Adoptive transfer of dendritic cells isolated from helminth-infected mice enhanced T regulatory cell responses in airway allergic inflammation

Our and others' previous studies have shown that Schistosoma japonicum (SJ) infection can inhibit allergic reactions. Moreover, we found that adoptive transfer of dendritic cells (DCs) from inhibited mice showed a similar inhibitory effect on allergy, suggesting a critical role of DCs in SJ-infected mediated inhibition of allergy. In this study, we further examined the mechanism by which DCs contribute to inhibition of allergy. Our results showed that DCs from SJ-infected mice (SJDCs) produced significantly higher levels of IL-10 compared to those from naive control mice (NDCs). Adoptive transfer of SJDCs, unlike NDCs, significantly increased CD4+CD25+Foxp3+ T cells and CD4+CD25+IL-10+ T cells regulatory T-cell responses in vivo. This was correlated with significantly reduced production of IL-4 and IL-5 by CD4+ T cells, eotaxin in lung tissues and reduced airway allergic inflammation in the SJDC recipients following allergen sensitization and challenge. These data suggest that helminth infection may induce tolerogenic DCs that can inhibit the development of airway allergic inflammation through enhancing T regulatory cell responses.     

Functional T cells in athymic nude mice.

After passage of spleen cells from nu/nu mice over a nylon wool column, concanavalin A-responsive cells can be detected in the presence of 2-mercaptoethanol, and specific cytotoxic T lymphocytes can be generated without exposure to interleukin 2 (IL-2). The spleen cells of the nu/nu mice born of nu/nu parents and nursed by nu/nu mothers had significantly fewer Thy-1+ T cells and a lesser capacity to generate cytotoxic T lymphocytes than did the conventionally bred nu/nu mice. Nonetheless, such cells were clearly present. IL-2 may act to cause these post-thymic T cells to proliferate. Therefore, it seems inappropriate to consider IL-2 as an inducer of the differentiation of T cells in the absence of thymic influence on the basis of the capacity of IL-2 to induce the appearance of a T-lymphocyte population in nu/nu mice.     

Recall helper T cell response: T helper 1 cell-resistant allergic susceptibility without biasing uncommitted CD4 T cells

Effector and memory T lymphocytes differ significantly, and there is no experimental evidence that memory cells are sufficient to render an otherwise normal individual susceptible to localized allergic inflammation. Furthermore, nothing is known about the kinetics of memory responses after inhalation of antigen or interplay between an allergen-specific memory helper T (Th) cell Th2 population and uncommitted or competing Th1 cells. To study these processes, T cell receptor-transgenic CD4(+) effector cells were generated in vitro, transferred into naive recipients, and allowed to resume a quiescent state. Inhalation of protein antigen reactivated these Ag-specific Th2 donor cells, leading to allergic pulmonary inflammation and airway hyperreactivity. Susceptibility was correlated with the size of the input Th2 population, but Th1 cells neither enhanced nor reduced inflammation in this model. Importantly, the reactivation of these antigen-experienced cells by inhaled antigen did not skew the cytokine balance of recipient-derived T cells recruited to the lung nor did it inhibit the development of donor-derived Th1 cells from uncommitted antigen-experienced cells that form a normal part of immune responses. These data indicate that a quiescent memory Th2-cell population can create susceptibility to allergic pulmonary inflammation in a manner refractory to inhibition by Th1 cells or endogenous inhibitory mechanisms.     

Targeting congestion in allergic rhinitis: the importance of intranasal corticosteroids.

The cardinal nasal symptoms of allergic rhinitis (AR) are sustained by an underlying inflammatory process. Congestion is one of the most prominent and distressing symptoms for patients and is strongly associated with a broadly deteriorated quality of life and significant losses in productivity. The purpose of this study was to explore the role of intranasal corticosteroids (INSs) in down-regulating the inflammatory response to allergen and their clinical efficacy on AR symptoms, particularly congestion. AR is characterized by an influx of inflammatory cells and mediators into the nasal mucosa after antigen exposure. The response is biphasic, encompassing an early and a late phase. Antigen exposure has a priming effect, decreasing the threshold for subsequent allergic reaction on rechallenge and increasing the responsiveness of the nasal mucosa. INSs are a mainstay of therapy for AR and the most effective intervention for nasal congestion and other nasal symptoms, with established superiority to antihistamines, decongestants, and leukotriene antagonists. In addition to symptom relief, INSs suppress numerous stages of the inflammatory cascade, inhibiting the influx of inflammatory cells and mediators. Topical nasal corticosteroids have a low incidence of local adverse effects, negligible systemic absorption, and excellent safety. Congestion is one of the most bothersome symptoms of AR. INS therapy improves AR symptoms, with particular efficacy in relieving congestion, by attenuating nasal hyperresponsiveness. Pretreatment with INSs has been shown to relieve early and late-phase clinical symptoms of AR. Modification of the disease process results in significant relief of symptoms and leads to fewer disease exacerbations.     

