) expression and M phi persistence in the absence of exogenous IL-4. Gingival M phi, when compared with monocytes (MN)/M phi from peripheral blood mononuclear cells (PBMC), expressed high levels of IL-4R mRNA. When gingival M phi were incubated with recombinant IL-4 (rIL-4), the cell viability was dramatically reduced by apoptosis. These findings clearly show that the lack of IL-4 may contribute to the persistent occurrence of M phi at the disease site and addition of exogenous rIL-4 to gingival M phi cultures leads to cell death by apoptosis.

Adult↗

PubMed1997

Affinity for [3H]iloprost binding sites and cAMP synthesis activity of a 3-oxa-methano prostaglandin I1 analog, SM-10906, in human platelets and endothelial cells.

SM-10902 ((+)-methyl [2-[(2R,3aS,4R,5R,6aS)-octahydro-5-hydroxy-4-[(E)-(3S,5S)-3- hydroxy-5-methyl-1-nonenyl]-2-pentalenyl]ethoxy]acetate) and its free acid, SM-10906 are new stable 3-oxa-methano prostaglandin (PG) I1 analogs. Their affinities for [3H]iloprost and [3H]PGE2 binding sites in human platelets and human umbilical vascular endothelial cells were compared with those of the PGI2 analog iloprost, PGE1 and PGE2 by the radioligand binding assay method. The cyclic AMP (cAMP) synthesis activity of these drugs were also determined in human umbilical vascular endothelial cells. We found that SM-10906 apparently displaced [3H]iloprost binding to the membrane fractions in those cells since the pKi values were 6.30 in platelets, 7.52 in vein endothelial cells and 6.31 in the arterial endothelial cells. The pKi values of SM-10906 for [3H]PGE2 binding sites were significantly lower than those obtained for [3H]iloprost binding. SM-10902, which is a prodrug of SM-10906, showed low affinity for [3H]iloprost binding sites in those cells. SM-10906 also dose-dependently enhanced the cAMP level in the vascular endothelial cells. Thus, these findings indicate that SM-10906 binds to [3H]iloprost binding sites and exhibits pharmacological functions such as an anti-platelet action and a cytoprotective action in endothelial cells through the elevation of intracellular cAMP contents.

Adult↗

PubMed1997

Acetaldehyde as well as ethanol is metabolized by human CYP2E1.

Acetaldehyde was oxidized by rat and human hepatic microsomes in the presence of NADPH. We designated this NADPH-dependent oxidation system MAOS (microsomal acetaldehyde-oxidizing system), to distinguish it from the NAD-dependent acetaldehyde oxidation system of acetaldehyde dehydrogenase in mitochondria and cytosol. This activity was increased 2.3-fold by giving rats ethanol. Judging from the Vmax/Km values, the metabolic capacity of rat hepatic microsomes for MAOS activity was increased 24-fold by ethanol. The acetaldehyde oxidation activity of eight forms of purified rat cytochrome P450 was investigated in a reconstituted system. CYP2E1 had the highest level, followed by CYP1A2 and 4A2. Immunoinhibition studies showed that an anti-CYP2E1 antibody inhibited 90% of the MAOS activity in rats given ethanol. NADPH-dependent acetate formation was 12% or 33.6% of the NAD-dependent acetate formation in liver homogenates of control rats and those treated with ethanol, respectively. We investigated human MAOS activity further. Among the 10 forms of human cytochrome P450 expressed in yeast, CYP2E1 had especially high acetaldehyde oxidation activity. The correlation of MAOS activity with the levels of immunoreactive CYP2E1 in individual human microsomes was highly significant (r2 = 0.88, P < .01). These results indicate that hepatic CYP2E1 mainly contributes to MAOS in rats and humans, the pathway of which may play an alternative role against acetaldehyde in the liver after alcohol consumption together with acetaldehyde dehydrogenase in the metabolism of acetaldehyde.

Acetaldehyde↗

PubMed1997

[Mucosal immune system and mucosal vaccine].

