The natural killer cell activating receptor, NKG2D, is critical to antibody-dependent chronic rejection in heart transplantation.

Chronic rejection is among the most pressing clinical challenges in solid organ transplantation. Interestingly, in a mouse model of heterotopic heart transplantation, antibody-dependent, natural killer (NK) cell-mediated chronic cardiac allograft vasculopathy occurs in some donor-recipient strain combinations, but not others. In this study, we sought to identify the mechanism underlying this unexplained phenomenon. Cardiac allografts from major histocompatibility complex (MHC) mismatched donors were transplanted into immune-deficient C57Bl/6.rag-/- recipients, followed by administration of a monoclonal antibody against the donor MHC class I antigen. We found marked allograft vasculopathy in hearts from C3H donors, but near-complete protection of BALB/c allografts from injury. We found no difference in recipient NK cell phenotype or intrinsic responsiveness to activating signals between recipients of C3H versus BALB/c allografts. However, cardiac endothelial cells from C3H allografts showed an approximately twofold higher expression of Rae-1, an activating ligand of the NK cell receptor natural killer group 2D (NKG2D). Importantly, the administration of a neutralizing antibody against NKG2D abrogated the development of allograft vasculopathy in recipients of C3H allografts, even in the presence of donor-specific antibodies. Therefore, the activating NK cell receptor NKG2D is necessary in this model of chronic cardiac allograft vasculopathy, and strain-dependent expression of NK activating ligands correlates with the development of this disease.

Circulating fibrocytes traffic to the lung in murine acute lung injury and predict outcomes in human acute respiratory distress syndrome: a pilot study.

BACKGROUND: Fibrosis is an integral component of the pathogenesis of acute lung injury and is associated with poor outcomes in patients with acute respiratory distress syndrome (ARDS). Fibrocytes are bone marrow-derived cells that traffic to injured tissues and contribute to fibrosis; hence their concentration in the peripheral blood has the potential to serve as a biomarker of lung fibrogenesis. We therefore sought to test the hypothesis that the concentration and phenotype of circulating fibrocytes in patients with ARDS predicts clinical outcomes. METHODS: For the animal studies, C57Bl/6 mice were infected with experimental Klebsiella pneumoniae in a model of acute lung injury; one-way ANOVA was used to compare multiple groups and two-way ANOVA was used to compare two groups over time. For the human study, 42 subjects with ARDS and 12 subjects with pneumonia (without ARDS) were compared to healthy controls. Chi-squared or Fisher's exact test were used to compare binary outcomes. Survival data was expressed using a Kaplan-Meier curve and compared by log-rank test. Univariable and multivariable logistic regression were used to predict death. RESULTS: In mice with acute lung injury caused by Klebsiella pneumonia, there was a time-dependent increase in lung soluble collagen that correlated with sequential expansion of fibrocytes in the bone marrow, blood, and then lung compartments. Correspondingly, when compared via cross-sectional analysis, the initial concentration of blood fibrocytes was elevated in human subjects with ARDS or pneumonia as compared to healthy controls. In addition, fibrocytes from subjects with ARDS displayed an activated phenotype and on serial measurements, exhibited intermittent episodes of markedly elevated concentration over a median of 1 week. A peak concentration of circulating fibrocytes above a threshold of > 4.8 × 106 cells/mL cells correlated with mortality that was independent of age, ratio of arterial oxygen concentration to the fraction of inspired oxygen, and vasopressor requirement. CONCLUSIONS: Circulating fibrocytes increase in a murine model of acute lung injury and elevation in the number of these cells above a certain threshold is correlated with mortality in human ARDS. Therefore, these cells may provide a useful and easily measured biomarker to predict outcomes in these patients.

Linking innate immunity and chronic antibody-mediated allograft rejection.

PURPOSE OF REVIEW: To summarize recent findings linking donor-specific antibodies with innate immunity resulting in chronic allograft rejection. RECENT FINDINGS: Studies in recent years highlight the significance of donor-specific antibodies (DSA) in both acute and chronic allograft rejection. Since chronic rejection is the leading cause of graft failure, this review centers on the contribution of three areas of innate immunity of particular recent focus: complement, NK cells, and macrophages. Recent advances indicate the diverse roles that complement components play both in directly initiating allograft injury and indirectly by contributing to enhanced alloreactivity. NK cells also have emerged as an additional innate response that directly links DSA with chronic graft injury. Finally, recent studies identify alternatively activated macrophages as an additional arm of innate immunity contributing to chronic allograft rejection. SUMMARY: Chronic allograft rejection involves a significant contribution of DSA and differing pathways of the innate immune system. However, key issues remain unresolved. First, it is not always clear which of these varied sources of innate immunity contributing to chronic rejection may be antibody dependent. Moreover, it is not yet clear if these innate pathways represent independent routes that contribute to chronic rejection or rather act in concert to mediate allograft injury.

