Interstitial Inflammatory Infiltration Research Articles

Histopathologic diagnosis of chronic graft-versus-host disease of the oral mucosa according to the National Institutes of Health Consensus.

ABSTRACTObjectiveTo validate the minimal criteria of the histopathologic diagnosis of oral chronic graft-versus-host disease, based on the histopathologic classification of the National Institutes of Health and correlate them with clinical features.MethodsForty-one specimens containing both oral mucosa and salivary glands were analyzed in slides stained with hematoxylin-eosin. The histological specimens were blindly examined by two trained pathologists using criteria recommended for the histopathologic diagnosis of chronic graft-versus-host disease proposed by the National Institutes of Health Consensus. The clinical classification of chronic graft-versus-host disease was correlated with analysis of slides.ResultsOur data showed that the epithelium was involved in 39/41 specimens, presenting acanthosis (29/70.7%), exocytosis of lymphocytes (29/70.7%), thickening of basal lamina (29/70.7%), and apoptosis (15/36.6%). Connective tissue presented interstitial inflammatory infiltrate (38/92.7%). Minor salivary glands showed periductal fibrosis (38/92.7%), mixed periductal inflammatory infiltrate (32/78%), ductal ectasia (30/73.2%), lymphocytes around and into acinar units (30/73.2%), and interstitial fibrosis (29/70.7%). The most common clinical manifestations were lichenoid aspect (40/97.6%), complaints of sensitivity to oral feeding (38/92.7%), and dry mouth sensation (36/87.8%).ConclusionThis study validated the National Institutes of Health Consensus of minimal histologic criteria for diagnosis of oral chronic graft-versus-host disease and has not found an association between the severity of clinical manifestation and the histopathological stage.

Comparison of myocardial T1 mapping techniques at 1.5T to detect interstitial fibrosis in patients with orthotopic cardiac transplant

Background Apoptotic death of interstitial cells and myocytes is a detrimental effect of the interstitial inflammatory infiltrate accompanying heart transplant rejection. This inflammatory reaction is followed by both replacement fibrosis and interstitial fibrosis which in the long term can impair diastolic and systolic ventricular (LV) function. Cardiac magnetic resonance (CMR) with gadolinium quantifies replacement fibrosis and new sequences with T1 mapping are proposed for the quantification of more elusive interstitial fibrosis. We aimed at determining the optimal T1 mapping approach to assess characteristic tissue composition in these patients.

Early protocol biopsies in pediatric renal transplantation: Interest for the adaptation of immunosuppression

GPB are often performed in PRT to detect subclinical acute rejection or IF/TA. Reducing immunosuppression side effects without increasing rejection is a major concern in PRT. We report the results of GPB in children transplanted with a steroid-sparing protocol adapted to immunological risk. Children under 18 yr who received a renal transplantation between April 1, 2009 and May 31, 2012 were included. Immunosuppression consisted of an antibody induction therapy, tacrolimus, and MMF for all recipients. CSs were administered to children under five yr old, or receiving a second allograft. Twenty-eight children were included, 50% were CSs free. GPB were performed between three and six months. IF/TA was documented in seven biopsies; four of these seven children were CS free. One child, with CSs, presented a borderline rejection, and another child, steroid free, with significant inflammatory interstitial infiltrate, considered as a subclinical rejection, was treated with CSs pulses. The median eGFR was stable (74, 67.5, and 82 mL/min/1.73 m² at, respectively, seven days, three months, and one yr). Patient and graft survival were 100%. These results have to be confirmed in a larger cohort, with long-term follow-up.

Abstract 30: Nuclear Factor of Activated T Cells-5(NFAT5) Plays a Protective Role in Renal Ischemia Reperfusion Injury(IRI)