Safety considerations of intranasal corticosteroids for the treatment of allergic rhinitis.

Allergic rhinitis (AR) is a major chronic inflammatory disease of the upper airways. AR is increasing in prevalence and causes negative effects on quality of life, impairs performance and productivity, and imposes a serious economic burden. More than 20% of the American population suffers from AR. Intranasal corticosteroids (INS) are an effective and safe first-line treatment for AR, with potent anti-inflammatory properties and a high therapeutic ratio. The systemic bioavailability of the majority of INS is relatively low; however, the pharmacokinetics of absorption, first-pass metabolism, volume of distribution, half-life, and clearance of INS varies considerably, depending on lipophilicity, receptor affinity, and lipid conjugation in the nasal tissue. The short-term (e.g., effect on linear lower-leg growth rate) and long-term (e.g., effect on height) systemic side effects of INS in patients with AR are determined by these important characteristics. AR is present in up to 75% of patients with asthma, and patients with AR are three times more likely to develop asthma compared with patients without AR. Therefore, the overall increased systemic steroid burden resulting from concomitant use of inhaled corticosteroids (ICS) and INS in adult and pediatric patients with comorbid AR and asthma warrants critical monitoring of systemic side effects. This review evaluates the overall safety of INS in AR and the importance of systemic safety considerations of INS, particularly when coadministered with ICS.     

经门静脉骨髓基质细胞移植治疗肝纤维化

目的: 探讨移植骨髓基质细胞(BMSCs)减轻小鼠肝纤维化的作用.方法: BALB/c小鼠BMscs分离培养及经门静脉移植到BALB/c小鼠肝脏,二乙基亚硝胺诱导肝纤维化.60只小鼠随机分为对照组.模型组及治疗组.3 mo后测定ALT、AST、透明质酸酶(HA)和层黏连蛋白(LN)浓度,及肝脏羟基脯氨酸(Hyp)含量.免疫组化检测肝脏a.平滑肌肌动蛋白(α-SMA)表达,及荧光原位杂交鉴定移植的BMSCs向肝细胞的分化.结果: BMsCs在添加肝细胞生长因子(HGF)的培养基中体外培养能分化为肝细胞样细胞.与模型组相比.移植BMscs能显著降低血清ALT、AST、HA和LN的水平以及肝脏Hyp含量和α-SMA的表达(208±44 U/L 341±66 U/L,372±84 U/L vs 506±81 U/L,289±74μg/L vs 362±83 μg/L,178±48 μg/L vs 232±63 ug/L,900±141 mg/g liver vs1255±205mg/g liver,,均p<0.01).荧光原位杂交显示DEN诱导的损伤肝脏中有骨髓来源的肝细胞,3 mo后10%的肝细胞来源于BMSCs.结论: 在肝纤维化模型中,经门静脉移植的BMscs能分化为肝细胞,有效地恢复肝功能和减轻肝纤维化.     

Activation and expansion of hapten- and protein-specific T helper cells from nonsensitized mice.

Hapten- and protein-antigen-specific T helper cells are usually expanded in vitro from lymphocytes obtained from sensitized animals. In this paper we report on the primary activation and proliferation in vitro of T helper cells from nonsensitized animals by using syngeneic cultured epidermal Langerhans cells as a source of potent antigen-presenting cells. The primary in vitro proliferation was blocked with monoclonal antibodies to Ia molecules, to lymphocyte function-associated antigen 1 (LFA-1), and to L3T4. T helper cell populations sensitized in vitro to haptens and protein antigens showed hapten- and antigen-specific proliferation when restimulated in vitro with spleen cells. Besides its experimental usefulness, in vitro generation of syngeneic specific T helper cells may afford possibilities for adoptive immunotherapy.     

