ADULT SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS – A CASE SERIES

Hemophagocytic lymphohistiocytosis is a hyper-inammatory condition that is either Familial (Primary) or Secondary to autoimmune diseases , infection, malignancy or other triggers.It is a cytokine storm syndrome where there inefcient antigen removal that leads to sustained cytokine release.It is a rare phenomenon occuring in adults that has got a specic trigger which is less documented and have a good response to steroids where as Familial form is a childhood disease due to genetic defects, both of which are life threatening and may need Allogenic bone marrow transplant. Macrophage activation syndrome is also a subtype of this entity that occurs in the treatment phase of SLE and Still's disease.We describe here 8 cases of secondary HLH, their primary triggers and treatment response.

Intervertebral disc decellularisation: progress and challenges

Intervertebral disc (IVD) degeneration and the consequent low-back pain (LBP) affect over 80 % of people in western societies, constituting a tremendous socio-economic burden worldwide and largely impairing patients’ life quality. Extracellular matrix (ECM)-based scaffolds, derived from decellularised tissues, are being increasingly explored in regenerative medicine for tissue repair. Decellularisation plays an essential role for host cells and antigen removal, while maintaining native microenvironmental signals, including ECM structure, composition and mechanical properties, which are essential for driving tissue regeneration. With the lack of clinical solutions for IVD repair/regeneration, implantation of decellularised IVD tissues has been explored to halt and/or revert the degenerative cascade and the associated LBP symptoms. Over the last few years, several researchers have focused on the optimisation of IVD decellularisation methods, combining physical, chemical and enzymatic treatments, in order to successfully develop a cell-free matrix. Recellularisation of IVD-based scaffolds with different cell types has been attempted and numerous methods have been explored to address proper IVD regeneration. Herein, the advances in IVD decellularisation methods, sterilisation procedures, repopulation and biocompatibility tests are reviewed. Additionally, the importance of the donor profile for therapeutic success is also addressed. Finally, the perspectives and major hurdles for clinical use of the decellularised ECM-based biomaterials for IVD are discussed. The studies reviewed support the notion that tissue-engineering-based strategies resorting to decellularised IVD may represent a major advancement in the treatment of disc degeneration and consequent LBP.

Hypersensitivity Pneumonitis: Diagnostic and Therapeutic Challenges

Hypersensitivity pneumonitis (HP) is one of the most common interstitial lung diseases (ILD), that presents unique challenges for a confident diagnosis and limited therapeutic options. The disease is triggered by exposure to a wide variety of inciting antigens in susceptible individuals which results in T-cell hyperactivation and bronchioloalveolar inflammation. However, the genetic risk and the pathogenic mechanisms remain incompletely elucidated. Revised diagnostic criteria have recently been proposed, recommending to classify the disease in fibrotic and non-fibrotic HP which has strong therapeutic and outcome consequences. Confident diagnosis depends on the presence of clinical features of ILD, identification of the antigen(s), typical images on high-resolution computed tomography (HRCT), characteristic histopathological features, and lymphocytosis in the bronchoalveolar lavage. However, identifying the source of antigen is usually challenging, and HRCT and histopathology are often heterogeneous and not typical, supporting the notion that diagnosis should include a multidisciplinary assessment. Antigen removal and treating the inflammatory process is crucial in the progression of the disease since chronic persistent inflammation seems to be one of the mechanisms leading to lung fibrotic remodeling. Fibrotic HP has a few therapeutic options but evidence of efficacy is still scanty. Deciphering the molecular pathobiology of HP will contribute to open new therapeutic avenues and will provide vital insights in the search for novel diagnostic and prognostic biomarkers.

Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Analysis of antigen-specific CD8+ T cells before and after antigen removal in human hepatitis C virus (HCV) infection confirmed pervasive phenotypic, functional, and transcriptional differences between exhausted and memory CD8+ T cells. After viral cure, we observed broad phenotypic and transcriptional changes in clonally stable exhausted T-cell populations suggesting differentiation towards a memory-like profile. However, functionally, the cells showed little improvement and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for shorter periods of time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved acute HCV infection. Thus, duration of T cell stimulation impacts the ability to recover from exhaustion, as antigen removal after long-term T cell exhaustion is insufficient for the development of key T cell memory characteristics.

Abstract 275: In Vitro Inflammatory Assays for Decellularized Xenogeneic Heart Valves

Intro: There is great interest in a decellularized xenogeneic heart valve for valve replacement due to the shortage of human tissue available for implant. However, decellularized xenografts have a poor clinical history due to incomplete antigen removal. The inflammatory potential of decellularized heart valves can be evaluated in vitro using assays that measure antigen presence and cytokine production by cultured human macrophages. This study tests the inflammatory potential of porcine aortic valves before and after decellularization. Methods: Decellularization was confirmed by histology and DNA quantification. Enzyme linked immunosorbent assays (ELISAs) tested for inflammatory potential using pooled human serum as a primary antibody. Additional tissue samples were cultured with THP-1 derived macrophages and the production of monocyte chemoattractant protein-1 (MCP-1) was measured. Results: Decellularization resulted in 99% removal of DNA. The decellularized valve conduit was found to be 2.49% as inflammatory as native tissue (Figure 1). Human macrophages cultured with native tissue produced approximately 10-fold more MCP-1 compared to decellularized tissue. Impact: The in vitro assays described quantify a reduced inflammatory response for decellularized heart valves. Future use of these assays can be used to further decrease the inflammatory potential, increasing the safety of decellularized xenogeneic heart valves.