Recovery from acute kidney injury includes restoration of GFR and tubular repair but may be associated with impaired renal hemodynamic and natriuretic responses that contribute to the development of salt-sensitive hypertension and chronic kidney disease. NFAT5, a transcription factor that protects the kidney from hypertonic stress also is activated by hypoxia, however, a functional role for this transcription factor in IRI has not been established. Mice were subjected to IRI by clamping of the left renal pedicle for 30 min followed by reperfusion for 3 or 48 hr. After 3 hr, analysis by qRT-PCR showed that the relative abundance of NFAT5 mRNA was similar in mTAL tubules, or outer medulla (OM), prepared from contralateral and clamped kidneys. However, after 48 hr NFAT5 mRNA accumulation increased approximately three-fold in both mTAL tubules (NFAT5/β-actin, 3.14 ± 0.32 to 0.95 ± 0.11, p<0.05) and OM (2.71 ± 0.43 to 0.82 ± 0.22, p<0.05). Mice were then either pretreated for 72 hr with an intrarenal injection of a lentivirus shRNA construct to knockdown functional NFAT5 (EGFP-U6-N5-ex8, n=6), or a control vector (EGFP-U6, n=6) before induction of IRI. NGAL and Kim1, established biomarkers of IRI, mRNA was dramatically increased after IRI and was further increased after knockdown of NFAT5 (NGAL: EGFP-U6-N5-ex8; 111.5 ± 10.9, EGFP-U6; 59 ± 6.2, p<0.05 and Kim1: EGFP-U6-N5-ex8; 25.8 ± 3.8, EGFP-U6; 12.9 ± 2.1, p<0.05), suggesting that inhibition of NFAT5 exacerbates damage in the TAL after IRI. Apoptotic cells in OM of the clamped kidney, with or without inhibition of NFAT5, were detected by TUNEL assay and quantitated by laser scanning cytometry. The number of apoptotic cells in the OM increased nearly 2-fold after knockdown of NFAT5 (%TUNEL to PI: EGFP-U6-N5-ex8; 34.5 ± 6.3, EGFP-U6; 19.7 ± 2.4, p<0.05). These data are consistent with H&E staining showing exacerbation of histological features including loss of brush border, flattened tubular epithelium, tubular dilation, tubular lumen debris, and interstitial inflammatory cell infiltration after knockdown of NFAT5. Collectively, the data suggest that NFAT5 is part of a protective mechanism in the TAL and OM that limits renal damage induced by IRI, and may attenuate long-term detrimental renal effects associated with IRI.

Cardiac magnetic resonance T1 mapping pre and post contrast characterizes the myocardium in orthotopic heart transplantation recipients without active rejection

Background: Transplant rejection is characterized by interstitial inflammatory infiltrate. This inflammatory reaction is followed by both replacement fibrosis and interstitial fibrosis which in the long term can impair diastolic and systolic ventricular (LV) function.Cardiac magnetic resonance (CMR) with gadolinium quantifies replacement fibrosis and compares well with biopsy in the diagnosis of heart transplant rejection. New T1 mapping sequences are proposed for the quantification of interstitial fibrosis. Methods: We studied 33 heart transplant patients (Tx) (7 Females), mean time from Tx 112±56 mo (range 2–1288) and 12 normals (N), age 48±13 and 40±11 p=0.04. Absence of active rejection was confirmed by EMB. CMR was performed on a 1.5 Tesla scanner (Siemens). Short axis SSFP cine images covering the LV were acquired; image position was used for T1-mapping and late gadolinium enhancement (LGE). MOLLI T1 maps were generated from 5-7 SSFP images with variable inversion preparation time as described by Messroghli (2007) before and after gadobutrol i.v. (0.15 mmol/kg). Region of interest were drawn on 3 short axis (base,mid,apex) average T1 values pre and post contrast administration (msec) were fitted by a non-linear curve. Data are mean±SD Results: Systolic function was similar in both groups Tx 65±10 vs N 67±5 p=0.69, LV Mass Index was slightly higher in Tx 76±17 vs 66±8 N p=0.16. In Tx pre -contrast T1 was longer 1020±93 vs 957±45 msec p<0.001, whereas post contrast was shorter 406±46 msec vs 455±35 msec p<0.001. In Tx with cytomegalovirus infection (n=17) T1 mean pre-contrast was significantly higher 1043±15 vs 981±46 p=0.018. T1 post-contrast but not pre-contrast was inversely correlated to time interval from Tx y=4925-0.327x; p<0.05. Patients with LVH (n=7) had a significantly higher T1 both pre (p=0.007) and post contrast (p=0.04). LV mass index was directly correlated to T1 pre P=0.05 and inversely correlated to T1 post (p=0.002). Twentythree out of 33 Tx had patchy LGE distribution mainly in the inferior RV insertion, 2 had a previous myocardial infarction and 8 did not show LGE. Conclusions: Patient transplanted with no active rejection show a significant increase of interstitial fibrosis which builds up over time. CMR beside anatomo-functional parameters combining LGE and T1 mapping can provide a useful non invasive characterization of the collagen deposition in transplanted hearts and allow a better insight into the progression of restrictive physiology

