Live varicella vaccine polarizes the mucosal adjuvant action of cholera toxin or its B subunit on specific Th1-type helper T cells with a single nasal coadministration in mice

This study was undertaken to determine whether the specific Th1- or Th2-cell response to varicella-zoster virus was induced predominantly by a mucosal adjuvant, cholera toxin, in mice. A commercially available live varicella vaccine (Oka strain) and cholera toxin or its B subunit were administered simultaneously via the nasal route. Delayed-type hypersensitivity to the Oka vaccine was induced, but the systemic neutralizing antibody response was low. The delayed-type hypersensitivity evoked after a single administration was relatively higher than that on administration three times. When spleen cells from mice immunized once with the vaccine and cholera toxin or its B subunit were restimulated with the live vaccine in vitro, there was greater thymidine uptake and production of interleukin- 2 (IL-2) than controls, but only a low level of IL-4 production. The production of IL-2 induced by the B subunit of cholera toxin was less than that by cholera toxin and a mutant of Escherichia coli enterotoxin on co-immunization with the vaccine in mice. Cholera toxin and its B subunit have been reported to induce predominantly a specific Th2-type T-cell response to various antigens. However, the Oka vaccine is an antigen that polarizes the activation of specific Th1/Th2-type T cells by cholera toxin or its B subunit to the Th1-type side. Cholera toxin and its B subunit are thus useful mucosal adjuvants for inducing cellular immunity to the Oka vaccine similar to Escherichia coli enterotoxin.     

Childhood blastic NK cell leukemia successfully treated with L-asparagenase and allogeneic bone marrow transplantation

Blastic NK cell lymphoma/leukemia is a rare and highly malignant neoplasia in both adults and children. It is characterized by lymphoblastoid morphology without cytoplasmic granules and immature NK cell immunophenotypes (CD56+, CD57-, CD16-). It has predilection for extranodal organ involvement, and the prognosis of affected patients is extremely poor under the current chemotherapy. We present a 14-year-old girl who was diagnosed as having blastic NK cell leukemia with mediastinal, pleural, and pericardial involvement. Immunophenotyping of her leukemic cells showed positive for CD2, CD5, CD7, CD34, CD56, HLA-DR, and cytoplasmic CD3. T cell receptor (TCR) and Immunoglobulin heavy chain genes were not rearranged. She received chemotherapy for acute lymphoblastic leukemia incorporating L-asparaginase (L-asp) which successfully induced complete remission. Bone marrow transplantation (BMT) from her HLA-identical sibling was conducted after two courses of consolidation therapy. Expression of aspargine synthetase (AS) protein in the leukemic cells at diagnosis was examined by an immunocytochemical method. She remains in hematological remission for over 36 months after BMT. The expression of AS protein was negative, suggesting that the leukemic cells were sensitive to L-asp. Induction and consolidation therapy incorporating L-asp followed by allo-BMT might be a promising treatment for child hood blastic NK cell leukemia, but more samples of the rare leukemia need to be studied before any definitive conclusions can be drawn.     

Induction of Thymus-Derived γδ T Cells by Escherichia coli Enterotoxin B Subunit in Peritoneal Cavities of Mice

We examined the activation of intraperitoneal T cells in BALB/c mice by the Escherichia coli enterotoxin B subunit, which induced a specific Th2 type of T-cell response to intraperitoneally coadministered bovine immunoglobulin G. The numbers of both γδ and αβ T cells increased significantly after intraperitoneal administration of the B subunit in a time-dependent manner; these numbers were not affected by the B-subunit G33D mutant, which is defective in GM₁ ganglioside-binding ability. Early after administration a small number of γδ T cells produced either interleukin-4 (IL-4) or gamma interferon, while late after administration primarily IL-10-producing γδ T cells were detected. γδ T cells induced by the B subunit did not express a characteristic V gene over the time course of the study. The induction of γδ T cells did not occur in athymic nu/nu mice but could be induced upon transplantation of fetal AKR thymus-like αβ T cells. γδ T cells in athymic nu/nu mice with a fetal thymic graft predominantly expressed the donor Thy-1.1 antigen but not the host Thy-1.2 antigen. The induction of these T cells, however, could not be restored by coadministration of the B subunit with peritoneal cells from normal mice. These results suggest that the B subunit activates intraperitoneal γδ and αβ T cells in a manner dependent upon its ability to bind to GM₁ ganglioside. γδ T cells induced by the B subunit are Th2-type cells derived from the thymus. These γδ T cells may be functionally involved in specific Th2 responses to the B subunit, which possibly acts as an adjuvant through the influence of αβ T cells.     

