Molecular Assessment of Microcirculation Injury in Formalin-Fixed Human Cardiac Allograft Biopsies With Antibody-Mediated Rejection.

Precise diagnosis of antibody-mediated rejection (AMR) in cardiac allograft endomyocardial biopsies (EMBs) remains challenging. This study assessed molecular diagnostics in human EMBs with AMR. A set of 34 endothelial, natural killer cell and inflammatory genes was quantified in 106 formalin-fixed, paraffin-embedded EMBs classified according to 2013 International Society for Heart and Lung Transplantation (ISHLT) criteria. The gene set expression was compared between ISHLT diagnoses and correlated with donor-specific antibody (DSA), endothelial injury by electron microscopy (EM) and prognosis. Findings were validated in an independent set of 57 EMBs. In the training set (n = 106), AMR cases (n = 70) showed higher gene set expression than acute cellular rejection (ACR; n = 21, p < 0.001) and controls (n = 15, p < 0.0001). Anti-HLA DSA positivity was associated with higher gene set expression (p = 0.01). Endothelial injury by electron microscopy strongly correlated with gene set expression, specifically in AMR cases (r = 0.62, p = 0.002). Receiver operating characteristic curve analysis for diagnosing AMR showed greater accuracy with gene set expression (area under the curve [AUC] = 79.88) than with DSA (AUC = 70.47) and C4d (AUC = 70.71). In AMR patients (n = 17) with sequential biopsies, increasing gene set expression was associated with inferior prognosis (p = 0.034). These findings were confirmed in the validation set. In conclusion, biopsy-based molecular assessment of antibody-mediated microcirculation injury has the potential to improve diagnosis of AMR in human cardiac transplants.

Vitamin D in renal transplantation - from biological mechanisms to clinical benefits.

Recent developments in our understanding of vitamin D show that it plays a significant role in immunological health, uniquely occupying both an anti-microbial and immunoregulatory niche. Vitamin D deficiency is widespread amongst renal transplant recipients (RTRs), thus providing one patho-mechanism that may influence the achievement of a successful degree of immunosuppression. It may also influence the development of the infectious, cardiovascular and neoplastic complications seen in RTRs. This review examines the biological roles of vitamin D in the immune system of relevance to renal transplantation (RTx) and evaluates whether vitamin D repletion may be relevant in determining immunologically-related clinical outcomes in RTRs, (including graft survival, cardiovascular disease and cancer). While there are plausible biological and epidemiological reasons to undertake vitamin D repletion in RTRs, there are few randomized-controlled trials in this area. Based on the available literature, we cannot at present categorically make the case for routine measurement and repletion of vitamin D in clinical practice but we do suggest that this is an area in urgent need of further randomized controlled level evidence.

Helicobacter pylori induces in-vivo expansion of human regulatory T cells through stimulating interleukin-1ß production by dendritic cells.

Helicobacter pylori is one of the most common infections in the world. Despite inciting inflammation, immunological clearance of the pathogen is often incomplete. CD4(+) CD25(hi) forkhead box protein 3 (FoxP3(+)) regulatory T cells (T(regs)) are potent suppressors of different types of immune responses and have been implicated in limiting inflammatory responses to H. pylori. Investigating the influence of H. pylori on T(reg) function and proliferation, we found that H. pylori-stimulated dendritic cells (DCs) induced proliferation in T(regs) and impaired their suppressive capability. This effect was mediated by interleukin (IL)-1ß produced by H. pylori-stimulated DCs. These data correlated with in-vivo observations in which H. pylori(+) gastric mucosa contained more T(regs) in active cell division than uninfected stomachs. Inciting local proliferation of T(regs) and inhibiting their suppressive function may represent a mechanism for the chronic gastritis and carcinogenesis attributable to H. pylori.

Successful retransplantation using rapamycin in a patient with previous calcineurin inhibitor-induced posterior leukoencephalopathy syndrome.

Posterior Leukoencephalopathy Syndrome (PLES) is a rare but serious neurological condition with many aetiologies. In the era of organ transplantation there have been sporadic reports of calcineurin-inhibitor associated PLES. We describe a case, with subsequent uneventful retransplantation using sirolimus.