Long-term observations of clinicopathological characteristics and outcome of Japanese patients with pauci-immune crescentic glomerulonephritis

The clinicopathological characteristics and outcome with pauci-immune crescentic glomerulonephritis (CreGN) are presumed to vary over time. We examined the characteristics and outcome of Japanese patients with CreGN according to the treatment periods. From 1968 to 2011, we examined a total of 102 patients diagnosed with pauci-immune CreGN by renal biopsy. The patients were divided into three groups according to the treatment periods-Group I (1968-1988, n=18), Group II (1989-2001, n=37; when the nationwide survey of rapidly progressive glomerulonephritis [RPGN] was performed in Japan), and Group III (2002-2011, n=47; after publication of the Japanese guideline for RPGN). There were no significant differences in blood pressure, renal function or anti-neutrophil cytoplasmic antibody titer between groups. On the other hand, the rate of crescent formation and degree of interstitial inflammatory cell infiltration were decreased in Group III. Serum creatinine (<3.0, 3.0-6.0, ≥6.0mg/dL) and crescent formation (<30, 30-50, 50-80, ≥80%) were significant renal prognostic factors in Group III [serum creatinine: hazard ratio (HR) 4.79, 95% confidence interval (CI) 1.43-16.1, P=0.011; crescent formation: HR 2.86, 95% CI 1.06-7.73, P=0.039]. Furthermore, renal survival rate of patients with crescent formation <50% and patient survival rate of patients with serum creatinine <3mg/dL were improved in Group III. Patients with CreGN were diagnosed in the early phase of crescent formation and outcome has improved in recent years.

Intracardiac injection of a capsid-modified Ad5/35 results in decreased heart toxicity when compared to standard Ad5

BackgroundClinical gene therapy trials for cardiovascular diseases have demonstrated the crucial role of efficient gene delivery and transfection technologies in achieving clinically relevant results. We hypothesized that the use of tropism-modified adenoviruses would improve transduction efficacy and to this end we analyzed the transduction efficiency and toxicity of standard Ad5 and tropism-modified Ad5/35 in combination with ultrasound-guided intramyocardial gene delivery.MethodsUltrasound-guided intracardiac injections were used to deliver 1 × 1010 pfu/ml Ad5-lacZ and Ad5/35-lacZ vectors into mouse left ventricle wall. Since Ad5/35 uses human CD46 as its primary receptor, we used transgenic hCD46Ge mice expressing human CD46 at levels comparable to man. Mice were sacrificed 6 or 14 days post-injection and immunohistochemistry and X-gal staining were used to detect transgene and viral receptor expression. Virus-induced cardiac toxicity was evaluated by a pathologist.ResultsThe intramyocardial injection was well tolerated and both Ad5-lacZ and Ad5/35-lacZ were able to give robust transgene expression after a single injection. Interestingly, while Ad5-lacZ was able to generate greater transgene expression than Ad5/35-lacZ, it also evoked more severe tissue damage with large areas of interstitial inflammatory cell infiltration and myocyte necrosis.ConclusionsUltrasound-guided intramyocardial injection is an effective and safe way to deliver vectors to the heart. The observed severe tissue damage of Ad5-lacZ greatly undermines the efficient transgene expression and suggests that Ad5/35 capsid modification can result in safer adenoviral vectors for cardiovascular gene therapy, although at the cost of some vector transduction efficacy.

