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author:("larch, Mark")
1.  The Effect of Rituximab on Vaccine Responses in Patients with Immune Thrombocytopenia 
Blood  2013;122(11):1946-1953.
B-cell depletion therapy may impair vaccine responses and increase infection risk in patients with immune thrombocytopenia (ITP). Capitalizing on a multicenter randomized placebo-controlled trial, we investigated the effects of rituximab on the antibody and cellular responses to Streptococcus pneumoniae polysaccharide vaccine and Haemophilus influenzae type b (Hib) conjugate vaccine in ITP patients. Of 60 patients in the main trial, 24 patients received both vaccines 6 months after rituximab (n=17) or placebo (n=7). Among 20 evaluable patients, 3/14 (21%) in the rituximab group and 4/6 (67%) in the placebo group achieved a 4-fold increase in anti-pneumococcal antibodies (p=0.12). For anti-Hib antibodies, 4/14 (29%) and 5/6 (83%), respectively, achieved a 4-fold increase (p<0.05). Fewer patients in the rituximab group demonstrated functional Hib killing (2/14 [14%] versus 5/6 [83%], p<0.05). Three of 14 rituximab-treated patients failed to respond to vaccines by any criteria. After vaccinations, pre-plasma cell blasts and interferon-γ secreting T-cells were reduced in rituximab-treated patients. We found that antibody responses were impaired for at least 6 months after rituximab. Cellular immunity was reduced in parallel with the depleted B-cell pool. These findings have implications for the timing of vaccinations and the mechanism of infection after rituximab in patients with ITP.
doi:10.1182/blood-2013-04-494096
PMCID: PMC3773242  PMID: 23851398 CAMSID: cams3208
3.  Airway hyperresponsiveness and bronchial mucosal inflammation in T cell peptide‐induced asthmatic reactions in atopic subjects 
Thorax  2007;62(9):750-757.
Background
Subjects with allergic asthma develop isolated late asthmatic reactions after inhalation of allergen‐derived T cell peptides. Animal experiments have shown that airway hyperresponsiveness (AHR) is CD4+ cell‐dependent. It is hypothesised that peptide inhalation produces increases in non‐specific AHR and a T cell‐dominant bronchial mucosal inflammatory response.
Methods
Bronchoscopy, with bronchial biopsies and bronchoalveolar lavage (BAL), was performed in 24 subjects with cat allergy 6 h after aerosol inhalation of short overlapping peptides derived from Fel d 1, the major cat allergen. Biopsy specimens and BAL fluid were studied using immunohistochemistry and ELISA.
Results
Twelve of the 24 subjects developed an isolated late asthmatic reaction without a preceding early (mast cell/histamine‐dependent) reaction characteristic of whole allergen inhalation. These responders had significant between‐group differences (responders vs non‐responders) in the changes (peptide vs diluent) in AHR (p = 0.007) and bronchial mucosal CD3+ (p = 0.005), CD4+ (p = 0.006) and thymus‐ and activation‐regulated chemokine (TARC)+ (p = 0.003) but not CD8+ or CD25+ cells or eosinophils, basophils, mast cells and macrophages. The between‐group difference for neutrophils was p = 0.05 but with a non‐significant within‐group value (peptide vs diluent, responders, p = 0.11). In BAL fluid there was a significant between‐group difference in TARC (p = 0.02) but not in histamine, tryptase, basogranulin, C3a or C5a, leukotrienes C4/D4/E4, prostaglandins D2 or F2α.
Conclusions
Direct activation of allergen‐specific airway T cells by peptide inhalation in patients with atopic asthma leads to increased AHR with local increases in CD3+ and CD4+ cells and TARC but no significant changes in eosinophils or basophil/mast cell products. These findings support previous animal experiments which showed a CD4+ dependence for AHR.
doi:10.1136/thx.2006.072041
PMCID: PMC2117301  PMID: 17389757
4.  Peptide immunotherapy in allergic asthma generates IL-10–dependent immunological tolerance associated with linked epitope suppression 
The Journal of Experimental Medicine  2009;206(7):1535-1547.
Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other (“linked”) epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10+ T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti–IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans.
doi:10.1084/jem.20082901
PMCID: PMC2715096  PMID: 19528258
5.  The IgE-facilitated allergen binding (FAB) assay: validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses 
Journal of immunological methods  2006;317(1-2):71-79.
The IgE-Facilitated Allergen Binding (IgE-FAB) assay represents an in vitro model of facilitated allergen presentation. Allergen-IgE complexes are incubated with an EBV-transformed B-cell line and complexes bound to CD23 on the surface of cells are detected by flow cytometry. Addition of serum from patients who have received allergen-specific immunotherapy has been shown previously to inhibit allergen-IgE complex binding to CD23 on B cells.
In this study, we describe the characterisation and analytical validation of the grass pollen-specific IgE-FAB assay according to guidelines from the International Conference on Harmonisation. We established the intra and inter -assay variability of IgE-FAB and have defined the detection limits of this assay. We have also demonstrated assay linearity and robustness. Using results from a randomised double-blind placebo controlled trial of grass pollen immunotherapy (n=33), we have defined the clinical sensitivity and specificity of the IgE-FAB assay using ROC curve analysis.
