Clinical outcomes of a novel therapeutic vaccine with Tax peptide‐pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study

Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type‐I (HTLV‐I)‐infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV‐I Tax‐specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti‐ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate‐ to high‐risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax‐specific CTL responses were observed with peaks at 16–20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide‐pulsed DC vaccine is a safe and promising immunotherapy for ATL.     

Hypercholesterolemia as a part of chronic GVHD after allogeneic stem cell transplantation

A 45-year-old female with acute myelogenous leukemia (AML-M6) received an allogeneic stem cell transplantation from an HLA-identical sibling donor in June 2002. Prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine (CsA) and short-term methotrexate. Acute GVHD did not occur and CsA was discontinued on day 145 after transplantation. However, soon thereafter she suffered from conjunctivitis, stomatitis and liver dysfunction with hypercholesterolemia and was diagnosed as having chronic GVHD. The liver dysfunction and hypercholesterolemia failed to improve despite the administration of CsA and prednisolone. Atrovastatin was not effective and immunosuppressive therapy for two months including ursodeoxycholic acid finally improved the jaundice and hypercholesterolemia. Although lipid metabolism analysis in this case disclosed the same findings as in other intrahepatic cholestatic liver diseases, the results show that the improvement of hypercholesterolemia in chronic GVHD needs the same treatment as chronic GVHD.     

Subacute cor pulmonale due to tumor embolism

We describe a patient wih subacute cor pulmonale caused by tumor emboli in the lungs. A 64-year-old female suffering from a subacute progressive cough and shortness of breathing died of severe pulmonary hypertension seven days after admission. Neither chest CT scans nor lung perfusion scintigraphy showed any abnormal findings. Microscopic examination after an autopsy revealed diffuse intravascular tumor emboli occluding not only the small pulmonary arteries and arterioles, but also the lymphatic vessels, which were suggested to be metastases of a breast carcinoma resected five years previously. Thus, pulmonary tumor embolism should be considered in the differential diagnosis of primary pulmonary hypertension, particularly in patients with a past history of cancers.     

Serum amyloid A and C‐reactive protein positive nodule in alcoholic liver cirrhosis,hard to make definite diagnosis

We describe a case of serum amyloid A (SAA) and C‐reactive protein (CRP) positive nodule detected by immunohistochemical analysis in a 37‐year‐old woman with alcohol‐related cirrhosis. Imaging studies at first admission pointed to hepatocellular carcinoma (HCC), a dysplastic nodule, an inflammatory pseudotumor or focal nodular hyperplasia (FNH). Ultrasonography‐guided biopsy in Segment 2 showed minimal atypical changes, except for a slight increase in cell density and micronodular cirrhosis in the non‐nodular portion. gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging carried out after a year and a half revealed hypervascularity in the arterial phase and isointensity in the hepatobiliary phase. Three years thereafter, however, the imaging displayed a change from isointensity to a defect in the hepatobiliary phase, and the nodule demonstrated minimal histological atypia. Immunohistochemical staining of the nodule was positive for SAA, CRP, liver fatty acid‐binding protein and glutamine synthetase, but negative for β‐catenin, heat shock protein 70 and Glypican 3. Organic anion transporter (OATP)8 staining was weaker in the nodule than in the non‐nodular portion of the alcohol‐related micronodular cirrhosis. The nodule was diagnosed as an SAA and CRP positive nodule, and HCC was ruled out. Despite the change from isointensity to a defect in the hepatobiliary phase, no evidence of HCC was found in the biopsy specimen. The change may be explained more by the weak OATP8 staining compared with that of alcohol‐related liver cirrhosis than by malignant transformation into HCC.     