Transfer of peanut allergy from donor to recipient after liver transplant

31 years old female with a history of contact dermatitis, eczema, allergic rhinitis, pernicious anemia, alopecia areata and latent tuberculosis was treated concurrently with methotrexate along with isoniazid and pyridoxine. Five months into the therapy she developed acute onset jaundice progressing into fulminant liver failure with altered mentation and worsening liver function tests. Extensive workup including serological and histopathological evaluation revealed drug-induced liver injury as the etiology of her liver failure and she underwent a successful orthotropic liver transplant. On post-transplant follow-up at four months, she was noted to have an allergic reaction consisting of a perioral rash and swelling (without anaphylaxis) after receiving a kiss from her significant other who had just eaten a peanut butter chocolate. She denied any history of allergic reaction to peanuts prior to the transplant. Percutaneous skin testing revealed immediate hypersensitivity to peanut, hazelnut, and pecan believed to be acquired newly post-transplant. Further investigation revealed that the organ donor had a documented history of systemic anaphylaxis from the peanut allergy and a positive peanut-specific IgE level. Also, another parallel solid organ recipient (lung transplant) from the same organ donor experienced a serious anaphylactic reaction after peanut exposure. This is a case of food (peanut) allergy transfer from the donor to the recipient after the liver transplant. This case highlights the importance of incorporating known donor allergies as a part of pre-transplant screening, given the potentially serious consequences from the transfer of allergies to a previously anergic recipient.     

Interleukin 7 receptor-deficient mice lack gammadelta T cells.

The interleukin 7 receptor (IL-7R) plays a crucial role in early B- and T-cell development. It consists of a unique a chain and a common gamma chain [IL-2 receptor gamma chain (IL-2Rgamma)]. Gene inactivation of IL-7, IL-7R, and IL-2Rgamma resulted in severe impairment of B and T lymphopoiesis in mice. In addition, IL-2Rgamma-deficient mice lack gammadelta T cells in the skin and have the impaired development of natural killer (NK) cells and intraepithelial lymphocytes. To explore the role of IL-7/IL-7R system in gammadelta T- and NK-cell development, we have generated and analyzed IL-7R-deficient mice. gammadelta T cells were absent from skin, gut, liver, and spleen in the deficient mice. In contrast, alphabeta T and B cells were detected in reduced, but certain, numbers, and NK cells developed normally. The gammadelta T-cell development in fetal and adult thymus was also completely blocked. These results clearly demonstrate that the signal from IL-7R is indispensable for gammadelta T-cell development in both thymic and extrathymic pathways. On the contrary, it is suggested that NK-cell development requires cytokine(s) other than IL-7.     

Transfer of specific immunity from donor to recipient of an allogeneic bone marrow graft: effect of conditioning on the specific immune response of the graft recipient

Transfer of specific immunity was investigated in a group of 28 paediatric and adult leukaemia patients during the first 100 d after allogeneic bone marrow transplantation (BMT). These patients and/or their donors were immunized 7-13 d before transplantation with the recall antigen tetanus toxoid (TT) and the neo-antigen Helix pomatia haemocyanin (HPH). The recipients were booster immunized with both antigens at day 42 after transplantation. Transfer of a primary IgM and IgG response to HPH was successful in most paediatric and adult patients, but transfer of a secondary response to TT was established in only a few paediatric recipients. After booster immunization at day 42 most paediatric recipients responded with a rise in serum antibody titre to HPH as opposed to only two of 18 adult recipients. This incapability of the adult recipients to mount a secondary immune response may be related to their conditioning regimen which included Campath-IG in vivo. The results from this study indicate that transfer of immunity against recall- and neo-antigens is possible. However, the establishment of long-term memory may be affected by the regimen used to condition the graft recipient.     

T cells from epicutaneously immunized mice are prone to T cell receptor revision

Epicutaneous immunization of T cell receptor (TCR) transgenic (Tg) mice whose CD4(+) T cells are specific for the Ac1-11 fragment of myelin basic protein (MBP) with Ac1-11 elicits T cells with dominant suppressor/regulatory activity that confers protection against Ac1-11-induced experimental autoimmune encephalomyelitis. We now report that such disease-resistant MBP TCR Tg mice also harbor a sizeable fraction of peripheral CD4(+) T cells lacking surface expression of the Tg TCR beta chain and expressing diverse, endogenously rearranged TCR beta chains. Ex vivo incubation at physiological temperature caused the loss of neo-beta-chain expression and reversion to the MBP alphabeta TCR(+) phenotype. The presence of recombination activating gene 1 and 2 proteins in CD4(+) T cells with revised TCRs was consistent with effective V(D)J recombination activity. The emergence of these cells did not depend on the thymic compartment. We conclude that in mice epicutaneously immunized with an autoantigen, peripheral specific T cells are susceptible to multiple mechanisms of tolerance.     

