Since the anti-IgE therapeutic concept was conceived in 1987, the lead product, omalizumab, a humanized antibody with a unique set of binding specificities, has been studied in more than 50 Phase II and III clinical trials in various allergic indications. Omalizumab (trade name Xolair) has been approved in the USA, EU, Taiwan and many other countries for treating patients 12 years and older with severe allergic asthma. Xolair has also been approved in EU in 2009 for treating patients 6 to 11 years old with severe allergic asthma. Omalizumab has been shown to be efficacious for treating allergic rhinitis in many organized, corporate-sponsored, placebo-controlled Phase II and III trails. Xolair has been shown to be efficacious in treating atopic dermatitis and urticaria in about 10 case series studies covering over 50 patients. In several major trials, Xolair has been shown to reduce the anaphylaxis risks and enhance the efficacy of allergen-based desensitization immunotherapy. More than 100,000 patients with severe allergic asthma, whose symptoms cannot be controlled even with high doses of corticosteroids, have been treated with omalizumab. In Taiwan, Xolair was approved for treating patients 12 years and older with severe allergic asthma in 2007 and a payment policy was issued by the Health Insurance Bureau in 2008. A few hundred patients with severe allergic asthma have been treated with Xolair in major medical centers with response rates estimated to be over 80%. In Taiwan, a small number of patients with severe atopic dermatitis have also been treated with Xolair in off-label uses with generally good results.

In this presentation, the “Skewed Antigen Exposure Theory” for explaining the increase of allergic disease in modern societies will be introduced. In the main body of the talk, the rationale for designing the anti-IgE drug, the structural basis for the unique set of binding specificity of anti-IgE, the main pharmacological effects of the anti-IgE drug, the clinical indications in which anti-IgE has been tried, and the combination of anti-IgE and immunotherapy as a new therapeutic approach will be discussed.

Henoch-Schönlein purpura (HSP) is a common systemic small vessel vasculitis in childhood; however, there have been few nationwide investigations. Further, the real immunopathogenic mechanisms of HSP are yet to be defined. In the past several years, we have studied the levels of autoantibody in HSP patients for the clarification of pathogenic mechanism of HSP. For the epidemiological study, the data of this study were derived from the research database of Bureau of National Health Insurance, Taiwan. From Jan 1999 to Dec 2002, children younger than 17 years of age with the diagnosis of HSP were recruited into this study. Data of each patient including sex, age, date of onset, length of hospitalization, and medical charge were recorded and analyzed. We have also studied the levels of IgA anti-cardiolipin and anti-endothelial cell antibody in the HSP patients. The frequency of TGF- secreting T cells in HSP patients was also analyzed in the study. Polymorphisms of TGF- promoter gene were also analyzed between HSP patients and normal controls. In our studies, we found that Childhood HSP in Taiwan was less frequent than the previous British report. HSP occurs commonly in autumn and winter; and in 3 to 12 yeas old children. The data also demonstrated that IgA anti-cardiolipin and anti-endothelial cells antibody could also be detected in HSP patients. Most recently, we also identified the promising antigenic peptides for the diagnosis of Henoch-Scholein purpura. We aim to set up the diagnosis kit for Henoch-Scholein purpura for the assessment of disease activity and long-term follow up of the patients with Henoch-Scholein purpura.

Aims
Recent advances in immunological techniques have lead to increased recognition of primary immunodeficiency diseases (PIDs). In this longitudinal study, we have attempted to describe the distribution, clinical features and molecular bases of PIDs in Taiwan for early recognition.

Materials and Methods
Patients diagnosed as the codes of the International Classification of Disease, Tenth Revision (ICD-10) and reported as the literatures were all enrolled since 1985. In addition to clinical manifestations and immunological functions, molecular and candidate-gene analysis were evaluated in selected patients after informed consents had been obtained.