Anti-LFA-1 induces CD8 T-cell dependent allograft tolerance and augments suppressor phenotype CD8 cells.

The induction of tolerance to transplanted organs is a major objective in transplantation immunology research. Lymphocyte function-associated antigen-1 (LFA-1) interactions have been identified as a key component of the T-cell activation process that may be interrupted to lead to allograft tolerance. In mice, αLFA-1 mAb is a potent monotherapy that leads to the induction of donor-specific transferable tolerance. By interrogating important adaptive and innate immunity pathways, we demonstrate that the induction of tolerance relies on CD8+T-cells. We further demonstrate that αLFA-1 induced tolerance is associated with CD8+CD28-T-cells with a suppressor phenotype, and that while CD8 cells are present, the effector T-cell response is abrogated. A recent publication has shown that CD8+CD28- cells are not diminished by cyclosporine or rapamycin, therefore CD8+CD28- cells represent a clinically relevant population. To our knowledge, this is the first time that a mechanism for αLFA-1 induced tolerance has been described.

Direct and indirect allograft recognition: pathways dictating graft rejection mechanisms.

PURPOSE OF REVIEW: The T cell-dependent recognition of allogeneic tissues and organs is complicated by the fact that both donor and host antigen-presenting cells can present donor antigens to host T cells. As such, these pathways result in T cells that can be restricted to either donor ('direct') or host ('indirect') major histocompatibility complex (MHC). These pathways are well recognized, but how these distinct patterns actually dictate allograft recognition is less clear. Thus, the purpose of the review is to summarize results from preclinical animal models in an attempt to clarify the distinct forms of allograft rejection dictated by these recognition pathways. RECENT FINDINGS: CD4 and CD8 donor MHC-restricted T cells are sufficient to reject allografts by a T-cell receptor-mediated direct ('cognate') interaction using a defined array of effector molecules. Conversely, 'noncognate' host MHC-restricted CD4 T cells must interact with intermediate host-type antigen-presenting cells and so greatly amplify the response by triggering antibody and inflammatory responses. SUMMARY: Importantly, 'cognate' CD4 and CD8 T cells have strikingly similar requirements for rejection, suggesting that this effector mechanism is dictated by the nature of allograft recognition rather than by T-cell subset. Conversely, 'noncognate' allograft recognition drives an increasingly appreciated role for inciting innate immunity in mediating allograft injury.

Outcomes following lung transplantation for American Indians/Alaska Natives in the United States.

Limited data is available for American Indians/Alaska Natives (AI/AN) undergoing lung transplant. The goal of our study was to assess outcomes for AI/AN lung transplant recipients (LTR). A retrospective review of data from the Organ Procurement and Transplant Network was performed comparing AI/AN (n = 88) and Caucasian (n = 22,767) LTRs between May 4, 2005 and October 31, 2019. AI/AN LTRs had worse functional parameters prior to transplantation but had similar post-transplant outcomes compared to Caucasians LTRs.

An Unexpected Cause of Lung Disease Identified After Lung Transplantation.

CASE PRESENTATION: A 54-year-old woman with systemic lupus erythematosus with associated interstitial lung disease (ILD) presented to the lung transplant clinic for assessment of candidacy for transplantation. She was initially diagnosed with ILD based on clinical and radiographic features (never underwent lung biopsy). In addition, she had associated mixed group I/III pulmonary arterial hypertension. The patient had no family history of pulmonary disease and had never used tobacco and did not have a history of illicit drug use. She was maintained on systemic immunosuppression with hydroxychloroquine, mycophenolate mofetil, and nintedanib for ILD as well as inhaled treprostinil, sildenafil, and macitentan for pulmonary arterial hypertension. Given her progressive symptoms on maximal medical therapy, she was referred for consideration to undergo lung transplantation.

Gender differences in obstructive sleep apnea and treatment implications.

Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness for millions of Americans. It is also a disease associated with an increased likelihood of hypertension, cardiovascular disease, stroke, daytime sleepiness, motor vehicle accidents, and diminished quality of life. A number of population-based studies have shown that OSA is more common in men than in women and this discrepancy is often evident in the clinical setting. There are a number of pathophysiological differences to suggest why men are more prone to the disease than women. Although the exact mechanisms are unknown, differences in obesity, upper airway anatomy, breathing control, hormones, and aging are all thought to play a role. The purpose of this review was to examine the literature on gender differences in OSA and to analyze whether or not these differences in pathogenic mechanisms affect diagnosis or treatment.

