Expression of an ovalbumin-specific V{beta}8.2 TCR transgene inhibits collagen arthritis in B10.Q mice

Previous studies have illustrated the importance of T cellsbearing ß TCRs in the induction and development ofcollagen induced arthritis (CIA) in mice. However, the scopeof TCR usage in CIA has yet to be clearly defined. Given theinherent diversity of the TCR repertoire, the relative flexibilityof the arthritogenic TCR repertoire specific for type II collagen(CII) is not clear. Therefore, we chose to examine the influenceof a highly skewed TCR repertoire on CIA. Arthritis susceptibleB10.Q (H-2^q) mice were mated with C57L (H-2^b) animals expressingan ovalbuminspecific V_ß8.2 TCR transgene (Tg) andTg⁺ offspring were further backcrossed to B10.Q. HomozygousH-2^a/q, V_ß8.2 Tg⁺ mice displayed a high level of V_ß8.2⁺T cells in peripheral blood. However, expression of some endogenousV_ß TCR, such as V_ß14, was still detected.Upon immunization with bovine CII in adjuvant, V_ß8.2Tg⁺ mice were highly resistant to CIA when compared with Tg^–littermates. Analysis of sera demonstrated a marked reductionin antibody specific for homologous mouse CII as well as heterologousbovine CII in Tg⁺ animals. Interestingly, V_ß8.2 Tg⁺mice still mounted good antibody responses following immunizationwith human thyroglobulin, indicating that the skewed TCR repertoireaffected anti-CII but not antithyroglobulin responses. Thus,our findings show that constraints placed on the TCR repertoireInhibit pathogenic responses against CII and suggest that inH-2^q mice the arthritogenlc TCR repertoire bears only limitedflexibility.     

Optimization of Drug-Like Properties of Nonsteroidal Glucocorticoid Mimetics and Identification of a Clinical Candidate

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An orally active, primate selective antagonist of LFA-1 inhibits delayed-type hypersensitivity in a humanized-mouse model

Compound I, a novel small molecule antagonist (Kd=6 nM) of human lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) was tested for activity in a humanized mouse model of delayed-type hypersensitivity (trans vivo delayed-type hypersensitivity). Trans vivo delayed-type hypersensitivity is a model for testing compounds with human targets in mice. Tetanus toxoid and 7-10x10(6) human peripheral blood mononuclear cells from tetanus-sensitized donors were coinjected into footpads of naive mice. Footpads were measured before and 24 h later. Injection of peripheral blood mononuclear cells plus antigen resulted in swelling of 0.178-0.254 mm, significantly greater than peripheral blood mononuclear cells or tetanus toxoid alone (P<0.05). Preincubation of peripheral blood mononuclear cells with anti-human major histocompatibility complex class II (MHCII) or anti-human LFA-1 monoclonal antibody (mAb), but not anti-mouse MHCII or anti-mouse LFA-1 mAb, significantly inhibited the response. Compound I inhibited footpad swelling in a dose related manner (0.1-100 mg/kg, p.o.; ED50 approximately 1 mg/kg), whereas its enantiomer had no effect. These data demonstrate the oral efficacy of a novel antagonist of LFA-1 in trans vivo delayed-type hypersensitivity.     

Dynamic balance and stepping versus tai chi training to improve balance and stepping in at-risk older adults

OBJECTIVES: To compare the effect of two 10-week balance training programs, Combined Balance and Step Training (CBST) versus tai chi (TC), on balance and stepping measures. DESIGN: Prospective intervention trial. SETTING: Local senior centers and congregate housing facilities. PARTICIPANTS: Aged 65 and older with at least mild impairment in the ability to perform unipedal stance and tandem walk. INTERVENTION: Participants were allocated to TC (n = 107, mean age 78) or CBST, an intervention focused on improving dynamic balance and stepping (n = 106, mean age 78). MEASUREMENTS: At baseline and 10 weeks, participants were tested in their static balance (Unipedal Stance and Tandem Stance (TS)), stepping (Maximum Step Length, Rapid Step Test), and Timed Up and Go (TUG). RESULTS: Performance improved more with CBST than TC, ranging from 5% to 10% for the stepping tests (Maximum Step Length and Rapid Step Test) and 9% for TUG. The improvement in TUG represented an improvement of more than 1 second. Greater improvements were also seen in static balance ability (in TS) with CBST than TC. CONCLUSION: Of the two training programs, in which variants of each program have been proven to reduce falls, CBST results in modest improvements in balance, stepping, and functional mobility versus TC over a 10-week period. Future research should include a prospective comparison of fall rates in response to these two balance training programs.     