In the recent years, mucosal immune system is recognized as the new world in the area of immunology. The host is continuously exposed to the numerous numbers of environmental antigens via the mucosa and the skin. A total surface area of the mucosa is approximately 200 times larger than that of the skin, and the former surface area contains a large numbers of lymphoid cells (> 10(11)). In order to provide an effective defence for the host by vaccine, it is logical to consider the mucosal immune system. According to the new informations obtained by the modern cellular and molecular immunobiological knowledges and approaches, the concept of the mucosal immune system has been rapidly proceeded to apply for the development of mucosal vaccine. In this report, we have reviewed and discussed the recent progress in the characterization of mucosal immune system and the development of mucosal vaccine.

Animals↗

PubMed1997

Metabolism of epinastine, a histamine H1 receptor antagonist, in human liver microsomes in comparison with that of terfenadine.

Epinastine is a non-sedative second-generation antiallergic drug, like terfenadine. In the present study, the metabolism of epinastine in human liver microsomes was investigated and compared with that of terfenadine. Terfenadine was extensively metabolized to terfenadine acid with a Km value of 1.78 microM, a Vmax value of 173.8 pmol/min/mg and a metabolic clearance (Vmax/Km) of 103.9. Epinastine, in contrast, was poorly metabolized by microsomes from the same source with a high Km value of 232 microM. Metabolic clearance of epinastine was only 0.832, which was lower by three orders of magnitude than that of terfenadine. Studies with microsomes expressing recombinant cytochrome P450 (CYP) species revealed that the CYP isoforms responsible for epinastine metabolism are CYP3A4, 2D6 and (to a minor extent) 2B6. Epinastine and terfenadine had no effect on CYP1A2 (theophylline 1-demethylation), 2C8/9 (tolbutamide hydroxylation) or 2E1 (chlorzoxazone 6-hydroxylation) activity, but weakly inhibited CYP2D6 (debrisoquine 4-hydroxylation) activity. CYP3A4 (testosterone 6 beta-hydroxylation) activity was strongly inhibited by terfenadine with a Ki value of 25 microM, whereas epinastine had no effect at up to 100 microM. Thus, epinastine is very poorly metabolized compared to terfenadine in human liver microsomes and does not inhibit CYP3A4 activity in vitro, unlike terfenadine.

Aryl Hydrocarbon Hydroxylases↗

PubMed1996

Multiple forms of human P450 expressed in Saccharomyces cerevisiae. Systematic characterization and comparison with those of the rat.

We systematically characterized the levels and substrate specificity of P450s from humans and rats to extrapolate drug metabolism data from experimental animals to humans. Human P450s (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2D6, 2E1, and 3A4) were expressed in Saccharomyces cerevisiae and purified. Rat P450s were purified from hepatic microsomes of rats. We investigated the catalytic activities of purified P450s in a reconstituted system. Human CYP2B6 and rat CYP2B1 had high lidocaine N-deethylation activity. Human and rat CYP2D forms had high debrisoquine 4-hydroxylation activity. Human CYP3A4 and rat CYP3A2 had high testosterone 2 beta- and 6 beta-hydroxylation activities in a modified reconstituted system with a lipid mixture. The hydroxylation site of testosterone by CYP2B6 (16 alpha- and 16 beta-positions) agreed with that by rat CYP2B1. Human CYP2E1 had the highest lauric acid (omega-1)-hydroxylation activity and also had catalytic properties similar to those of rat CYP2E1. Human CYP2A and 2C forms had catalytic properties in testosterone metabolism different from those of rats. Antibodies raised against purified P450s were used to measure the levels of hepatic P450s. The level of CYP3A4 was the highest in human hepatic microsomes, comprising 30-40% of the total P450. CYP2C9 comprised 10-20% of the total. The levels of CYP1A2, 2A6, 2C8, 2D6, and 2E1 were moderate (5-15% of total P450). CYP2B6 content was very low. The information of this study is useful for drug metabolism and toxicological studies.

Animals↗

PubMed1996

Interleukin 2 (IL-2) and interleukin 7 (IL-7) reciprocally induce IL-7 and IL-2 receptors on gamma delta T-cell receptor-positive intraepithelial lymphocytes.

