Xiu-Min Li

Elevated Immune Response in the Brain of Autistic Patients

UNLABELLED This study determined immune activities in the brain of ASD patients and matched normal subjects by examining cytokines in the brain tissue. Our results showed that proinflammatory cytokines (TNF-alpha, IL-6 and GM-CSF), Th1 cytokine (IFN-gamma) and chemokine (IL-8) were significantly increased in the brains of ASD patients compared with the controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no significant difference. The Th1/Th2 ratio was also significantly increased in ASD patients. CONCLUSION ASD patients displayed an increased innate and adaptive immune response through the Th1 pathway, suggesting that localized brain inflammation and autoimmune disorder may be involved in the pathogenesis of ASD.

A murine model of IgE-mediated cow's milk hypersensitivity.

BACKGROUND Cows milk allergy (CMA) is one of the leading causes of food allergy in children. Understanding the mechanisms involved in the development of CMA has been hampered by the lack of suitable animal models. OBJECTIVE We sought to develop a mouse model of IgE-mediated cows milk hypersensitivity (CMH) that mimics the clinical features of immediate CMA in humans. METHODS Three-week-old C3H/HeJ mice were sensitized by intragastric administration of cows milk (CM) plus cholera toxin and boosted 5 times at weekly intervals. RESULTS CM-specific IgE antibody levels were significantly increased at 3 weeks and peaked at 6 weeks after the initial feeding. Intragastric challenge with CM at week 6 elicited systemic anaphylaxis accompanied by vascular leakage, significantly increased plasma histamine, and increased intestinal permeability to casein. Histologic examination of intestinal tissue revealed marked vascular congestion, edema, and sloughing of enterocytes. The role of IgE in mediating CMH was confirmed by abrogation of passive cutaneous anaphylaxis reactions by heat inactivation of immune sera. Development of IgE-mediated CMH in this model is likely to be TH2 cell mediated because in vitro stimulation of spleen cells from mice allergic to CM induced significant increases in the levels of IL-4 and IL-5, but not IFN-gamma. CONCLUSION This model should provide a useful tool for evaluating the immunopathogenic mechanisms involved in CMA and for exploring new therapeutic approaches.

Crosstalk between Muscularis Macrophages and Enteric Neurons Regulates Gastrointestinal Motility

Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility. PAPERFLICK:

Engineered Recombinant Peanut Protein and Heat-Killed Listeria monocytogenes Coadministration Protects Against Peanut-Induced Anaphylaxis in a Murine Model

Peanut allergy (PNA) is the major cause of fatal and near-fatal anaphylactic reactions to foods. Traditional immunotherapy using peanut (PN) protein is not an option for PNA therapy because of the high incidence of adverse reactions. We investigated the effects of s.c. injections of engineered (modified) recombinant PN proteins and heat-killed Listeria monocytogenes (HKLM) as an adjuvant on anaphylactic reactions in a mouse model of PN allergy. PN-allergic C3H/HeJ mice were treated s.c. with a mixture of the three major PN allergens and HKLM (modified (m)Ara h 1–3 plus HKLM). The effects on anaphylactic reactions following PN challenge and the association with Ab levels and cytokine profiles were determined. Although all mice in the sham-treated groups exhibited anaphylactic symptoms with a median symptom score of 3, only 31% of mice in the mAra h 1–3 plus HKLM group developed mild anaphylaxis, with a low median symptom score of 0.5. Alterations in core body temperature, bronchial constriction, plasma histamine, and PN-specific IgE levels were all significantly reduced. This protective effect was markedly more potent than in the mAra h 1–3 protein alone-treated group. HKLM alone did not have any protective effect. Reduced IL-5 and IL-13, and increased IFN-γ levels were observed only in splenocytes cultures from mAra h 1–3 plus HKLM-treated mice. These results show that immunotherapy with modified PN proteins and HKLM is effective for treating PN allergy in this model, and may be a potential approach for treating PNA.