Second-generation lymphocyte function-associated antigen-1 inhibitors: 1H-imidazo[1,2-alpha]imidazol-2-one derivatives

A novel class of lymphocyte function-associated antigen-1 (LFA-1) inhibitors is described. Discovered during the process to improve the physicochemical and metabolic properties of BIRT377 (1, Figure 1), a previously reported hydantoin-based LFA-1 inhibitor, these compounds are characterized by an imidazole-based 5,5-bicyclic scaffold, the 1,3,3-trisubstituted 1H-imidazo[1,2-alpha]imidazol-2-one (i.e. structure 3). The structure-activity relationship (SAR) shows that electron-withdrawing groups at C5 on the imidazole ring benefit potency and that oxygen-containing functional groups attached to a C5-sulfonyl or sulfonamide group further improve potency. This latter gain in potency is attributed to the interaction(s) of the functionalized sulfonyl/sulfonamide groups with the protein, likely polar-polar in nature, as suggested by SAR data. X-ray studies revealed that these bicyclic inhibitors bind to the I-domain of LFA-1 in a pattern similar to that of compound 1.     

Short ragweed allergen induces eosinophilic lung disease in HLA-DQ transgenic mice

The human leukocyte antigen (HLA) restriction of the IgE response to different allergens in humans has been a subject of numerous published studies. However, the role and contribution of specific HLA class II molecules in the pathogenesis of allergic airway inflammation are unknown and difficult to assess. HLA-DQ6 and HLA-DQ8 transgenic mice lacking endogenous mouse class II gene expression were actively immunized and later challenged intranasally with short ragweed (SRW) allergenic extract. The HLA-DQ transgenic mice developed pulmonary eosinophilia and lung tissue damage. We also found an increase in total protein (TP) level and IL-5 production in bronchoalveolar lavage (BAL) fluid and an increase in SRW-specific Th2-type immunoglobulins (IgG1, IgG2b) and total serum IgE levels. Under similar treatment, DQ-negative full-sib control mice were normal. The allergic response could be significantly inhibited or abrogated in HLA-DQ mice by systemic treatment with anti-DQ mAb. The in vivo responses of HLA-DQ6 and HLA-DQ8 mice showed differences in terms of levels of eosinophilia, BAL protein, IL-5 concentration, and lung hyperreactivity to inhaled methacholine. These findings demonstrate the crucial role for specific HLA-DQ molecules in SRW-specific CD4(+) T-cell activation and resulting recruitment of eosinophils into the airways.     

Clinical profile of the functionally selective glucocorticoid receptor agonist BI 653048 in healthy male subjects

Background: An efficacious anti-inflammatory corticosteroid with reduced side effects has been long sought. We report the pooled results from three clinical proof-of-mechanism Phase I studies of BI 653048 in healthy subjects, a functionally selective, nonsteroidal glucocorticoid (GC).

Research design and methods: Three Phase I trials were conducted: a single rising-dose study and a multiple rising-dose study to evaluate the safety, tolerability, and pharmacokinetics of BI 653048, and a multiple parallel-arm-dose study with intravenous lipopolysaccharide challenge to assess in vivo pharmacodynamics. The pharmacodynamics, efficacy, and safety of BI 653048 and prednisolone were compared.

Results: Treatment with 200 mg BI 653048 was associated with a reduced expression of IL1R2, ITGB3, and SDPR versus 20 mg prednisolone; comparable levels of FKBP5, ZBTB16, and DDIT4 expression were observed. Changes in C-peptide, glucose, insulin, and cortisol were moderate compared with prednisolone. A greater reduction of osteocalcin was observed with 200 mg BI 653048 versus 20 mg prednisolone. Comparable anti-inflammatory efficacy was demonstrated for 200 mg BI 653048 and 20 mg prednisolone. BI 653048 was well tolerated in healthy subjects.

Conclusion: BI 653048 demonstrated the desired anti-inflammatory effects of the nonsteroidal GC; however, the undesirable side-effect profile associated with GC steroids could not be disassociated from BI 653048.

Trial registration: ClinicalTrials.gov identifiers NCT02217644, NCT02217631, and NCT02224105.