Banff Lung Report: Current knowledge and future research perspectives for diagnosis and treatment of pulmonary antibody-mediated rejection (AMR).

The Lung session of the 2017 14th Banff Foundation for Allograft Pathology Conference, Barcelona focused on the multiple aspects of antibody-mediated rejection (AMR) in lung transplantation. Multidimensional approaches for AMR diagnosis, including classification, histological and immunohistochemical analysis, and donor- specific antibody (DSA) characterization with their current strengths and limitations were reviewed in view of recent research. The group also discussed the role of tissue gene expression analysis in the context of unmet needs in lung transplantation. The current best practice for monitoring of AMR and the therapeutic approach are summarized and highlighted in this report. The working group reached consensus of the major gaps in current knowledge and focused on the unanswered questions regarding pulmonary AMR. An important outcome of the meeting was agreement on the need for future collaborative research projects to address these gaps in the field of lung transplantation.

RNA expression profiling of nonhuman primate renal allograft rejection identifies tolerance.

Tolerance induction to prevent allograft rejection is a long-standing clinical goal. However, convincing and dependable tolerance identification remains elusive. Hypothesizing that intragraft RNA expression is informative in both rejection and tolerance, we profile intrarenal allograft RNA expression in a mixed chimerism renal allograft model of cynomolgus monkeys and identify biologically significant tolerance. Analysis of 67 genes identified 3 dominant factors, each with a different pattern of gene expressions, relating to T cell-mediated rejection (TCMR), chronic antibody-mediated rejection (CAMR), or Tolerance. Clustering these 3 factors created 9 groups. One of the 9 clustered groups, the Tolerance cluster, showed the lowest probability of terminal rejection, the longest duration of allograft survival, and the lowest relative risk of terminal rejection. The Tolerance factor consists of a novel set of gene expressions including cytokine and immunoregulatory genes adding mechanistic insights into tolerance. The Tolerance factor could not be identified within current pathologic diagnostic categories. The TCMR and CAMR factors are dominant to the Tolerance factor, causing rejection even if the Tolerance factor is present. These 3 factors determine the probability of terminal rejection or tolerance. This novel a posteriori approach permits identification of pathways of rejection, including tolerance.

RNA expression profiling of renal allografts in a nonhuman primate identifies variation in NK and endothelial gene expression.

RNA transcript expression estimates are a promising method to study the mechanisms and classification of renal allograft rejections. Here we use the Nanostring platform to profile RNA expression in renal allografts in a nonhuman primate (NHP), the Cynomolgus monkey. We analyzed protocol and indication 278 archival renal allograft samples, both protocol and indication from 76 animals with diagnoses of chronic antibody-mediated rejection (CAMR), acute cellular rejection (TCMR), and MIXED (both CAMR and TCMR), plus normals and samples with no pathological rejection using a Cynomolgus-specific probe set of 67 genes. Analysis identified RNA expression heterogeneity of endothelial and NK genes within CAMR and TCMR, including the stages of CAMR. Three factors were partitioned into additional groups. One group with the longest allograft survival time is pure CAMR without NK or CD3. Three mixed groups show variation in NK and CD3. TCMR was split into 2 groups with variation in NK genes. Additional validation of the complete gene-set correlated many of the genes with diagnoses of CAMR, MIXED, and TCMR rejections and with Banff histologic criteria defined in human subjects. These NHP data demonstrate the utility of RNA expression profiling to identify additional heterogeneity of endothelial and NK RNA gene expressions.

Chronic Antibody-Mediated Rejection in Nonhuman Primate Renal Allografts: Validation of Human Histological and Molecular Phenotypes.

Molecular testing represents a promising adjunct for the diagnosis of antibody-mediated rejection (AMR). Here, we apply a novel gene expression platform in sequential formalin-fixed paraffin-embedded samples from nonhuman primate (NHP) renal transplants. We analyzed 34 previously described gene transcripts related to AMR in humans in 197 archival NHP samples, including 102 from recipients that developed chronic AMR, 80 from recipients without AMR, and 15 normal native nephrectomies. Three endothelial genes (VWF, DARC, and CAV1), derived from 10-fold cross-validation receiver operating characteristic curve analysis, demonstrated excellent discrimination between AMR and non-AMR samples (area under the curve = 0.92). This three-gene set correlated with classic features of AMR, including glomerulitis, capillaritis, glomerulopathy, C4d deposition, and DSAs (r = 0.39-0.63, p < 0.001). Principal component analysis confirmed the association between three-gene set expression and AMR and highlighted the ambiguity of v lesions and ptc lesions between AMR and T cell-mediated rejection (TCMR). Elevated three-gene set expression corresponded with the development of immunopathological evidence of rejection and often preceded it. Many recipients demonstrated mixed AMR and TCMR, suggesting that this represents the natural pattern of rejection. These data provide NHP animal model validation of recent updates to the Banff classification including the assessment of molecular markers for diagnosing AMR.

Blended learning in orthodontic diagnosis: an interactive approach.