Effects of cilostazol in kidney and skeletal striated muscle of Wistar rats submitted to acute ischemia and reperfusion of hind limbs

To investigate the effect of cilostazol, in kidney and skeletal muscle of rats submitted to acute ischemia and reperfusion. Fourty three animals were randomized and divided into two groups. Group I received a solution of cilostazol (10 mg/Kg) and group II received saline solution 0.9% (SS) by orogastric tube after ligature of the abdominal aorta. After four hours of ischemia the animals were divided into four subgroups: group IA (Cilostazol): two hours of reperfusion. Group IIA (SS): two hours of reperfusion. Group IB (Cilostazol): six hours of reperfusion. Group IIB (SS) six hours of reperfusion. After reperfusion, a left nephrectomy was performed and removal of the muscles of the hind limb. The histological parameters were studied. In kidney cylinders of myoglobin, vacuolar degeneration and acute tubular necrosis. In muscle interstitial edema, inflammatory infiltrate, hypereosinophilia fiber, cariopicnose and necrosis. Apoptosis was assessed by immunohistochemistry for cleaved caspase-3 and TUNEL. There was no statistically significant difference between groups. Cilostazol had no protective effect on the kidney and the skeletal striated muscle in rats submitted to acute ischemia and reperfusion in this model.

IgG4-related kidney disease

IgG4-related kidney disease is a term that refers to any form of renal involvement by IgG4-related disease (IgG4-RD), a recently recognized systemic immune-mediated disease. The most common renal manifestation is IgG4-related tubulointerstitial nephritis (IgG4-TIN), which presents as acute or chronic renal insufficiency, renal mass lesions, or both. On biopsy, IgG4-TIN shows a plasma cell-rich interstitial inflammatory infiltrate with increased IgG4+ plasma cells, along with expansile interstitial fibrosis; tubular basement membrane immune complex deposits are common. IgG4-TIN usually shows a brisk response to immunosuppressive therapy. Glomeruli may be affected by IgG4-RD, usually in the form of membranous glomerulonephritis. Other patterns of glomerular disease include IgA nephropathy, membranoproliferative glomerulonephritis, and endocapillary or mesangioproliferative immune complex glomerulonephritis. IgG4-related plasma cell arteritis has also been observed in the kidney. This review describes the histopathologic and immunophenotypic patterns of renal involvement by IgG4-RD, with associated clinical, radiographic, and serologic features.

Pityriasis Rotunda

We present a male patient with polycythemia vera (PV) in whom pyoderma gangrenosum (PG) was induced by subcutaneous injections of interferon-α2beta (IFN-α2b).The patient presented with a 6 cm wide necrotic ulcer on the external aspect of his left thigh, which was surrounded by an erythematous and indurated plaque. He also had a simetrical but smaller 2 cm of size ulcer on the external aspect of the right thigh. Histopathological examination showed a massive perivascular and interstitial inflammatory infiltrate. It was vastly composed of neutrophils and secondary formation of interstitial neutrophilic microabscesses was also observed.To our knowledge only two cases of PG secondary to IFN-α2b injections have been reported, none of them in a patient with PV. Physicians should be aware of these IFN-α2b-related local adverse effects as they might become extremely severe. Immediate local discontinuation of drug administration is mandatory. In order to avoid these complications, alternating injection sites is highly advisable.

Protective Effect of Infliximab on Ischemia/Reperfusion-Induced Damage in Rat Kidney

Objective: To investigate the protective effect of infliximab on ischemia–reperfusion (I/R) injury of the rat kidney. Methods: Twenty-eight male Wistar albino rats were divided into four groups: sham-operated, I/R, I/R with infliximab administered before ischemia [I/R + infliximab (bi)], and I/R with infliximab administered before reperfusion [I/R + infliximab (br)]. After a right nephrectomy to produce damage, the left renal vessels were occluded for 60 min, followed by 24-h reperfusion in rats. Changes in the rat kidney were observed by measuring the tissue levels of malondialdehyde (MDA), myeloperoxidase (MPO), glutathione (GSH), and superoxide dismutase (SOD) and by evaluating hematoxylin–eosin (H&E)-stained and periodic acid–Schiff (PAS) sections. Results: The MDA and MPO levels in the I/R group were significantly higher than in the other groups (p < 0.05), and the SOD and GSH levels in the I/R + infliximab (bi) and I/R + infliximab (br) groups were significantly higher than in the I/R group (p < 0.05). However, histological examination revealed that the I/R + infliximab (bi) group and the I/R + infliximab (br) group had significantly fewer tubular changes and interstitial inflammatory cell infiltration than the I/R group. Conclusion: These results show that infliximab may protect against I/R injury in the rat I/R model.

