PD-1 and CTLA-4 up regulation on donor T cells is insufficient to prevent GvHD in allo-HSCT recipients.

The expression of checkpoint blockade molecules PD-1, PD-L1, CTLA-4, and foxp3+CD25+CD4+ T cells (Tregs) regulate donor T cell activation and graft-vs-host disease (GvHD) in allogeneic hematopoietic stem cell transplant (allo-HSCT). Detailed kinetics of PD-1-, CTLA-4-, and PD-L1 expression on donor and host cells in GvHD target organs have not been well studied. Using an established GvHD model of allo-HSCT (B6 → CB6F1), we noted transient increases of PD-1- and CTLA-4-expressing donor CD4+ and CD8+ T cells on day 10 post transplant in spleens of allo-HSCT recipients compared with syngeneic HSCT (syn-HSCT) recipients. In contrast, expression of PD-1- and CTLA-4 on donor T cells was persistently increased in bone marrow (BM) of allo-HSCT recipients compared with syn-HSCT recipients. Similar differential patterns of donor T cell immune response were observed in a minor histocompatibility (miHA) mismatched transplant model of GvHD. Despite higher PD-1 and CTLA-4 expression in BM, numbers of foxp3+ T cells and Tregs were much lower in allo-HSCT recipients compared with syn-HSCT recipients. PD-L1-expressing host cells were markedly decreased concomitant with elimination of residual host hematopoietic elements in spleens of allo-HSCT recipients. Allo-HSCT recipients lacking PD-L1 rapidly developed increased serum inflammatory cytokines and lethal acute GvHD compared with wild-type (WT) B6 allo-HSCT recipients. These data suggest that increased expression of checkpoint blockade molecules PD-1 and CTLA-4 on donor T cells is not sufficient to prevent GvHD, and that cooperation between checkpoint blockade signaling by host cells and donor Tregs is necessary to limit GvHD in allo-HSCT recipients.

Autopsy demonstration of intramyocardial polymer gel emboli associated with a giant-cell reaction following cardiac catheterization: a case report.

BACKGROUND: Foreign body type granulomatous vasculitis has been reported in blood vessels of the brain, lungs, and skin of the foot following intravascular instrumentation with devices coated with hydrophilic polymer gel. We report a case of intramyocardial polymer gel emboli associated with granulomatous vasculitis following cardiac catheterization. METHOD: Autopsy observations in a 77-year-old woman are presented. The patient experienced an acute myocardial infarction requiring catheterization and coronary stenting. The patient returned with a pseudoaneurysm at the site of catheterization and shortly after suffered a fatal arrhythmia. RESULTS: Microscopically, multiple small vessels within the myocardium were noted to contain a basophilic, amorphous, focally lamellated, focally granular material. A granulomatous inflammatory response was noted in the vessels containing the foreign material. CONCLUSIONS: Our case is the first to our knowledge to document intramyocardial vessel gel emboli following a cardiac catheterization with stenting. Although the microscopic finding of emboli within vessels does not seem to be the immediate cause of death in our case, it is highly possible that it contributed to the patient's demise.

Postmortem demonstration of the source of pulmonary thromboembolism: the importance of the autopsy.

Periprostatic or paravaginal venous thromboses are rarely considered clinically as sites of clot origin in patients with pulmonary thromboembolism. The majority of emboli have been demonstrated to originate in the veins of the legs. This report raises awareness of pelvic vein thrombosis as a potential source of pulmonary embolism that is rarely considered or detected clinically, and which usually requires postmortem examination for recognition. It also reviews the possible routes emboli may take to reach the lungs.