CpG Oligodeoxynucleotides Can Reverse Th2-Associated Allergic Airway Responses and Alter the B7.1/B7.2 Expression in a Murine Model of Asthma

CpG oligodeoxynucleotides (CpG-ODN) administered during Ag sensitization or before Ag challenge can inhibit allergic pulmonary inflammation and airway hyperreactivity in murine models of asthma. In this study, we investigated whether CpG-ODN can reverse an ongoing allergic pulmonary reaction in a mouse model of asthma. AKR mice were sensitized with conalbumin followed by two intratracheal challenges at weekly intervals. CpG-ODN was administered 24 h after the first Ag challenge. CpG-ODN administration reduced Ag-specific IgE levels, bronchoalveolar lavage fluid eosinophils, mucus production, and airway hyperreactivity. We found that postchallenge CpG-ODN treatment significantly increased IFN-γ concentrations and decreased IL-13, IL-4, and IL-5 concentrations in bronchoalveolar lavage fluids and spleen cell culture supernatants. Postchallenge CpG-ODN treatment also increased B7.1 mRNA expression and decreased B7.2 mRNA expression in lung tissues. These results suggest that CpG-ODN may have potential for treatment of allergic asthma by suppressing Th2 responses during IgE-dependent allergic airway reactions. The down-regulation of Th2 responses by CPG-ODN may be associated with regulation of the costimulatory factors B7.1 and B7.2.

Efficacy and mechanisms of action of traditional Chinese medicines for treating asthma and allergy

BACKGROUND Although corticosteroids and beta(2)-agonists are effective in managing asthma symptoms, a curative therapy for asthma is lacking. Traditional Chinese medicine (TCM), used in Asia for centuries, is beginning to play a role in Western health care as a complementary and alternative medicine modality. There is increasing scientific evidence supporting the use of TCM for asthma treatment. OBJECTIVE This review article discusses promising TCM interventions for asthma and explores their possible mechanisms of action. METHODS We first reviewed 5 clinical studies of antiasthma TCM herbal remedies published between 2005 and 2007. We then summarized possible mechanisms underlying their effects on the basis of data in the original articles, published abstracts, and available databases. Possible mechanisms include anti-inflammation, inhibition of airway smooth muscle contraction, and immunomodulation. Research on TCM herbal therapy for food allergy is rare, and we therefore focused on the effect and mechanism of action of food allergy herbal formula-2 on a murine model of peanut allergy and preliminary clinical study results. CONCLUSION Evidence from clinical studies supports beneficial effects of TCM herbal therapy on asthma. A number of mechanisms may be responsible for efficacy of these agents. Strong preclinical study data suggest the potential efficacy of food allergy herbal formula-2 for food allergy.

Food Allergy Herbal Formula-2 silences peanut-induced anaphylaxis for a prolonged posttreatment period via IFN-γ-producing CD8+ T cells

BACKGROUND Food allergy is a serious and sometimes fatal condition for which there is no cure. We previously reported that Food Allergy Herbal Formula (FAHF)-2) protected peanut-allergic mice against anaphylactic reactions as long as 4 weeks posttherapy. This formula is now in clinical trials in the United States. OBJECTIVE We sought to determine whether FAHF-2-mediated protection could be extended long-term and explored the mechanisms underlying its persistent immunomodulatory effects. METHODS Peanut-allergic mice received FAHF-2 daily orally by gavage for 7 weeks, and then received 7 oral peanut challenges at intervals of 4 to 10 weeks over a period of 36 weeks. For mechanistic studies, some mice received CD4(+) or CD8(+) T-cell-depleting antibodies or IFN-gamma-neutralizing antibodies. Anaphylactic symptoms, body temperatures, and plasma histamine levels were recorded after each challenge, and peanut-specific immunoglobulin levels and cytokine profiles of splenocytes, mesenteric lymph node cells, and purified CD4(+) and CD8(+) T cells were determined. RESULTS Food Allergy Herbal Formula-2 treatment protected mice from anaphylaxis for more than 36 weeks after discontinuing treatment. Peanut-specific IgE levels were reduced as much as 50%, whereas IgG(2a) levels were increased as much as 60%, and these effects persisted over time. T(H)2 cytokine production by CD4(+) T cells from FAHF-2-treated mice was reduced as much as 75%, whereas CD8(+) T-cell IFN-gamma production was markedly increased by as much as 85% at the final challenge. Neutralization of INF-gamma and depletion of CD8(+) T cells markedly attenuated FAHF-2 efficacy. CONCLUSIONS Food Allergy Herbal Formula-2 provides long-term protection from anaphylaxis by inducing a beneficial shift in allergen-specific immune responses mediated largely by elevated CD8(+) T-cell IFN-gamma production.