Suppression of IgE secretion from hybridoma cells in allotype congenic mice: suppression of allotype 7a by T cells in allotype b mice.

Anti-2,4-dinitrophenyl (DNP) IgE producing hybridoma B 53 when injected subcutaneously is established equally well in syngeneic BALB/c (heavy-chain allotype a) and congenic CB20 (heavy-chain allotype b) mice. However, secretion of anti-DNP IgE monoclonal antibody is greatly suppressed in CB20 mice. B 53 cells taken from the subcutaneous tumors of CB20 mice produce anti-DNP IgE in vivo in BALB/c mice and in vitro. No difference was observed in IgE production between these cells and the controls taken from BALB/c mice. The suppression of IgE production was due to T cells and/or their product(s) of CB20 mice.     

Naive T cells proliferate strongly in neonatal mice in response to self-peptide/self-MHC complexes

Adult naive T cells, which are at rest in normal conditions, proliferate strongly when transferred to lymphopenic hosts. In neonates, the first mature thymocytes to migrate to the periphery reach a compartment devoid of preexisting T cells. We have extensively analyzed the proliferation rate and phenotype of peripheral T cells from normal C57BL/6 and T cell antigen receptor transgenic mice as a function of age. We show that, like adult naive T cells transferred to lymphopenic mice, neonatal naive T cells proliferate strongly. By using bone-marrow transfer and thymic-graft models, we demonstrate that the proliferation of the first thymic emigrants reaching the periphery requires T cell antigen receptor-self-peptide/self-MHC interactions and is regulated by the size of the peripheral T cell pool.     

Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice

BACKGROUND/AIMS: Mutations in SLC25A13, encoding the mitochondrial aspartate-glutamate carrier citrin, cause adult-onset type II citrullinemia (CTLN2) in humans. We have previously reported that although citrin-knockout (Ctrn-/-) mice fail to display symptoms of CTLN2, liver perfusion revealed a deficit in ureogenesis from ammonia accompanied by an increase in the perfusate lactate-to-pyruvate (L/P) ratio. The present study explores the effects of pyruvate, aspartate and citrate on improving the abnormalities observed in the Ctrn-/- liver. METHODS: We measured the rate of ureogenesis from ammonium chloride using the liver-perfusion system. RESULTS: Pyruvate infusion lowered the L/P ratio and corrected the deficit in ureogenesis in the Ctrn-/- liver. This effect was found to be dose-dependent in both instances. Phenazine methosulfate, a cytosolic oxidant, also improved the rate of ureogenesis in the Ctrn-/- liver and led to a fall in the L/P ratio. The addition of aspartate or citrate did not change either the rate of ureogenesis or the L/P ratio in the Ctrn-/- liver. CONCLUSIONS: Citrin deficiency disturbs urea synthesis primarily as a result of an elevated cytosolic NADH/NAD+ ratio owing to limited reoxidation of reducing equivalents. Clinically, pyruvate may have a therapeutic benefit for CTLN2 patients.     

Proliferative response in solid culture of T cells from healthy aged subjects

T lymphocytes from healthy aged subjects were challenged with 12-O-tetradecanoylphorbol-13-acetate (TPA, a T-cell mitogen) in solid cultures and compared under the same experimental conditions to a group of younger controls. The aged cells showed diminished proliferation and incorporation of tritiated thymidine (3H-Tdr). However, when unfractionated peripheral blood mononuclear cells or isolated T cells from the aged individuals were cultured in the presence of 2-mercaptoethanol, autologous erythrocytes or co-cultured with a non-T cell fraction, an increased proliferative response was observed. Our results suggest that the reduction in proliferative capacity of aged T cells observed in liquid culture is also elicited in solid conditions. However, under appropriate signals a TPA-susceptible T-cell subpopulation may contribute significantly in enhancing their in vitro response. This in turn would suggest that age-related cellular changes are intrinsic in nature and not fully reversible with potentiating factors.