High Levels of a Major Histocompatibility Complex II–Self Peptide Complex on Dendritic Cells from the T Cell Areas of Lymph Nodes

T lymphocytes recirculate continually through the T cell areas of peripheral lymph nodes. During each passage, the T cells survey the surface of large dendritic cells (DCs), also known as interdigitating cells. However, these DCs have been difficult to release from the lymph node. By emphasizing the use of calcium-free media, as shown by Vremec et al. (Vremec, D., M. Zorbas, R. Scollay, D.J. Saunders, C.F. Ardavin, L. Wu, and K. Shortman. 1992. J. Exp. Med. 176:47–58.), we have been able to release and enrich DCs from the T cell areas. The DCs express the CD11c leukocyte integrin, the DEC-205 multilectin receptor for antigen presentation, the intracellular granule antigens which are recognized by monoclonal antibodies M342, 2A1, and MIDC-8, very high levels of MHC I and MHC II, and abundant accessory molecules such as CD40, CD54, and CD86. When examined with the Y-Ae monoclonal which recognizes complexes formed between I-A^b and a peptide derived from I-Eα, the T cell area DCs expressed the highest levels. The enriched DCs also stimulated a T-T hybridoma specific for this MHC II–peptide complex, and the hybridoma underwent apoptosis. Therefore DCs within the T cell areas can be isolated. Because they present very high levels of self peptides, these DCs should be considered in the regulation of self reactivity in the periphery.     

A case of huge omental-origin liposarcoma controlled by a combination of ifosfamide and adriamycin

A 51-year-old woman came to our hospital after a medical check -up. She suffered from abdominal distension. Abdominal CT revealed the abdominal cavity filled with omental cake. The preoperative diagnosis was unassertive. Laparotomy through midline incision was performed. The bulk of the omental tumor occupied the abdominal cavity, but infiltrated the bowel or abdominal wall less. Fractional resection of the tumor, right hemicolectomy, sigmoidectomy, wedge resection of small intestine and left ovariectomy were performed in parallel. Resected specimens weighed 6. 6 kg in total. The operation was considered palliative because of the peritoneal dissemination. Postoperative intraabdominal administration of cisplatin(50mg) made the ascites disappear. She was discharged 3 weeks after the operation. The final diagnosis was liposarcoma(myxoid type), and 5 courses of adjuvant chemotherapy with adriamycin and ifosfamide were performed. No relapse was found 11 months after the operation, but tumor regrowth occurred in the thoracic and abdominal cavity and the patient died 14 months after the operation.     

A case of AFP-producing gastric cancer resected after efficient S-1/CDDP combination chemotherapy

A 62-year-old male was diagnosed as AFP-producing gastric cancer with lymph node metastases and multiple liver metastases. He was treated with S-1 and CDDP combination chemotherapy. At the end of the first course, both primary and metastatic lesions were remarkably decreased in size, and the serum AFP level was also decreased. The chemotherapy was effective against the cancer and led to a partial response (PR) according to the RECIST guideline. Following the nine months of PR, the primary lesion which had once nearly disappeared, emerged again. Because distant lymph node metastases and liver metastases were considered to have disappeared, distal gastrectomy with D2 lymphadenectomy was performed. The patient received S-1 monotherapy for 6 months after the operation. At present the patient has achieved progression-free survival for 1 year and 3 months after the operation. Though AFP-producing gastric cancer is known for its poor prognosis, combination treatment such as operation or hepatic arterial infusion chemotherapy may improve the prognosis in patients with advanced AFP-producing gastric cancer when systemic chemotherapy is effective.     

Antitumor activity of type III interferon alone or in combination with type I interferon against human non‐small cell lung cancer

The antitumor activities of type III interferon (IFN) (interleukin [IL]‐28 and IL‐29) and the combination of type III IFN and type I IFN (IFN‐α) were evaluated using human non‐small cell lung cancer (NSCLC). The expression of type III and type I receptor complexes was detected in NSCLC lines. IL‐29 significantly inhibited the in vitro growth of a wide range of NSCLC lines in a dose‐dependent fashion. To a lesser degree, IL‐28A also displayed growth inhibitory activity. Antitumor activity of type III IFN is associated with cell cycle arrest at the G1 phase and apoptosis. IL‐29 upregulated cyclin‐dependent kinase inhibitor p21Waf1/Cip1 in cells sensitive, but not insensitive, to antiproliferative activity, and knockdown of p21 with small interfering RNA largely attenuated the antiproliferative effect. Intratumoral and systemic administration of IL‐29 inhibited OBA‐LK1 and LK‐1, but not A549, tumor growth in severe combined immunodeficiency mice. Immunohistochemical analyses demonstrated marked upregulated p21 and downregulated Ki‐67 expression in tumors treated with IL‐29. The interferon combination of IL‐29 and IFN‐α displayed a more effective antiproliferative effect and a more intense p21 expression than each reagent alone in vitro. Furthermore, interferon combination therapy suppressed in vivo NSCLC growth more effectively than interferon monotherapy. These findings demonstrate that type III IFN can mediate direct antitumor activities via increased p21 expression and induction of apoptosis and cooperate with type I IFN to elicit more efficient direct antitumor activities, and suggest the possibility that type III IFN might improve the efficacy and reduce the side‐effects of type I IFN cancer therapy. (Cancer Sci 2011; 102: 1977–1990)     

Morphology and fluorescein leakage in diabetic retinal microaneurysms: a study using multiple en face OCT angiography image averaging

Graefe's Archive for Clinical and Experimental Ophthalmology - To investigate the relevance of microaneurysm morphology in optical coherence tomography angiography (OCTA) image averaging and...     