In conclusion, the IgE-FAB assay is reproducible, robust, sensitive and specific method suitable as a tool for monitoring inhibitory antibody function from patients receiving allergen immunotherapy.
doi:10.1016/j.jim.2006.09.004
PMCID: PMC1934503  PMID: 17070537
IgE-facilitated allergen presentation; Allergen-specific immunotherapy; Allergic rhinitis; IgG blocking antibodies; Assay validation
6.  Immunotherapy with Allergen Peptides 
Specific allergen immunotherapy (SIT) is disease-modifying and efficacious. However, the use of whole allergen preparations is associated with frequent allergic adverse events during treatment. Many novel approaches are being designed to reduce the allergenicity of immunotherapy preparations whilst maintaining immunogenicity. One approach is the use of short synthetic peptides which representing dominant T cell epitopes of the allergen. Short peptides exhibit markedly reduced capacity to cross link IgE and activate mast cells and basophils, due to lack of tertiary structure. Murine pre-clinical studies have established the feasibility of this approach and clinical studies are currently in progress in both allergic and autoimmune diseases.
doi:10.1186/1710-1492-3-2-53
PMCID: PMC2873623  PMID: 20525144
allergy; epitope; IL-10; immunological tolerance; immunotherapy; peptide; regulatory T cell; T cell
7.  Tregs and allergic disease 
Journal of Clinical Investigation  2004;114(10):1389-1397.
Allergic diseases such as asthma, rhinitis, and eczema are increasing in prevalence and affect up to 15% of populations in Westernized countries. The description of Tregs as T cells that prevent development of autoimmune disease led to considerable interest in whether these Tregs were also normally involved in prevention of sensitization to allergens and whether it might be possible to manipulate Tregs for the therapy of allergic disease. Current data suggest that Th2 responses to allergens are normally suppressed by both CD4+CD25+ Tregs and IL-10 Tregs. Furthermore, suppression by these subsets is decreased in allergic individuals. In animal models, Tregs could be induced by high- or low-dose inhaled antigen, and prior induction of such Tregs prevented subsequent development of allergen sensitization and airway inflammation in inhaled challenge models. For many years, allergen-injection immunotherapy has been used for the therapy of allergic disease, and this treatment may induce IL-10 Tregs, leading to both suppression of Th2 responses and a switch from IgE to IgG4 antibody production. Improvements in allergen immunotherapy, such as peptide therapy, and greater understanding of the biology of Tregs hold great promise for the treatment and prevention of allergic disease.
doi:10.1172/JCI200423595
PMCID: PMC525754  PMID: 15545986
8.  Immunoglobulin E–independent Major Histocompatibility Complex–restricted T Cell Peptide Epitope–induced Late Asthmatic Reactions  
The Journal of Experimental Medicine  1999;189(12):1885-1894.
Intradermal administration of short overlapping peptides derived from chain 1 of the cat allergen Fel d 1 (FC1P) that did not cross-link IgE, elicited isolated late asthmatic reactions with no visible early or late cutaneous response in 9/40 cat-allergic asthmatics. Four of the nine were human histocompatibility leukocyte antigen DR13–positive, as compared with only 1/31 nonreactors. The other five reactors expressed either DR1 or DR4. To confirm major histocompatibility complex restriction, fibroblast cell lines transfected with HLA-DR molecules were used to present FC1Ps to cat allergen–specific T cell lines derived from subjects before peptide injection. FC1P3 (peptide 28–44 of Fel d 1 chain 1) was recognized in the context of DR13 alleles (DRB1*1301, 1302) and induced specific T cell proliferation and IL-5 production. T cells from a DR1+ responder proliferated and produced IL-5 in the presence of FC1P3 and DR1 (DRB1*0101) fibroblast cell lines, whereas T cells from a DR4+ subject recognized FC1P2 (peptide 22–37) when presented by DRB1*0405. We conclude that short, allergen-derived peptides can directly initiate a major histocompatibility complex–restricted, T cell–dependent late asthmatic reaction, without the requirement for an early IgE/mast cell–dependent response, in sensitized asthmatic subjects.
PMCID: PMC2192970  PMID: 10377184
T lymphocyte; Fel d 1; allergen; allergy; human histocompatibility leukocyte antigen
9.  T Cell Epitope Immunotherapy Induces a CD4+ T Cell Population with Regulatory Activity 
PLoS Medicine  2005;2(3):e78.
Background
Synthetic peptides, representing CD4+ T cell epitopes, derived from the primary sequence of allergen molecules have been used to down-regulate allergic inflammation in sensitised individuals. Treatment of allergic diseases with peptides may offer substantial advantages over treatment with native allergen molecules because of the reduced potential for cross-linking IgE bound to the surface of mast cells and basophils.
Methods and Findings
In this study we address the mechanism of action of peptide immunotherapy (PIT) in cat-allergic, asthmatic patients. Cell-division-tracking dyes, cell-mixing experiments, surface phenotyping, and cytokine measurements were used to investigate immunomodulation in peripheral blood mononuclear cells (PBMCs) after therapy. Proliferative responses of PBMCs to allergen extract were significantly reduced after PIT. This was associated with modified cytokine profiles generally characterised by an increase in interleukin-10 and a decrease in interleukin-5 production. CD4+ cells isolated after PIT were able to actively suppress allergen-specific proliferative responses of pretreatment CD4neg PBMCs in co-culture experiments. PIT was associated with a significant increase in surface expression of CD5 on both CD4+ and CD8+ PBMCs.
Conclusion
This study provides evidence for the induction of a population of CD4+ T cells with suppressor/regulatory activity following PIT. Furthermore, up-regulation of cell surface levels of CD5 may contribute to reduced reactivity to allergen.
Immunotherapy is one approach to treating cat allergy and asthma. One mechanism of action might be that it induces a population of CD4 positive T cells with suppressor activity
doi:10.1371/journal.pmed.0020078
PMCID: PMC1069669  PMID: 15783262

Results 1-9 (9)