Pulmonary impact of N-acetylcysteine in a controlled hemorrhagic shock model in rats

BackgroundExperimental hemorrhagic shock (HS) is based on controlling bleeding and the treatment of fluid resuscitation to restore tissue oxygenation and perfusion. The HS could promote ischemia/reperfusion injury, which induces a general exacerbation of the inflammatory process, initially compromising the lungs. N-acetylcysteine (NAC), an antioxidant, may attenuate ischemia/reperfusion injury. This study evaluated the effect of NAC in association with fluid resuscitation on pulmonary injury in a controlled HS model in rats. MethodsMale Wistar rats were submitted to controlled HS (mean arterial pressure of 35 mm Hg for 60 min). Two groups were constituted according to resuscitation solution administered: RLG (Ringer’s lactate solution) and RLG+NAC (Ringer’s lactate in association with 150 mg/kg NAC. A control group was submitted to catheterization only. After 120 min of resuscitation, bronchoalveolar lavage was performed to assess intra-alveolar cell infiltration and pulmonary tissue was collected for assessment of malondialdehyde, interleukin 6, and interleukin 10 and histopathology. ResultsCompared with the RLG group, the RLG+NAC group showed lower bronchoalveolar lavage inflammatory cell numbers, lower interstitial inflammatory infiltration in pulmonary parenchyma, and lower malondialdehyde concentration. However, tissue cytokine (interleukin 6 and interleukin 10) expression levels were similar. ConclusionN-acetylcysteine was associated with fluid resuscitation–attenuated oxidative stress and inflammatory cell infiltration in pulmonary parenchyma. N-acetylcysteine did not modify cytokine expression.

An itchy rash in a young Caucasian woman

We report of a 23-year-old woman who presented with a six-month history of a recurring, pruritic rash located on her chest, upper abdomen and most recently on the lower back. Until then the patient had been healthy. She did not take any medications, was not aware of any allergies or a family his-tory of skin diseases.The rash had occurred initially six months ago and was marked by an acute onset and a chronic recurrent course. The patient noted a timely association between the onset of the skin lesions and the start of a vegetarian diet. Further-more physical activity and sweating worsened the symptoms.Clinically the woman presented with erythematous patches and urticarial papules as well as crusted vesicles and pustules with an erythematous base that were located on the chest and the inframammary folds and distributed in a symmetrical fashion (Figure 1A, B). Under the provisional diagnosis of an autoimmune bullous disease, the woman had recently received systemic and topical corticosteroids. Lesions progressed under this therapy. Additionally, new pink, slightly urticarial papules and plaques developed on the back. Intense pruritus was the main complaint of the patient. This symptom did not respond to antihistamine or steroid therapy.Routine laboratory tests including blood count, blood chemistry, and serum protein levels were normal. No ele-vated antinuclear antibody titers were found. Direct and indirect immunofluorescence assays and an ELISA to rule out an autoimmune bullous disease were performed and were negative.A skin biopsy taken from one of the most recent lesions on the back showed a sparse perivascular lymphocytic cell infiltrate with occasional neutrophils and a discrete edema of the papillary dermis (Figure 2). No epidermal changes were present. In contrast to these subtle changes, a skin biopsy taken from a fully developed inframammary lesion displayed dramatic epidermal changes consisting of ballooning of kera -tinocytes, necrosis en masse of keratinocytes with intraepi-dermal vesiculation and exocytosis of neutrophils and eosin -ophils. The epidermal changes were accompanied by a dense superficial interstitial and perivascular dermal inflammatory cell infiltrate consisting of lymphocytes mainly, but also neu -trophils and eosinophils (Figures 3, 4).The clinical and histopathologic findings summoned up to the diagnosis of prurigo pigmentosa. Alternative diagno-

Fatal Human Co-infection withLeptospiraspp. and Dengue Virus, Puerto Rico, 2010

Fatal Human Co-infection with<i>Leptospira</i>spp. and Dengue Virus, Puerto Rico, 2010

Feline morbillivirus, a previously undescribed paramyxovirus associated with tubulointerstitial nephritis in domestic cats