Prostaglandin E Receptor Subtypes EP2 and EP4 Promote TH1 Cell Differentiation and TH17 Cell Expansion Through Different Signaling Modules

It is well known that prostaglandin (PG) E₂ exerts T cell suppression in vitro through elevating cAMP by its receptors, EP2 and EP4. However, such an action is rarely detected in vivo, leaving PGE₂-mediated immunosuppression an enigma. Here we show that under strong TCR stimulation, PGE₂ facilitates T helper-1 (T_H-1) differentiation through activation of phosphatidylinositol-3-kinase (PI3K) by EP2 and EP4. The PGE₂-EP4 signaling is also required for IL-23 production by activated dendritic cells (DCs), and the PGE2-EP2/EP4 signaling amplifies IL-23-mediated T_H-17 cell expansion. Administration of an EP4-selective antagonist in vivo to mice subjected to experimental allergic encephalomyelitis (EAE) decreases accumulation of both T_H-1 and T_H-17 cells in regional lymph nodes, and suppresses the disease progression. These results suggest PGE₂ promotes immune inflammation through T_H-1 differentiation and T_H-17 expansion and the EP4 antagonism is therapeutically useful for various immune diseases.

     

Urinary vanin‐1 associated with chronic kidney disease in hypertensive patients: A pilot study

Hypertension and chronic kidney disease (CKD) are serious interrelated public health problems. Despite the monitoring and control of high blood pressure, symptoms of CKD are not usually apparent in its early stages. Previously, we reported the utility of urinary vanin‐1 as an early biomarker of kidney injury in spontaneously hypertensive rats, but it remains unknown whether urinary vanin‐1 is associated with CKD in humans. In this study, we estimated associations between urinary vanin‐1 and parameters of kidney function in a cross‐sectional study of hypertensive patients. We measured concentrations of vanin‐1 using spot urine from 147 adult hypertensive patients (mean age, 72.8 years; 39.5% women). Patients were divided into 2 groups based on the median of the estimated glomerular filtration rate (eGFR). The group with eGFR < 60 mL/min per 1.73 m² showed significantly higher levels of urinary vanin‐1 than those with eGFR ≥ 60 mL/min per 1.73 m². On univariate analysis, urinary vanin‐1 as well as neutrophil gelatinase‐associated lipocalin (NGAL) showed significant negative correlations with eGFR; however, multivariate analysis revealed that urinary vanin‐1, but not NGAL, significantly correlated with eGFR. In addition, urinary vanin‐1 had a significant positive correlation with the urinary protein‐to‐creatinine ratio (UPCR) (r = 0.21; P = .021) and albumin‐to‐creatinine ratio (UACR) (r = 0.61; P < .01). In conclusion, urinary vanin‐1 is associated with lower eGFR and higher UPCR and UACR, and might be a potential marker of decreased kidney function in hypertensive patients. Further studies are needed to confirm these findings.     

CD48 as a novel molecular target for antibody therapy in multiple myeloma

Monoclonal antibody (mAb) drugs are desirable for the improvement of multiple myeloma (MM) treatment. In this study, we found for the first time that CD48 was highly expressed on MM plasma cells. In 22 out of 24 MM patients, CD48 was expressed on more than 90% of MM plasma cells at significantly higher levels than it was on normal lymphocytes and monocytes. CD48 was only weakly expressed on some CD34(+) haematopoietic stem/progenitor cells, and not expressed on erythrocytes or platelets. We next examined whether CD48 could serve as a target antigen for mAb therapy against MM. A newly generated in-house anti-CD48 mAb induced mild antibody-dependent cell-mediated cytotoxicity and marked complement-dependent cytotoxicity against not only MM cell lines but also primary MM plasma cells in vitro. Administration of the anti-CD48 mAb significantly inhibited tumour growth in severe combined immunodeficient mice inoculated subcutaneously with MM cells. Furthermore, anti-CD48 mAb treatment inhibited growth of MM cells transplanted directly into murine bone marrow. Finally and importantly, we demonstrated that the anti-CD48 mAb did not damage normal CD34(+) haematopoietic stem/progenitor cells. These results suggest that the anti-CD48 mAb has the potential to become an effective therapeutic mAb against MM.