Delayed Serotonin Syndrome in the Setting of a Mixed Fluoxetine and Serotonin Antagonist Overdose.

BACKGROUND Serotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone. Treatment is focused on withdrawal of serotonergic agents, which leads to resolution in the majority of cases. In the setting of serotonergic overdose, the onset of serotonin syndrome is usually within 4 to 13 h. Here, we report a case of delayed-onset serotonin syndrome in a patient who ingested a mixture of longer-acting serotonin agonists with serotonin antagonists. CASE REPORT A 24-year-old male was transferred to our medical intensive care unit with hypotension and altered mental status after an overdose of fluoxetine, cyproheptadine, trazodone, olanzapine, risperidone, and bupropion. After approximately 72 h, the patient developed symptoms of fever, lower leg clonus, hyperreflexia, and agitation. He was diagnosed with delayed-onset serotonin syndrome, which responded well to re-administration of cyproheptadine, leading to resolution of symptoms by day 5 of his stay. CONCLUSIONS In this present case, our patient presented with the longest reported delay in the onset of serotonin syndrome after intentional ingestion. This was likely secondary to co-ingestion of long-acting serotonin agonists with protective shorter-acting serotonin antagonists (cyproheptadine and olanzapine). Clinicians should consider delayed-onset serotonin syndrome when patients ingest longer-acting serotonergic agents with serotonin antagonists.

Update on Bronchiolitis Obliterans Syndrome in Lung Transplantation.

Lung transplantation has become an important therapeutic option for patients with end-stage organ dysfunction; however, its clinical usefulness has been limited by the relatively early onset of chronic allograft dysfunction and progressive clinical decline. Obliterative bronchiolitis is characterized histologically by luminal fibrosis of the respiratory bronchioles and clinically by bronchiolitis obliterans syndrome (BOS) which is defined by a measured decline in lung function based on forced expiratory volume (FEV1). Since its earliest description, a number of risk factors have been associated with the development of BOS, including acute rejection, lymphocytic bronchiolitis, primary graft dysfunction, infection, donor specific antibodies, and gastroesophageal reflux disease. However, despite this broadened understanding, the pathogenesis underlying BOS remains poorly understood and once begun, there are relatively few treatment options to battle the progressive deterioration in lung function.

In-hospital cardiac arrest.

In-hospital sudden cardiac arrest and resuscitation is distinct from out-of-hospital sudden cardiac arrest (OOHSCA) and warrants specific attention. Sudden cardiac arrest (SCA) is a manifestation of an underlying process rather than a disease itself. The complex, multiorgan system dysfunction common among the inpatient population can precipitate SCA by both similar and very different mechanisms than OOHSCA. The diagnostic and treatment algorithms of SCA remain largely the same between the inpatient and outpatient arenas. The application of complex diagnostic and therapeutic interventions is permissible, but such tools must not interrupt or delay the important basics of cardiac arrest management in the inpatient setting, including adequate chest compressions and timely defibrillation when appropriate.

The snow-shoveler's ST elevation myocardial infarction.

Heavy snowfall, cold temperatures, and low atmospheric pressure during the winter months have been associated with increased adverse cardiovascular events. However, only a few cases of the "snow shoveler's infarction" have been reported. The investigators describe their experience with 6 patients presenting with ST elevation myocardial infarctions, all within a 24-hour period during an unprecedented snowfall (4 of whom were shoveling snow), and provide a detailed review of previously reported cases of snow shoveler's infarction. Consistent with other reports, most patients reported here had the traditional cardiac risk factors of hypertension, hyperlipidemia, diabetes mellitus, tobacco use, and sedentary lifestyle. Unique to this case series, however, was that the 4 patients who had histories of coronary artery disease and previous coronary artery stenting all presented with subacute stent thromboses documented on coronary angiography performed emergently. Moreover, these patients constituted 25% of all subacute stent thromboses diagnosed in the cardiac catheterization laboratory in the preceding 12 months. In conclusion, these findings suggest that in typically sedentary individuals with cardiac risk factors or histories of coronary artery disease, snow shoveling may trigger ST elevation myocardial infarction and therefore should be avoided. This may be most critical in patients with histories of coronary stent placement, considering that these findings suggest that snow shoveling may precipitate subacute stent thrombosis.