We describe the discovery and isolation of a paramyxovirus, feline morbillivirus (FmoPV), from domestic cat (Felis catus). FmoPV RNA was detected in 56 (12.3%) of 457 stray cats (53 urine, four rectal swabs, and one blood sample) by RT-PCR. Complete genome sequencing of three FmoPV strains showed genome sizes of 16,050 bases, the largest among morbilliviruses, because of unusually long 5' trailer sequences of 400 nt. FmoPV possesses identical gene contents (3'-N-P/V/C-M-F-H-L-5') and is phylogenetically clustered with other morbilliviruses. IgG against FmoPV N protein was positive in 49 sera (76.7%) of 56 RT-PCR-positive cats, but 78 (19.4%) of 401 RT-PCR-negative cats (P < 0.0001) by Western blot. FmoPV was isolated from CRFK feline kidney cells, causing cytopathic effects with cell rounding, detachment, lysis, and syncytia formation. FmoPV could also replicate in subsequent passages in primate Vero E6 cells. Infected cell lines exhibited finely granular and diffuse cytoplasmic fluorescence on immunostaining for FmoPV N protein. Electron microscopy showed enveloped virus with typical "herringbone" appearance of helical N in paramyxoviruses. Histological examination of necropsy tissues in two FmoPV-positive cats revealed interstitial inflammatory infiltrate and tubular degeneration/necrosis in kidneys, with decreased cauxin expression in degenerated tubular epithelial cells, compatible with tubulointerstitial nephritis (TIN). Immunohistochemical staining revealed FmoPV N protein-positive renal tubular cells and mononuclear cells in lymph nodes. A case-control study showed the presence of TIN in seven of 12 cats with FmoPV infection, but only two of 15 cats without FmoPV infection (P < 0.05), suggesting an association between FmoPV and TIN.

Efficacy of tocilizumab, a humanized neutralizing antibody against interleukin-6 receptor, in progressive renal injury associated with Castleman's disease

Castleman's disease is a benign lymphoproliferative disorder in which interleukin-6 (IL-6), a pleiotropic proinflammatory cytokine, is thought to play a pathogenetic role. Presented is the case of a 72-year-old man with Castleman's disease who exhibited progressive renal dysfunction with proteinuria. Renal biopsy revealed mesangial hypercellularity and matrix expansion in most glomeruli and peritubular inflammatory cell infiltration. Immunofluorescence studies showed intense deposition of IgG in a granular pattern along the glomerular basement membrane. Histological features were compatible with membranoproliferative glomerulonephritis accompanied by interstitial inflammatory cell infiltration. Immunohistological analysis showed that IL-6 was abundantly expressed by tubular cells and interstitial macrophages, suggesting involvement of IL-6 in the renal injury. As a result of administration of tocilizumab, a humanized anti-IL-6 receptor antibody, the patient experienced clinical and biochemical improvement of Castleman's disease, including marked reduction of proteinuria and stabilization of renal function. These findings suggest the efficacy of tocilizumab against Castleman's disease and its renal complications.

Delayed Renal Function Recovery From Drug-Induced Acute Interstitial Nephritis

IntroductionAcute interstitial nephritis, considered one of the major causes of reversible acute kidney injury, was frequently encountered as drug-treatment complication in the early stage of infection control. In some cases, drug-induced acute interstitial nephritis (DIAIN) resulted in delayed function recovery or chronic kidney disease. To study the underlying mechanism, the authors investigated the clinical and pathological features of DIAIN patients with delayed renal function recovery. The delayed recovery group consisted of patients with reduced renal function for more than 3months after diagnosis. MethodsIn this retrospective study, 18 patients with DIAIN from January 2003 to December 2009 were identified as the delayed recovery group, whereas 54 patients with DIAIN who recovered completely within 3months were treated as the control group. Clinical and pathological features were compared between the 2 groups. ResultsIn the delayed recovery group, the average age at onset was 48.8years, antibiotics and herbs were the 2 main causative drugs and the dominant extra-renal manifestation was gastrointestinal symptomatology. In comparison with patients in the control group, patients in the delayed recovery group had longer interval time from disease onset to hospitalization, and they presented with less oliguria. Moreover, these patients had higher levels of urine retinol binding protein, and more renal interstitial inflammatory cell infiltrations were observed in their renal histology. ConclusionAging, long interval time from disease onset to hospitalization and renal interstitial inflammatory cell infiltration may predict delayed renal function recovery.