Results
One hundred and eighty-seven patients (from 170 families) diagnosed as PIDs were enrolled from mainly five tertiary medical centers. The distribution by an update eight categories showed 49 patients (15 females/34 males; 26.2%) with “predominant antibody deficiencies”, 32 patients (6/26; 17.1%) with “T- and B-cell immunodeficiency”, 21 patients (6/15; 11.2%) with “congenital defects of phagocyte”, 65 patients (17/48; 34.8%) with “other well-defined immunodeficiency syndromes”, four patients (2/2; 2.1%) with “disease in immune dysregulation” (Chediak-Higashi syndrome in 2; familial hereditary hemophagocytosis in 1 and Immunodeficiency polyendocrinopathy enteropathy and X-linked in 1) and 15 patients with complement deficiencies (6/9; 8.0%). None had “defects in innate immunity” or “autoinflammatory disorders”. Pseudomonas and Salmonella spp. were the two most identified microorganisms in septicemia (41.0%; 32/78 episodes). Twenty-eight patients (15.0%) had mortality. Hematopoietic stem cell transplantation succeeded in 12 of 19 patients. In addition to 29 patients with DiGeorge syndrome recognized by FISH, direct sequencing identified 19 unique mutations from 42 families, reflecting distinct Taiwan geography, although a selection bias may exist.

Conclusions
Compared with Western countries, higher percentage of unique mutations (19/42; 45.2%) implies genetic diversity in Formosa island. However, Taiwanese PIDs patients with “predominant antibody deficiencies” are the second common, but “other well-defined immunodeficiency syndromes” are much more. Both “defects in innate immunity” and “autoinflammatory disorders” are not found. Adult PIDs patients with common variable immunodeficiency are few, but more popular in Western country. This study to date reflects underestimation of disease load. Early suspicion for a diagnosis of PIDs makes possible early definitive therapy and avoids the complications of pretreatment infections or autoimmunity. In Wisconsin, newborn screening has included patients with severe combined immunodeficiency (SICD) and/or 22q11 deletion syndrome for timely transplantation in the first 3.5 months of SCID life.

Insulin-dependent diabetes mellitus (IDDM), or type I diabetes, is a T cell-mediated autoimmune disease. A widely used animal model for dissecting immunopathologic mechanisms in IDDM and developing preventive and/or therapeutic strategies is the non-obese diabetic (NOD) mouse, an inbred strain that spontaneously develops autoimmune diabetes resembling human IDDM. To directly dissect the immunopathogenic mechanisms of type I diabetes and to develop potential therapeutic strategy for this autoimmune disease, we have already established several novel transgenic and knockout NOD mice in our lab: one is the Th1 and Th2 double transgenic NOD mouse which provides the best in vivo model to study the pathogenic nature and the differentiation of helper T cell subsets during the diabetogenic process in IDDM；the other is the IL-12 knockout NOD mouse which provides the best model to investigate directly the regulation of IL-12 on autoimmune response in NOD mice. To further delineate the protective roles of some novel immune modulatory molecules, such as soluble decoy receptor 3 (DcR3), cytotoxic T lymphocyte antigen 4 (CTLA4), program death ligand 1 and 2 (PD-L1 and 2), heme oxygenase 1 (HO-1), in the autoimmune process and search for potential preventive and/or therapeutic targets in this disease, we generated (a) insulin promoter (pIns)-sDcR3 transgenic NOD mice, (b) pIns-single chain anti-CTLA4 transgenic NOD mice, (c) pIns-single chain anti-4-1BB transgenic NOD mice, (d) pIns-PD-L1 transgenic NOD mice (e) pIns-PD-L2 transgenic NOD mice (f) pIns-HO-1 transgenic NOD mice. Making full use of these unique mouse strains, we are quantitatively and qualitatively investigating the immunopathogenic mechanisms of autoimmune diabetes and provide valuable information for the development of novel immunotherapies. Meanwhile, by using the established lenti-viral system in our lab, we are currently transducing various immunomodulatory genes into islets and investigating the function and survival of these genetically modified graft islets. This may provide tremendous help for successful islet transplantation in the future. Finally, we are also generating target gene-specific lenti-siRNA-mediated knockdown NOD mice and investigating potential role of those genes in immunopathogenic process in type I diabetes. To delineate further the potential roles of (1) some novel immunopathogenic cytokines, such as IL-23 and IL-27; (2) some immunomodulatory receptors such as TLR-4; (3) some Th1 response-inducing genes, such as T-bet, or STAT1/4, in autoimmune diabetes, we generated functional knockdown NOD mice insufficient for those genes via direct lenti-siRNA transduction or direct microinjection of shRNA constructs in NOD embryos. Now we already obtained IL-23 and IL-27 knockdown NOD mice and currently investigate their phenotypes. These novel knockdown NOD mice will provide the best models to investigate directly the regulation of those genes on autoimmune immune response in NOD mice.