Non-anaphylactic combination of partially deleted fragments of the major house dust mite allergen Der f 2 for allergen-specific immunotherapy

Allergen-specific immunotherapy, in which repeated injections of allergens over prolonged periods are used to induce tolerance, has proven an effective treatment of allergy. A major side effect of allergen-specific immunotherapy is anaphylactic reaction. House dust mite allergens are major causative factors associated with various allergic diseases. Der f 2 is the major house dust mite allergen composed of 129 amino acid residues. Analysis using deletion mutants of Der f 2 suggested that T-cell epitopes of Der f 2 were multiple in mite-allergic patients. We found that some IgE epitopes were renatured by dialysis of a mixture of two denatured C- and N-terminal deletion mutants, 1-112 and 85-129 in 13 patients out of 14. On the other hand, IgE binding activity was negative in the separately dialyzed fragments and their mixture in each patient tested. Furthermore, we demonstrated that neither of the two separately prepared polypeptides induced in vivo skin prick test reactivity. These findings are important for improvement of T-cell targeting allergen-specific immunotherapy and development of monovalent IgE haptens. The use of combinations of overlapping non-anaphylactic fragments of allergen covering all of the T-cell epitopes achieves the removal of IgE reactivity, the cause of harmful anaphylactic reactions, without affecting the T-cell reactivity essential for immunotherapy, offering potentially safer and more effective treatment for allergic disease.     

Cloned Th cells confer eosinophilic inflammation and bronchial hyperresponsiveness

BACKGROUND: The essential role of Th cells and T cell cytokines in eosinophilic inflammation has been established. METHODS: To determine whether Th cells are sufficient for the development of airway eosinophilic inflammation, ovalbumin-reactive murine Th clones were established and infused into unprimed mice. RESULTS: Eosinophilic infiltration into the lung was induced upon antigen inhalation in parallel with the rise in bronchoalveolar lavage fluid (BALF) eosinophil peroxidase activity. Neither IgG, IgA, nor IgE antibodies were present in this model. Pathological examination showed swelling and desquamation of epithelial cells, mucous plugs, and goblet cell hyperplasia, all of which well resemble human asthma. Fluorescent probe labeled Th clones migrated into the lung prior to the eosinophil accumulation. Bronchial hyperresponsiveness (BHR) was clearly induced upon antigen inhalation. Anti-IL-5 monoclonal antibody abrogated the responses. Dexamethasone and cyclosporin A suppressed cytokine production by Th cells both in vitro and in vivo, BALF eosinophilia, and BHR. The number of eosinophils recovered in the BALF correlated with the intensity of BHR. CONCLUSION: The results clearly indicated that monoclonal Th cells are sufficient for the development of both airway eosinophilia and BHR. Agents capable of downregulating IL-5 production seem promising for the treatment of bronchial asthma.     

Pulmonary dirofilariasis: computed tomography findings and correlation with pathologic features

OBJECTIVE: The purpose of this study was to describe the computed tomography (CT) and pathologic features of 5 nodules of pulmonary dirofilariasis in 4 patients. METHODS: Four patients with 5 nodules of pathologically confirmed pulmonary dirofilariasis who under went CT were enrolled, and the imaging interpretations were retrospectively compared with the histopathologic characteristics. RESULTS: Three of the 4 patients had a solitary nodule, and the remaining patient had 2 nodules. All the nodules were distributed in the right lower lobe and were attached to the pleura. They were all round or oval in shape and ranged in size from 11 to 22 mm in largest diameter (mean=17 mm). On thinner section CT, the nodules had a well-defined smooth margin with or without a shallow notch; they were connected to the arterial branch and, occasionally, to the venous branch. On contrast-enhanced CT, all the nodules contained a homogeneous low-attenuation area, which corresponded to areas of coagulative necrosis on histopathologic examination. CONCLUSION: Although the CT findings of a pulmonary dirofilariasis nodule are nonspecific, awareness of the findings on contrast-enhanced CT and the pathologic appearance of this rare benign condition may facilitate its differentiation from a malignant nodule.     

Self-expandable metallic stent placement for patients with inoperable esophageal carcinoma: investigation of the influence of prior radiotherapy and chemotherapy

Purpose The aim of this study was to evaluate the efficacy and complications of self-expandable metallic stent placement for patients with inoperable esophageal carcinoma after radiotherapy and/or chemotherapy. Materials and methods We obtained data from 19 patients with advanced or recurrent esophageal carcinoma between 1996 and 2000. In all patients, a self-expandable metallic stent was placed under fluoroscopic guidance. Dysphagia before and after stent placement was graded. Complications after stent placement were also evaluated. Data were compared between patients with and without prior radiotherapy and/or chemotherapy. Results The procedure was technically successful in all but one patient. The dysphagia grade improved in all patients. No life-threatening complications occurred. The other major complications such as mediastinitis occurred in two patients, and pneumonia and funnel phenomenon occurred in one patient each. These patients had a history of radiotherapy and/or chemotherapy prior to stent placement. Eight of the twelve patients with prior radiotherapy and/or chemotherapy compared with one of seven patients without prior therapy had persistent chest pain, which was a statistically significant difference (P < 0.05). Conclusion Placement of self-expandable metallic stents was effective for patients with advanced or recurrent esophageal carcinoma. However, prior irradiation and/or chemotherapy increased the risk of persistent chest pain after stent placement.