Surveillance Renal Allograft Biopsy on Diagnosis of BK Virus Nephropathy in Chinese Renal Transplant Recipients

Objective: We prospectively investigated 121 renal allograft biopsy specimens performed in our center. Methods: BKVAN was diagnosed by light microscopic examination and a positive immunohistochemistry staining of anti-SV40 large T antibody in a biopsy specimen. Results: Of the 121 patients, nine were diagnosed with BKVAN (7.4%). Nine patients whith BKVN classically presents as allograft dysfunction with an asymptomatic rise in serum creatinine, about 3 to 39 months posttransplant. Urinary decoy cells are positive in two patients (22.2%). The histologic changes of BKVN are not pathognomonic, and can be mistaken for allograft rejection, ie, tubulointerstitial nephritis with varying degrees of inflammatory infiltrates, tubulitis and tubular atrophy, and fibrosis. Typical findings on histology are focal interstitial mononuclear inflammatory cell infiltrates, presence of plasma cells, necrotic tubular epithelium, and presence of homogenous intranuclear inclusion bodies. Immunohistochemistry with SV40 staining were positive in allograft. Graft loss occurred in one patient and the other 8 showed progressive allograft dysfunction. Conclusion: The definitive diagnosis of BKV disease requires renal biopsy. Immunohistochemistry with SV40 staining has been used as an indirect method to document the presence of BKVAN.

Infection of Hantaan virus strain AA57 leading to pulmonary disease in laboratory mice

Hantaan virus (HTNV) is a causative agent of hemorrhagic fever with renal syndrome (HFRS). The pathogenesis of HFRS has not been fully elucidated, mainly due to the lack of a suitable animal model. In laboratory mice, HTNV causes encephalitis. However, that symptom is dissimilar to human hantavirus infections. We found that HTNV strain AA57 (isolated from Apodemus agrarius in Far East Russia) caused pulmonary disease in 2-week-old ICR mice. The clinical signs of the infected mice were piloerection, trembling, hunching, labored breathing, and body-weight loss. A large volume of pleural effusion was collected from thoracic cavities of the dead mice. Overall, 45% of the mice inoculated with 3000 focus forming units (FFU) of the virus began to show clinical symptoms at 8 days post-inoculation, and 25% of the inoculated mice died within 3 days of onset of the disease. The morbidity and mortality rates of the mice inoculated with 30–30,000FFU of HTNV strain AA57 were roughly equivalent. The highest rates of virus positivity (11/12) and the highest titers of HTNV strain AA57 were detected in the lungs of the dead mice, while lower detection rates and viral titers were found in the heart, kidneys, spleen, and brain. Interstitial pneumonia, perivascular edema, hemorrhage, inflammatory infiltration and vascular failure were observed in the lungs of the sick mice. Hantaviral antigens were detected in the lung endothelial cells of the sick mice. The symptoms and pathology of this mouse model resemble those of hantavirus pulmonary syndrome (HPS) and, to a certain extent, those of HFRS. This is the first report that, in laboratory mice, the HFRS-related hantavirus causes a HPS-like disease and shares some symptom similarities with HFRS.

SPARC Oppositely Regulates Inflammation and Fibrosis in Bleomycin-Induced Lung Damage

Fibrosis results from inflammatory tissue damage and impaired regeneration. In the context of bleomycin-induced pulmonary fibrosis, we demonstrated that the matricellular protein termed secreted protein acidic and rich in cysteine (SPARC) distinctly regulates inflammation and collagen deposition, depending on its cellular origin. Reciprocal Sparc(-/-) and wild-type (WT) bone marrow chimeras revealed that SPARC expression in host fibroblasts is required and sufficient to induce collagen fibrosis in a proper inflammatory environment. Accordingly, Sparc(-/-) >WT chimeras showed exacerbated inflammation and fibrosis due to the inability of Sparc(-/-) macrophages to down-regulate tumor necrosis factor production because of impaired responses to tumor growth factor-β. Hence, the use of bone marrow cells expressing a dominant-negative form of tumor growth factor-β receptor type II under the monocyte-specific CD68 promoter, as a decoy, phenocopied Sparc(-/-) donor chimeras. Our results point to an unexpected dual role of SPARC in oppositely influencing the outcome of fibrosis.