Safety, tolerability, and immunologic effects of a food allergy herbal formula in food allergic individuals: a randomized, double-blinded, placebo-controlled, dose escalation, phase 1 study

BACKGROUND Food allergy is a common and serious health problem. A new herbal product, called food allergy herbal formula 2 (FAHF-2), has been demonstrated to have a high safety profile and potent long-term efficacy in a murine model of peanut-induced anaphylaxis. OBJECTIVE To evaluate the safety and tolerability of FAHF-2 in patients with food allergy. METHODS In this randomized, double-blinded, placebo-controlled, dose escalation, phase 1 trial, patients received 1 of 3 doses of FAHF-2 or placebo: 2.2 g (4 tablets), 3.3 g (6 tablets), or 6.6 g (12 tablets) 3 times a day for 7 days. Four active and 2 placebo patients were treated at each dose level. Vital signs, physical examination results, laboratory data, pulmonary function test results, and electrocardiogram data were monitored. Immunomodulatory studies were also performed. RESULTS Nineteen food allergic participants were included in the study. Two patients (1 in the FAHF-2 group and 1 in the placebo group) reported mild gastrointestinal symptoms. One patient withdrew from the study because of an allergic reaction that was unlikely related to the study medication. No significant differences were found in vital signs, physical examination results, laboratory data, pulmonary function test results, and electrocardiogram data obtained before and after treatment visits. Significantly decreased interleukin (IL) 5 levels were found in the active treatment group after 7 days. In vitro studies of peripheral blood mononuclear cells cultured with FAHF-2 also demonstrated a significant decrease in IL-5 and an increase in culture supernatant interferon gamma and IL-10 levels. CONCLUSIONS FAHF-2 appeared to be safe and well tolerated in patients with food allergy.

Induction of tolerance after establishment of peanut allergy by the food allergy herbal formula‐2 is associated with up‐regulation of interferon‐γ

Background Peanut (PN)‐anaphylaxis is potentially life threatening. We previously reported that a Chinese herbal medicine preparation, food allergy herbal formula‐2 (FAHF‐2), prevented peanut allergy (PNA) in mice when administered during sensitization.

Role of TLR4 in allergic sensitization to food proteins in mice

Allergic sensitization to food proteins and other allergens is increasing in prevalence. One hypothesis for this increase is that the decreased rate of infections or exposure to microbial products leaves the immune system susceptible to inappropriate reactivity to innocuous antigens through the lack of development of regulatory cells. We hypothesized that constitutive Toll‐like receptor (TLR)4 signaling (presumably via the commensal flora) could inhibit the development of allergic sensitization to food proteins. We tested this hypothesis by sensitizing TLR4+ and TLR4− mice on two genetic backgrounds, C3H and BALB/c, to two common food allergens [β‐lactoglobulin (βLG) and peanut (PN)]. B‐cell responses were not significantly influenced by TLR4 status. T‐cell responses were Th2 skewed in TLR4‐deficient C3H mice compared with TLR4 sufficient C3H mice, but this pattern of Th2 skewing was not observed in TLR4‐deficient mice on a BALB/c background. In anaphylaxis‐susceptible C3H mice, TLR4 deficiency was associated with increased severity of anaphylaxis to PN, and decreased severity of anaphylaxis to βLG. In anaphylaxis‐resistant BALB/c mice, TLR4 deficiency was not sufficient to render mice susceptible to PN‐induced anaphylaxis. We conclude that although TLR4 status can influence T‐cell responses and anaphylaxis severity, the nature of the influence is highly antigen‐ and strain‐dependent.