Analysis of tolerance induction using triple chimeric mice: major histocompatibility complex-disparate thymus, hemopoietic cells, and microenvironment

BACKGROUND: Although bone marrow transplantation (BMT) has become a valuable strategy for the treatment of various intractable diseases in recent years, success rates remain low in elderly patients because of low thymic function. We have previously shown that fetal thymus transplantation (TT) with BMT is effective for elderly recipients in mice. METHODS: We performed fully major histocompatibility complex (MHC)-mismatched fetal TT from B6 (H-2) mice plus allogeneic BMT from C3H/HeN (H-2) mice by intra-bone marrow-BMT (IBM-BMT) using congenitally athymic nude (nu/nu) BALB/c (H-2), or BALB/c adult-thymectomized recipients to obtain triple chimeras. We next carried out the IBM-BMT+TT using senescence-accelerated mouse P1 strain (SAMP1) to examine whether this method would be applicable to aging mice. RESULTS: Triple chimeric mice survived for a long period with sufficient T-cell functions comparable to the mice treated with BMT plus MHC-matched TT, whereas those without TT survived for a short period with insufficient T-cell reconstitution. Almost all the hematolymphoid cells were derived from donor bone marrow cells. Interestingly, they showed tolerance to all three types of MHC determinants with donor-derived thymic dendritic cells in TT. Triple chimeric SAMP1 also survived for long periods with T-cell functions restored in contrast to non-TT SAMP1 recipients. CONCLUSION: These findings suggest that third party combined TT with allogeneic IBM-BMT may be more advantageous for elderly recipients with low thymic function, than IBM-BMT alone (without TT).     

In vitro activities of oral cephem and telithromycin against clinical isolates of major respiratory pathogens in Japan

The in vitro antibacterial activities of oral cephem antibiotics and ketolide telithromycin against major respiratory pathogens possessing beta-lactam-resistant mutations (within the pbp gene) and/or macrolide-resistant genes (erm and mef) were examined in clinical isolates collected at 66 institutes in all over the Japan between 2002 and 2003. Telithromycin showed the strongest antibacterial activity against methicillinsusceptible Staphylococcus aureus strains with and without macrolide-resistant genes, such as ermA or ermC gene. All the cephem antibiotics showed potent antibacterial activity against Streptococcus pyogenes, with minimum inhibitory concentrations (MICs) of 0.015 mg/L or lower. Cefdinir had a much higher MIC90 against genotypic penicillin-resistant Streptococcus pneumoniae (gPRSP) than cefditoren and cefcapene (8 mg/L cefdinir vs. 1 mg/L cefditoren and cefcapene). The majority of gPRSP harbored either ermB or mefA, and the antibacterial activity of telithromycin against these strains was decreased however some susceptibility was still sustained. Cefditoren exerted the strongest antibacterial activity against beta-lactamase-negative ampicillin-resistant Haemophilus influenzae, with an MIC90 of 0.5 mg/L. These results underline the importance of checking the susceptibility and selecting an appropriate antibiotic against target pathogens.     

Extensive studies on perfusion method plus intra-bone marrow-bone marrow transplantation using cynomolgus monkeys

The collection of bone marrow cells (BMCs) using a perfusion method has been advantageous not only because of the low contamination of BMCs with T cells from the peripheral blood but also the enrichment of stromal cells, which support hemopoiesis. Before the application of this new method to humans, its safety needed to be confirmed using cynomolgus monkeys. We therefore performed the perfusion method on more than 100 cynomolgus monkeys using the long bones (such as the humerus and femur) and also the iliac bones (for human application); in the more than 150 trials to date, there have been no accidental deaths. Furthermore, the technical safety of a new method for the intra-bone marrow (IBM) injection of BMCs (termed IBM-bone marrow transplantation) has also been confirmed using 30 monkeys. Disclosure of potential conflicts of interest is found at the end of this article.     

Booster effect of interleukin-2 on natural killer 1.1+ cells stimulated by administration of macrophage colony-stimulating factor in mice

The authors studied the combined effects of macrophage colony-stimulating factor (M-CSF) and interleukin (IL)-2 on the functions and antitumor activity of natural killer (NK) 1.1+ cells in vitro and in vivo. NK1.1+ cells were isolated from the spleen of mice treated with saline or M-CSF, and their functions (proliferation, production of IFN-gamma, and cytotoxicity) evaluated in vitro. Although the proliferation of and production by NK1.1+ cells was stimulated by the addition of IL-2, the cells from the M-CSF-treated mice responded better. Furthermore, the cytotoxicity against Yac-1 cells and B16 melanoma cells was stimulated by M-CSF administration and enhanced by the addition of IL-2 and IL-12. These results demonstrated that M-CSF treatment augmented the functions of NK1.1 cells, and IL-2 and IL-12 boosted these activities in vitro. The authors then examined the effects of co-administration of M-CSF and IL-2 in vivo. The clearance of B16 cells in lung was augmented by the administration of M-CSF but not IL-2. However, M-CSF + IL-2 treatment further enhanced the clearance activity. The anti-metastatic activity was also enhanced by the M-CSF + IL-2 treatment. Furthermore, the survival of B16-bearing mice was prolonged by M-CSF + IL-2. These results suggested that administration of IL-2 boosts the functions of NK1.1+ cells, which are augmented preliminarily by the administration of M-CSF.