Interactive multimedia programs can provide an opportunity for authentic learning both inside and outside the classroom. McGill University designed an interactive Orthodontic Diagnosis program on CD-ROM that has been used successfully in the faculty of dentistry to provide undergraduate students with interactive tutorials and exercises to help them recognize developing malocclusions. Key aspects of this multimedia program are the use of an outside-in approach to diagnosis as well as sound instructional design that provides practice opportunities and feedback to students. The goal is to bridge the gap between theoretical knowledge and the practical skills needed to be a successful dentist.

Bullous pemphigoid--management of a patient with oral and skin lesions.

A case of bullous pemphigoid with extra-oral and intraoral lesions in a 60-year-old female is reported. Diagnosis is based on histopathology and direct immunofluorescence, and the treatment regime described included oral prescription of prednisolone and topical application of a mixture of fluocinonide ointment and triamcinolone acetonide in Orabase on the oral lesions.

Bullous diseases in Malaysia: epidemiology and natural history.

The characteristics of three primary bullous diseases, pemphigus, pemphigoid, and dermatitis herpetiformis, seen in this country, probably reflecting this region, are discussed and compared to those reported in the literature in the West. One hundred and forty-eight patients with bullous diseases were seen over a period of 15 years. The criteria for confirmation of clinical diagnosis were the findings of the direct immunofluorescent test. Pemphigus vulgaris was the commonest bullous disease. The incidence of bullous pemphigoid was highest in the Indians of Malaysian origin, and they are also more likely to develop pemphigus vulgaris than any other ethnic group. Linear IgA type formed the entire group of dermatitis herpetiformis. The granular type was not seen at all. The patients were treated with prednisolone alone or together with methotrexate or azathioprine. Dapsone alone controlled the dermatitis herpetiformis. The known association between pemphigus and other diseases with immunologic disturbances was not found in this study. The natural history of the bullous disease as seen in the follow-up patients is described. Deaths in pemphigus and pemphigoid were more due to either complications of steroid therapy or unassociated diseases than the primary disease itself. Introduction of immunofluorescence as a diagnostic tool in pemphigus and extension of this facility to other bullous diseases has led to detailed characterization of these diseases as seen in the West; however, publications in English dealing with epidemiologic aspects of bullous diseases in this region are rare.(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombotic thrombocytopenic purpura with terminal pancytopenia.

A 27 year old housewife developed thrombotic thrombocytopenic purpura during the twelfth week of pregnancy. She had partial response to initial plasma infusion and subsequent plasmapheresis. However, her clinical course was complicated by the development of severe pancytopenia the consequence of a hypocellular marrow. She succumbed to septicaemic shock one month after diagnosis. The development of hypocellular marrow in thrombotic thrombocytopenic purpura has not been reported before.

Therapeutic intervention scoring system in medical intensive care.

A scoring system based on therapeutic intervention on critically ill patients called the therapeutic intervention scoring system (TISS) was used to assess the quantity of care provided in a medical intensive care unit. Besides observing the unit census, the severity of illness and the work load were studied. The survival rate was 77 percent. The non-survivors had admission TISS points higher than the survivors and their mean daily TISS was more than 20 points. The survivors at discharge had a mean TISS of five points. The work load showed that a nurse can effectively manage two patients who together may accumulate 24 TISS points per day. TISS points per patient rather than bed occupancy is a better indicator of the nurse's work load. Admission criteria and procedures before death certification are outlined.

Stevens-Johnson syndrome. A review of 34 cases.

Stevens-Johnson syndrome is relatively rare. The authors report a retrospective study of 34 patients seen at the University Hospital in Malaysia over 16 years and discuss the epidemiology, clinical features, complications, investigations, etiologic association, mortality, sequelae, course of the disease, and the use of steroid.

Erythema multiforme--response to corticosteroid.

We studied the response to treatment in 25 patients with erythema multiforme minor, 13 of whom were given corticosteroid while 12 were not. Apart from a shorter duration of fever, the steroid-treated group did not respond better than the non-steroid treated group.

Bullous diseases: a 7-year survey of experience with 77 patients.

A prospective study of 77 consecutive patients with bullous diseases was done to study the pattern and natural history. Pemphigus was the commonest with 45 patients (59%) followed by pemphigoid with 21 patients (27%). Pemphigoid was more common in Indians than in other ethnic groups and its age of onset was a decade later than pemphigus. Unusual immunofluorescent findings in both diseases are discussed. Six of the 7 patients with dermatitis herpetiformis had linear IgA in the dermo-epidermal junction and the classical papillary IgA deposits were absent. Ultrastructural findings of pemphigoid and dermatitis herpetiformis confirmed earlier reports. Chronic bullous dermatoses of childhood was seen in 4 patients, all of whom had total remission within one year of onset disease.

Lupus nephritis and lupus band test.

Twenty-seven patients with histologically confirmed lupus nephritis were studied to identify the incidence of lupus band and its significance to histological patterns of nephritis and complement levels. It was found that the kidney involvement is 2.5 times more frequent in lupus band positive patients. The association of a positive lupus and low C3 level signifies the presence of diffuse proliferative glomerulonephritis rather than membranous glomerulonephritis. The results, together with earlier reports, are discussed.