Long-term safety of subcutaneous immunotherapy with TO-204 in Japanese patients with house dust mite-induced allergic rhinitis and allergic bronchial asthma: Multicenter,open label clinical trial

Background

To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial.

Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: implications for molecular mimicry and cross-recognition among mitochondrial autoantigens

The anti-mitochondrial antibody response in primary biliary cirrhosis (PBC) is primarily directed at E2 components of PDC, OGDC, and BCOADC, and E3BP. Previous work has shown that the immunodominant autoreactive T- cell epitope is the PDC-E2 163-176 peptide, restricted by HLA DR53. To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls. Interestingly, fine specificities were unique for every single T-cell clone, but the clones could be categorized into two distinct groups based on recognition motifs of the T-cell receptor (TCR) ligand: group A (170)ExDK(173) and group B (168)EIExD(172). (170)E is the most critical TCR contact residue for both groups of cloned T-cell lines, whereas (173)K and (168)E are the critical TCR contact residues for group A and group B cloned T-cell lines, respectively. More importantly, some group A-cloned T-cell lines cross-reacted to human E3BP 34-47, human OGDC-E2 100-113, and several peptides derived from various microbial proteins carrying an ExDK motif, whereas group B-cloned T-cell lines reacted only to E3BP 34-47 carrying an EIExD motif. Furthermore, an RGxG motif was exclusively found in the complementarity-determining region (CDR3) of the TCR Vbeta in the group B-cloned T-cell lines, while G, S, and/or R were frequently found in the CDR3 of the TCR Vbeta in the group A-cloned T-cell lines. These data provide a framework for understanding molecular mimicry among mitochondrial antigens.     

Genetic Characterization of Coronaviruses from Domestic Ferrets,Japan

We detected ferret coronaviruses in 44 (55.7%) of 79 pet ferrets tested in Japan and classified the viruses into 2 genotypes on the basis of genotype-specific PCR. Our results show that 2 ferret coronaviruses that cause feline infectious peritonitis–like disease and epizootic catarrhal enteritis are enzootic among ferrets in Japan.     

Oral vaccination against HPV E7 for treatment of cervical intraepithelial neoplasia grade 3 (CIN3) elicits E7-specific mucosal immunity in the cervix of CIN3 patients

Background

Cervical intraepithelial neoplasia grade 3 (CIN3) is a mucosal precancerous lesion caused by high-risk human papillomavirus (HPV). Induction of immunological clearance of CIN3 by targeting HPV antigens is a promising strategy for CIN3 therapy. No successful HPV therapeutic vaccine has been developed.

Methods

We evaluated the safety and clinical efficacy of an attenuated Lactobacillus casei expressing modified full-length HPV16 E7 protein in patients with HPV16-associated CIN3. Ten patients were vaccinated orally during dose optimization studies (1, 2, 4, or 6 capsules/day) at weeks 1, 2, 4, and 8 (Step 1). Seven additional participants were only tested using the optimized vaccine formulation (Step 2), giving a total of 10 patients who received optimized vaccination. Cervical lymphocytes (CxLs) and peripheral blood mononuclear cells (PBMCs) were collected and E7 specific interferon-γ-producing cells were counted (E7 cell-mediated immune responses: E7-CMI) by ELISPOT assay. All patients were re-evaluated 9 weeks after initial vaccine exposure using cytology and biopsy to assess pathological efficacy.

Results

No patient experienced an adverse event. E7-CMI in both CxLs and PBMCs was negligible at baseline. All patients using 4–6 capsules/day showed increased E7-CMI in CxLs, whereas patients using 1–2 capsules/day did not. No patient demonstrated an increase in E7-CMI in their PBMCs. In comparison between patients of cohorts, E7-CMI at week 9 (9 wk) in patients on 4 capsules/day was significantly higher than those in patients on 1, 2, or 6 capsules/day. Most patients (70%) taking the optimized dose experienced a pathological down-grade to CIN2 at week 9 of treatment. E7-CMI in CxLs correlated directly with the pathological down-grade.

Conclusions

Oral administration of an E7-expressing Lactobacillus-based vaccine can elicit E7-specific mucosal immunity in the uterine cervical lesions. We are the first to report a correlation between mucosal E7-CMI in the cervix and clinical response after immunotherapy in human mucosal neoplasia.     

Persistent Hypoglycemia Induced by Long-acting Insulin Degludec

A 58-year-old Japanese man was brought to the emergency room due to disturbance of consciousness. He regained consciousness on the day of admission and started taking hospital meals, but he needed intravenous glucose administration for eight days. The total amount of glucose administration was 4,464 g. It took over three weeks for exogenous insulin to be almost undetectable. While degludec binds to albumin and exerts glucose-lowering effects for a long time, the above-mentioned period of three weeks was consistent with the half-life of albumin. Hypoglycemia induced by massive dose of insulin degludec is persistent and prominent.     

Early invasive colorectal carcinomas with submucosal invasion: radiographic characteristics with barium double contrast images

Background: We assessed the radiographic characteristics of early colorectal carcinomas with submucosal invasion (CCSI) with the use of double-contrast images. Methods: From 1989 to 1997, 193 patients with 196 CCSI lesions underwent double-contrast barium enema examinations. Three gastrointestinal radiologists retrospectively reviewed the radiographic characteristics of the lesions and classified them as protruding and depressed types by consensus. Further, subclassifying the protruding into lobular and smooth types was accomplished on the basis of surface structure. Each type was compared with pathologic findings of resected specimens. Results: The incidence of the protruding type was 98.0%, and that of the depressed type was only 2.0%. The proportion of smooth lesions was 49.0% for the protruding type; these had a mean diameter of 17.9 mm, which was significantly smaller than the 23.1 mm mean observed for lobular lesions (p < 0.01). Of the smooth lesions, 44.7% demonstrated massive invasion, whereas 91.8% of lobular lesions exhibited only slight or moderate invasion into the submucosa (p < 0.01). The extent of invasion of the smooth lesions was greater than that for their lobular counterparts in terms of venous and lymph node involvement. Conclusion: Almost all CCSIs could be identified radiologically as protruding lesions; these had a smooth rather than a lobulated surface and demonstrated greater malignancy, despite the smaller size. It is clinically important to discriminate these from other polypoid lesions in establishing patient treatment. Double-contrast imaging is useful for evaluation of the surface characteristics of CCSIs in barium enema studies.