In this study, we describe the interaction between cytokine and cytokine receptor (R) for the activation and proliferation of gamma delta T-cell receptor-positive T cells (gamma delta T cells). gamma delta T cells isolated from murine intestinal intraepithelial lymphocytes (IELs) were separated into gamma delta (Dim) and gamma delta (Bright) fractions according to the intensity of gamma delta T-cell receptor expression. The gamma delta T cells express low levels of IL-2R and IL-7R as shown by flow cytometry and reverse transcriptase-PCR analysis, whereas gamma delta (Bright) T cells did not express either receptor. Our study also revealed that recombinant marine (rm)IL-2 and rmIL-7 reciprocally induced high expressions of IL-7R and IL-2R, respectively, on gamma delta (Dim) T cells but not on gamma delta (Bright) cells. Thus, treatment of gamma delta (Dim) T cells with rmIL-2 and rmIL-7 resulted in high proliferative responses, whereas gamma delta (Bright) T cells did not respond to these two cytokines. The sources of these two cytokines for gamma delta T cells were neighboring epithelial cells (IL-7) and alpha beta T cells (IL-2 and IL-7). Cytokine signaling by IL-2 and IL-7 from alpha beta T cells and epithelial cells was necessary for the expression of IL-7R and IL-2R, respectively, on a subset of gamma delta T cells (e.g., gamma delta (Dim) T cells) in mucosa-associated tissue for subsequent activation and cell division.

Animals↗

PubMed1996

gamma/delta T cell-deficient mice have impaired mucosal immunoglobulin A responses.

Mucosal tissues of mice are enriched in T cells that express the gamma/delta T cell receptor. Since the function of these cells remains unclear, we have compared mucosal immune responses in gamma/delta T cell receptor-deficient (TCRdelta-/-) mice versus control mice of the same genetic background. The frequency of intestinal immunoglobulin (Ig) A plasma cells as well as IgA levels in serum, bile, saliva, and fecal samples were markedly reduced in TCRdelta-/- mice. The TCRdelta-/- mice produced much lower levels of IgA antibodies when immunized orally with a vaccine of tetanus toxoid plus cholera toxin as adjuvant. Conversely, the antigen-specific IgM and IgG antibody responses were comparable to orally immunized control mice. Direct assessment of the cells forming antibodies against the tetanus toxoid and cholera toxin antigens indicated that significantly lower numbers of IgA antibody-producing cells were present in the intestinal lamina propria and Peyer's patches of TCRdelta-/- mice compared with the orally immunized control mice. The selective reduction of IgA responses to ingested antigens in the absence of gamma/delta T cells suggests a specialized role for gamma/delta cells in mucosal immunity.

Animals↗

PubMed1996

Role of gamma delta T cells in the regulation of mucosal IgA response and oral tolerance.

In this short review, we first described experiments that show that prolonged oral immunization with a protein vaccine, such as DT, induced systemic unresponsiveness in the presence of antigen-specific mucosal IgA responses. Mucosal T cells, such as IEL, may play an important role for the maintenance of antigen-specific IgA responses because these T cells are able to respond to stimulation signals provided by antigen even when T-cell unresponsiveness was induced in systemic tissue, such as spleen of mice orally tolerized with the protein DT. Inasmuch as IEL contain a high frequency of gamma delta T cells, it was logical to postulate that mucosal gamma delta T cells are essential regulatory T cells for the induction of IgA responses in oral tolerance. To this end, our previous studies showed that adoptive transfer of mucosal gamma delta T cells from IEL of mice orally tolerized with SRBC to the recipient mice with systemic unresponsiveness to the same antigen resulted in the abrogation of unresponsiveness to Ig synthesis, including those of IgA isotype. In this regard, when the mucosal immune system of TCR-delta-/- and their control mice was examined, lower numbers of IgA antibody-producing cells were noted in TCR-delta-/- mice in comparison to control background mice. Further, the level of IgA in fecal extracts was also low in TCR-delta-/- mice. These findings suggested that loss of gamma delta T cells in down-regulation of IgA B-cell responses.

Administration, Oral↗